Biochem Exam 2

Front 1

configuration of all natural occurring sugars

Back 1

D configuration

Front 2

which C is used to determine D or L

Back 2

penultimate (next to last C), on the right is D, on the left is L

Front 3

equation for total # of isomers of carbohydrates

Back 3

total # of isomers = 2^n (where n = # of chiral carbons)

Front 4

where is the C=O for aldoses and ketoses

Back 4

aldoses: on the top carbon
ketoses: on the number 2 carbon (second from top)

Front 5

aldose structures we need to know

Back 5

glceraldehyde = C3, structure (OH group on chiral carbons) is right
erythrose = C4, structure is right, right (from closes to C=O to furthest, top to bottom)
ribose = C5, structure is right, right, right
glucose = C6, structure is right, left, right, right
mannose = C6, structures is left, left, right, right
galactose = C6, structure is right, left, left, right

Front 6

ketose structures we need to know

Back 6

dihydroxyacetone = C3, (C = O) to the right
erythulose = C4, structures is right (from closes to C=O to furthest, top to bottom)
ribulose = C5, structure is right, right
fructose = C6, structure is left, right, right (looks like glucose)

Front 7

isomers

Back 7

have similar but not identical atomic arrangements

Front 8

steroisomers

Back 8

isomers that have differing arrangements around a chiral C, include enantiomers, epimers, diasteromers and anomers

Front 9

enantiomers

Back 9

are non-superimposable mirror images, have identical chemical and physical properties (melting point, solubility, reactivity) but different biological activities, they rotate plane-polarized light (d to the right and l to the left)

Front 10

racemic mixtures

Back 10

1:1 mixtures of D and L, are not optically active

Front 11

epimers

Back 11

have more than one chiral C but only one differs in arrangement, not enantiomers

Front 12

diastereomers

Back 12

stereoisomers that are not enantiomers or epimers

Front 13

fisher projection

Back 13

1. right and left are towards us, up/down is away
2. want 1 (most oxidized) up
3. can switch neighbors, but then have to switch configuration
4. D is clockwise, L is counterclockwise

Front 14

alpha vs. beta configuration in ring structures

Back 14

alpha the OH is on the right, beta the OH is on the left

Front 15

distribution of alpha vs. beta of ring structures in solutions

Back 15

2/3 beta, 1/3 alpha, 1% open chain form

Front 16

anomers

Back 16

occur when a planar carbon undergoes a reaction to become a chiral carbon (the changed carbon is the anomeric carbon)

Front 17

can enzymes differentiate D vs. L or alpha vs. beta?

Back 17

yes can differentiate both

Front 18

in ring form how can one determine D vs. L config

Back 18

look at #5 C, if #6 is up then D, if down then L

Front 19

derivatives of monosaccharides

Back 19

alcohols, acids, esters, amino sugars, acetals, nucleoside DiPO4

Front 20

alcohol derivatives of monosaccharides

Back 20

carb is reduced
glucose -> glucitol
mannose -> mannitol (plants)
galactose -> galactitol (dulcitol)
ribose -> ribitol (component of riboflavin)
inositol (component of phospholipids and IP3)

Front 21

galactosemia

Back 21

can cause cataracts, a result from having too much glucose or galactose in the body (which is a reducing medium) and reduce these two

Front 22

acid derivatives of monosaccharides

Back 22

carb is oxidized (either at C1 or C6)
-glucuronic acid: oxidation on C6, used in detox, phenolics, conjugation with steroids, bilirubin, component of connective tissue, hyaluronic acid, and chondroitin SO4
-gluconic acid: oxidation on C1, used in conversion of glucose to ribose

Front 23

ester derivatives of monosaccharides

Back 23

alcohol (supplied by the carb) + acid (PO4) = ester + water
form phospho-esters, sulfoesters
ex: chondroitin SO4, keratin SO4, heparin

Front 24

amino sugar derivatives of monosaccharides

Back 24

amino substitution for the hydroxyl (abundant on Carbs), normally on C2, can form NAG, NAM, NANA (Tay-Sachs disease), can act as antigens, antibodies, hormones, bacterial cell wall, connective tissue, glycoproteins

Front 25

glycosidic bonds

Back 25

a special bond between the anomeric OH of one sugar and an OH of another, cannot mutorotate, may be linear or branched, may have mixed carbohydrates, may have mixed types of bonds, may have many saccharide units

Front 26

acetal derivateives of monosaccharides

Back 26

formed from glycosidic bonds (C-O-C-O-C), forms disaccharides, oligosaccharides, polysaccharides

Front 27

types of glycosidic bonds

Back 27

alpha 1, 4
beta 1, 4
alpha 1, 3
alpha 1, 6
alpha vs. beta determined by the configuration of C1 (the anomeric C)

Front 28

nucleoside DiPO4s derivatives of monosaccharides

Back 28

carbohydrates combine with UTP or GTP via two phosphates, results in an activated sugar

Front 29

features of disaccharides

Back 29

2 sugars joined by a glycosidic bond, may be the same (glu + glu -> maltose, homodissacharides) or different (glu + gal -> lactose, heterodisaccharides), can be any type of glycosidic bond

Front 30

reducing vs. non-reducing end

Back 30

reducing end-a hemiacetal that can open (mutarotate), CHO can reduce Fe3+ to Fe2+ and itself becomes oxidezed
non-reducing end-this end can’t open

Front 31

maltose

Back 31

starch digests into maltose, a glu-alpha, 1-4 glu

Front 32

isomaltose

Back 32

glu-alpha, 1-6 glu

Front 33

cellobiose

Back 33

plant cell wall are composed of repeating units of cellobiose, humans can’t break these bonds, composed of glu-beta, 1-4 glu

Front 34

chitin

Back 34

exoskeleton of insects and crustacean are composed of repeating units of chitin, NAG-beta, 1-4 NAG

Front 35

lactose

Back 35

mammalian milk is the only source of lactose, GAL beta, 1-4 GLU

Front 36

sucrose

Back 36

common table sugar from beets and cane is sucrose, GLU alpha 1-2 FRU, non-reducing sugar, both ends can’t open

Front 37

plant starches

Back 37

composed of amylose (25-30%) and amylopectin (70-75%)
amylose-linear composed of Glu alpha 1-4, has a variable length (few to 300 residues) and tightly coild (6 residues/turn)
amylopectin-branched, contains GLU alpha 1-6 bonds, 15-25 residues between the branches, several non-reducing ends and one reducing end

Front 38

animal starch

Back 38

the only animal starch is glycogen, similar to amylopectin but is more frequently branched and thus tighter and more compact (8-12 residues between branches)

Front 39

cellulose

Back 39

polysaccharide of cellobiose, the most abundant biomolecule, can’t be digested by mammals (can’t digest beta 1-4 except the dimer form as found in lactose)

Front 40

glycosaminoglycans

Back 40

repeating units of sugar acid-sugar amine with alternating bonds

Front 41

MDR for carbohydrates

Back 41

100 gm/day to avoid being ketotic (make fatty acids from fat), ~400 kCal/day which is 20% of 2000 kCal diet, normal carb intake is about 200 gm/day

Front 42

forms of ingested carbohydrates

Back 42

monosaccharides, disaccharides, polysaccharides (starches)

Front 43

salivary amylase

Back 43

in mouth, breaks down starch (specifically amylose and amylopectin) 2 at a time making maltose (makes dimers, but can also make trimers maltotriose)

Front 44

acid hydrolysis in the stomach

Back 44

some non-specific digestion of carbohydrates in the stomach

Front 45

pepsin digestion in the stomach

Back 45

used to breakdown proteins, not carbs, but breakdown of proteins may release some carbohydrates for use (not really carbohydrate breakdown)

Front 46

watery phase of digestion

Back 46

secretin is stimulated by the low pH of substance that enters the small intestine, tells the downstream pancreas to release bicarbonate and H2O to neutralize the acidity of the chyme

Front 47

exocrine response of digestion

Back 47

different type of cell (different from the cell that detects the low pH and releases secretin) releases pacreozymin (PZ) and cholecystokinin (CCK) (which form from a single polypeptide)

Front 48

pancreozymin (PZ)

Back 48

tells the pancreas to release enzymes such as proteases, carbohydrases, nucleases, lipases and phospholipases (released as zymogens, activated in the gut)

Front 49

cholecsytokinin

Back 49

tells the gallbladder to release bile which helps emulsify fat

Front 50

pancreatic amylase

Back 50

carbohydrase, breaks down starch into dimers and trimers (maltose, isomaltose, maltotriose), cleaves from the non-reducing end until it reaches a branch point where it is unable to breakdown branches, forms limit dextrins

Front 51

limit dextrins

Back 51

are branched chains of carbohydrates

Front 52

sucrase

Back 52

release by mucosal cells in the small intestine to the lumen, used to breakdown sucrose into glucose and fructose

Front 53

lactase

Back 53

released by mucosal cells in the small intestine to the lumen, used to breakdown lactose into glucose and galactose, may lose ability to make lactase to breakdown lactose (lactose intolerance)

Front 54

glucose-sodium symport

Back 54

used to take monosaccharides in the lumen of the gut into the bloodstream, symport protein is found on mucosal cell membranes and takes in monosaccharides and Na+ (which is in high concentration in the lumen) and brings them both in, monosaccharide then diffuses into the bloodstream and Na+ is transported back into the lumen through an Na+/K+ ATPase (is an antiport, uses about 25% of energy intake)

Front 55

is there a difference in the uptake of the different monosaccharides through the glucose-sodium symport

Back 55

yes there is, if glucose is 100%, galactose is 110% and fructose is 80%, due mostly to there affinity for the symport

Front 56

liver and affinity for glucose

Back 56

has glucokinase which has a high Km for glucose, allows other cells to get glucose first such as brain, heart, muscle, RBC, adipocytes and the liver itself

Front 57

brain and glucose uptake

Back 57

very high affinity for glucose, diffusion, ~20-25% of blood glucose, has regulatory mechanisms for controlling [glucose], low go get food, high stop eating, no insulin receptor to tell the brain to take in more glucose during hyperglycemic times

Front 58

heart and muscle and glucose uptake

Back 58

takes in glucose through diffusion, if [glucose] is high then can store some glucose as glycogen, has TCA cycle and glycolysis

Front 59

insulin and its effect on glucose uptake of cells with insulin receptors (muscle, liver, abipocyte)

Back 59

insulin is released in response to high glucose levels, released by pancreas and tells cells with insulin receptors to take in more glucose and store it as glycogen to lower the blood glucose level, INC glucose uptake by 3-4X

Front 60

RBC and glucose uptake

Back 60

takes in glucose through diffusion, first to get glucose, doesn’t store glucose as glycogen and has no insulin effect, no TCA cycle (no mito)

Front 61

liver and glucose uptake

Back 61

takes in glucose through diffusion, traps glucose in liver first as Glucose-6-P and then as glycogen, goes through glycolysis and TCA cycle

Front 62

insulin and its affect on the liver for lowering blood sugar

Back 62

1. stimulates glycogen synthesis through G-6-P, best way to reduce blood sugar that is high
2. stimulates phosphorylation of glucose into G-6-P
3. stimulates production of pyruvate (stimulates glycolysis)
4. stimulates production of fatty acids through acetyl-CoA

Front 63

adipocytes and glucose uptake

Back 63

need insulin to take in glucose, only takes in glucose and stores it when [glu] is high, insulin also stimulates the production of fatty acids in the adipocyte from acetyl-CoA, insulin inhibits release of fatty acids to blood from triglycerides (don’t want to release fatty acids when glucose levels are high in the blood)

Front 64

names of compounds in glycolysis

Back 64

1. glucose
2. glucose-6-phosphate
3. fructose-6-phosphate
4. fructose 1,6 bisphosphate
5. a. glyceradlhyde 3 phosphate and b. dihydroxyacetylphosphate (DHAP) these two are interchangeable
6. 1,3 bisphosphoglyceric acid (made from adding phosphate and using NAD+ as oxidizing agent, recycled from pyruvate to lactate step if anaerobic, through oxidative phosphorylation if aerobic)
7. 3 phosphoglyceric acid
8. 2 phosphoglyceric acid
9. phosphoenol pyruvate
10. pyruvate (C3H6O3), (tautomerizes from ene-ol form into a keto form)
11. lactate, can form lactate if anaerobic, pyruvate is reduced to lactate and uses NADH as reducing agent, NADH from the production of 1,3 BPA, recycling of NADH and NAD+

Front 65

splitting of fructose-1,6 bisphosphate

Back 65

split in between C 3 and 4, C1-3 form DHAP and C4-6 form Glyceraldehyde-3-P (GAP), Keq favors DHAP formation 20:1, normally consume GAP though to pull it more towards equal concentrations

Front 66

names of enzymes of glycolysis

Back 66

1. glucokinase/hexokinase, needs ATP
2. glucose-6-phosphate isomerase
3. phosphofructokinase (PFK), needs ATP
4. aldolase (the splitting reaction) and triose isomerase (the interchangeable reaction between DHAP and GAP)
-----------------------------------------------------------------------------------------------------
steps 5-10 occur 2X (1 glucose makes 2 DHAP/GAP)
5. glyceraldehyde 3 phosphate dehydrogenase, needs Pi and NAD+
6. phosphoglycerate kinase, produces ATP
7. phosphoglycerate mutase
8. enolase, gives off H2O
9. pyruvate kinase, produces ATP
10. lactate dehydrogenase (makes lactate from pyruvate), needs NADH

Front 67

endergonic vs. exergonic phases of glycolysis

Back 67

initially need two ATP to jumpstart the reaction, then release a total of 4ATP during the exergonic phase to give a net gain of two ATP

Front 68

how much energy in a glucose molecule and what percent of that energy is made in glycolysis (both anaerobic and aerobic)

Back 68

38 ATP in glucose (this is at 40% efficiency), anaerobic glycolysis makes 2, so ~5% of glucose in ATP is made from anaerobic glycolysis, aerobic glycolysis makes 8 ATP, so 20%, leftover 30 made in oxidative phosphorylation

Front 69

methods of recycling NADH in glycolysis

Back 69

1. anaerobic-NADH is consumed by LADH to produce NAD+ which is consumed by glyceraldehyde 3 phosphate to produce NADH which is consumed by LADH…
2. aerobic-NAD+ is regenerated by oxidative phosphorylation when NADH created by glyceraldehyde 3 phosphate is shuttled to mito and used, regenerates NAD+, lactate is not produced at high quantities during aerobic conditions

Front 70

energy in aerobic glycolysis

Back 70

NADH wants to be oxidized to form NAD+ (-15 Kcal/mole), ½ O2 -> H2O (-38 Kcal/mol), net of -53 Kcal/mol *.40 efficiency gives 21.2 Kcal/mol to make 3 ATP, makes a total of 8 ATP

Front 71

advanatage of LDH reaction (why go anaerobic glycolysis)

Back 71

to regenerate NAD+ under anaerobic conditions for G-3-P dehydrogenase reaction, it allows for glycolysis to keep going anaerobically

Front 72

irreversible steps of glycolysis

Back 72

irreversible have very large Keqs, reversible have smaller Keqs
1. at hexokinase: Keq = 1000, never have enough ADP or G6P to make it reversible
2. at phosphofructokinase: same argument as hexokinase
3. at pyruvate kinase: Keq of 100,000

Front 73

how to overcome irreversible steps to make glucose from lactate for G-6-P’ase and F-1,6-bisP’ase

Back 73

not truly the reverse step, more of a bypass step, gluconeogenesis
1. G -> G-6-P vs. G-6-P -> G: G-6-P loses a Pi (not making an ATP) by adding H2O, use G-6-P phosphatase
2. F-6-P -> F 1,6 bisP vs. F 1,6 bisP -> F-6-P: similar to that above, lose a Pi (not making an ATP) by adding H2O, use F-1,6-bisP phosphatase
3. tissues capable of doing this reaction, liver: 80%, kidney: 20%, these tissues have the needed enzymes

Front 74

how to overcome the irreversible PEP -> pyruvate step to make PEP from pyruvate

Back 74

step of glucneogenesis
1. pyruvate + CO2 + ATP -> OAA (oxaloacetic acid)
a. catalyzed by Pyr-carboxylase
2. OAA + GTP -> PEP + CO2 (released)
a. catalyzed by PEP carboxykinase

Front 75

Cori Cycle

Back 75

allows the heart and skeletal muscles to still function in anaerobic conditions (for a bit), TCA is turned off in the muscles when anaerobic, pyruvate is turned into lactate, lactate leaves the muscle enters the bloodstream and enters the liver, the liver turns Pyr -> PEP -> Glu which is shuttled back to the muscle

Front 76

How is the GAP dehydrogenase reaction reversible?

Back 76

need +22 Kcal/mol to create the anhydride bond and create NADH from NAD+, where does that energy come from, from oxidation of aldehyde to acid, is -22 Kcal/mol

Front 77

how can glycolysis be blocked by the heart during acid buildup?

Back 77

when lactate is produced it lowers the pH associated with the heart, a low enough pH inhibits GAP Dehydrogenase, basicly tells the cell to stop making acid

Front 78

what happens if the body is flooded with arsenate?

Back 78

can tie up all ADP without any use

Front 79

what is the best way to regulate glycolysis?

Back 79

at the irreversible steps, these are the regulating steps

Front 80

regulation of glycolysis through HK/GK

Back 80

if shutdown enzyme, then glucose is not trapped in the cell, regulate through different Kms in different tissues (GK=liver 10^-2, HK=rest 10^-5)
1. HK is inhibited by high G-6-P and high ATP, not GK (K4 is negligible) allows for storage when G-6-P is high

Front 81

regulation of glycolysis through PFK

Back 81

the key regulatory step, the rate limiting step
1. inhibition by high [ATP], if get pass the PFK step, then ATP synthesis is going to happen, acts as an allosteric inhibitor that changes the configure of enzyme when ATP high
2. activation by high [AMP], not ADP because always have lots of it, ADP + ADP -> ATP + AMP, high [AMP] signals very low energy charge in cell, energy charge is normally 0.85
3. inhibition by high [citrate], a byproduct of TCA cycle, leaves mito and has an inhbitiory effect on PFK
4. activation by high [F-2,6 bisP], take some F-6-P and turn into F-2,6-bisP (an allosteric modulator of PFK1, catalyzed by PFKII and uses ATP, [F 2,6 bisP] INC when F-6-P INC and stimulates PFK1

Front 82

Energy charge

Back 82

energy charge = ([ATP] + ½ [ADP]) / [AMP] + [ADP] + [ATP]
energy charge = [NADH]/[NAD+]

Front 83

regulation of glycolysis through pyruvate kinase

Back 83

1. inhibition through ATP
2. inhibition through [Ala], interconvertible with pyruvate, if high [Ala] then use to make pyruvate to power glycolysis
3. inhibition through glucagon
4. activation through [ADP]
5. activation through [F 1,6 biP], in a feedforward activation
6. activation through insulin

Front 84

interconnecting pathways of glycolysis

Back 84

can make or break down glycogen, can make and degrade pentoses, can make serine, HbO2, fatty acids (from C2 of TCA, acetyl CoAs), triglycerides (from DHAP and fatty acids)

Front 85

how is mannose used for glycolysis

Back 85

mannose is an epimer of glucose
1. mannose phosphorylated with a hexokinase at C6 to form mannose 6-phosphate and trap it into the cell, uses ATP
2. then use mannose-6-P isomerase to form fructose-6-phosphate

Front 86

how is fructose used for glycolysis

Back 86

fructose is an isomer of glucose, cost is still 2 ATPs
1. use fructokinase to phosphorylate at C1 to give fructose-1-phosphate, use ATP
2. then use fructose-1-aldolase to cleave it into DHAP and glyceraldehyde
3. glyceraldehyde can then be converted to GAP through a glyceraldehyde kinase and ATP

Front 87

fructolysis

Back 87

a metabolic process in sperm cell where fructose is used as a source of energy before glucose (generally fructose is used before glucose), fructose comes in downstream of PFK1 regulatory site and so is used preferentially, if there is no fructose available for the sperm cell then they die, seminal vesicle turns glucose into fructose

Front 88

essential fructosuria

Back 88

disease caused by a defect in fructokinase, cannot trap fructose as fructose-1-kinase for fructose utilization, relatively benign disease, just tell patient to reduce fructose intake, similar to diabetes, symptoms include:
1. fructosemia-high fructose in blood
2. fructosuria-fructose in urine
3. polyuria-too much urea/urinie
4. polydipsia-drink a lot (dehydrated)

Front 89

fructose intolerance

Back 89

defect in fructose-1-phosphate aldolase, fructose trapped in cell is not cleaved and stays trapped in there, ATP is constantly used to keep trapping fructose but it is not used, leads to high ADP and decrease in free phosphates leading to hypohosphatemia (low [phosphate]), can also lead to hypoglycemia because there is a DEC in availability of phosphate for glycogen degradation (phosphorolysis)

Front 90

how is galactose used in glycolysis

Back 90

1. galactose + ATP -> galactose-1-phosphate + ADP
a. catalyzed by galactokinase
2. galactose-1-P + UTP -> UDP-galactose + PPi
a. catalyzed by Gal-1-P UTP pyrophosphorylase
3. UDP-Galactose -> UDP-glucose
a. catalyzed by UDP-galactose-4-epimerase
4. take in another galactose-1-phosphate and join with the UDP-glucose to form glucose-1-phosphate and regenerate UDP galactose
a. catalyzed by uridyl transferase
5. Glucose-1-phosphate -> Glucose-6-phoshpate
a. catalyzed by phosphogluomutase

Front 91

galactosemia

Back 91

high galactose in blood, can be caused by any defect in galactose utilization for glycolysis, but most frequently missing a uridly transferase

Front 92

alternative route for making UDP-glucose from glucose

Back 92

can take Glucose-6-phosphate use phosphoglucomutase and make G-1-P then add a UTP to form UDP-glucose for glycogen synthesis in well fed state

Front 93

glycogen synthesis

Back 93

take UDP-glucose (made form glucose or galactose) and + to a pre-existing glycogen (glycogen is never degraded completely, just need enough so it acts like a primer), catalyzed by glycogen synthase, break off UDP from UDP-glucose and add to C4 end of non-reducing end, recycle UDP into UTP through degradation of ATP into ADP

Front 94

importance of glycogen synthesis

Back 94

save us from typing up phosphates and act as an energy store when one is well fed

Front 95

4:6 transferase

Back 95

the branching enzyme of glycogen synthesis, when adding more and more glucose, this enzyme notices a minimum of 11 residues on a branch, removes 8 (to 12?), breaks the alpha 1,4 bond and makes an alpha 1,6 bond adding the 8 (to 12) residues, this increases the number of free ends formed for additional glucose addition

Front 96

glycogen degradation

Back 96

occurs at the non-reducing end, remove glucose one at a time, use glycogen phosphorylase to add a Pi to glycogen and make glucose-1-phosphate and (glycogen)n-1, can then use phosphoglucmutase to make G-6-P

Front 97

4:4 transferase

Back 97

the debranching enzyme, glycogen phosphorylase breaks down glycogen until 4 residues are left on the top and bottom side of the alpha 1,6, 4:4 transferase takes the top 3 and adds it to the reducing end of the bottom 4, 4:4 transferase then cleaves off the lone 4th glucose on the top side as free glucose, this leaves a long chain for glycogen phosphorylase to work on

Front 98

under the well fed condition, insulin causes glycogen production in which organs

Back 98

liver and muscles

Front 99

liver and glycogen breakdown during fasting stages

Back 99

breaks down glycogen into glucose-6-phosphate then uses glucose-6-phosphate phosphatase to form free glucose which diffuses to the outside of the cell, glycogen breakdown to glycogen stimulated by both glucagon and epinephrine

Front 100

muscle and glycogen breakdown during fasting stages

Back 100

breaks down glycogen into glucose-6-phosphate, but does not have glucose-6-phosphate phosphatase, so is not activated when hypoglycemic, activated during anaerobic or high stress signals, therefore glycogen breakdown occurs through epinephrine and muscle makes ATP to move away from the stress (which releases epinephrine from the adrenal medulla)

Front 101

which pancreatic cells secrete insulin and glucagon

Back 101

alpha cells secrete glucagon while beta cells secrete insulin

Front 102

epinephrines effect on insulin

Back 102

epinephrine can block insulin effect, can cause a stress induced hyperglycemia

Front 103

how do glucagon and epinephrine outside the cell have an effect on the inside of the cell?

Back 103

they are 1st messengers, bind to receptors on the membrane, cause a change in confo of receptor, interacts with a G protein (trimer with alpha, beta and gamma subunits, has GDP bound on alpha subunit), alpha subunit separates from the beta and gamma subunits and replaces GDP for GTP, this activates adenyl cyclase which changes ATP into 3’,5’ cyclic AMP (which is a second messenger)

Front 104

how does cAMP activate glycogen breakdown

Back 104

cAMP is made through a cascade, cAMP then activates protein kinase by binding to the regulatory unit and freeing the catalytic unit, the catalytic unit has two functions important to glycogen breakdown:
1. it phosphorylates glycogen phosphorylase kinase with ATP on a serine activating it, GP kinase then phosphorylates glycogen phosphorylase with an ATP activating it, glycogen phosphorylase then breaks down glycogen into glucose which can become glucose-1-phosphate which can then become glucose-6-phosphate and UDP-glucose
2. it can phosphorylate glycogen synthase inactivating it so that glycogen synthesis is stopped

Front 105

advantages to using the cAMP cascade pathway

Back 105

1. rapid-it is in a stepwise fashion with each of the players in the pathway in place for rapid activation
2. amplifies the signal at each step-find that there is ~1000X amplification in turnover at each step and overall causes a 10^9 X amplification

Front 106

inhibition of cAMP (when glucose levels begin to rise too high)

Back 106

1. signal reduction by high blood sugar-occurs when too much glucose is made by glycogen breakdown and blood glucose levels rise high, causes an inhibition of glucagon (which is used as a 1st messenger in cAMP pathway
2. turn off G-protein-the active G protein has an ATP bound to the alpha subunit, alpha subunit has a GTPase activity built in to deactivate the alpha subunit by hydrolyzing GTP into GDP which causes it to bind with the beta and gamma subunit agains
3. degrade cAMP with phosphodiesterase (PDE)-cleaves cAMP into an inactive 5’AMP
4. dephosphorylation of proteins-done with phosphoproteinphosphatase, inactivates glycogen phosphatase and activates glycogen synthase

Front 107

what happens if PDE is inhibited?

Back 107

leads to high [cAMP], this allows for the pathway downstream of cAMP to stay active, methyl xanthines (trimethyl-caffeine and dimethyl-theophyllin (used for asthma)) inhibit PDE by binding to it and blocking it, looks like alanine

Front 108

phosphoproteinphosphatase

Back 108

PPP, normally in an inactive form (PPPi), there is a PPP inhibitor (PPP-I) that inhibits active PPP (PPPa) into PPPi, PPP-I has an inactive form (PPP-I-P), need a kinase to turn PPP-I into PPP-I-P, insulin (under high glucose levels) allows the kinase to be present that turns PPP-I into PPP-I-P, this allows PPPa to be made which dephosphorylates proteins (which inactivates glycogen phosphatase and activates glycogen synthase)

Front 109

insulin receptor

Back 109

has 4 subunits (2 alpha outside and 2 beta inside the cell), transmembrane, characteristics include:
1. receptor acquires activity-occurs when insulin binds, causes a change in the conformation of the beta portions so that it becomes an enzyme
2. tyrosine rich beta subunits-about 3-5 tyrosines are found on the beta tail
3. tyrosin kinase-the kinases use ATP to phosphorylate itself (autophosphorylation)
4. acquires new kinase activity-is a serine kinase, kinase activity occurs after autophosphorylation, now able to phosphorylate other proteins (specifically the kinase that turns PPP-I to PPP-I-P which (inactivates the inhibitor to PPP)

Front 110

how does the insulin receptor work when trying to reduce blood glucose levels

Back 110

1. it stimulates the removal of a phosphate from glycogen synthase, activating it and INC glycogen synthesis
2. it inhibits the phosphorylation of glycogen phosphorylase causing a DEC in glycogen degradation

Front 111

hexose monophosphate shunt (HMPS)/pentose phosphate pathway (PPP)

Back 111

another pathway for glucose-6-phosphate, can make DNA, RNA, fatty acids and store extra energy when the cell no longer needs anymore ATP, is found in the well fed stage and the body wants to enter a growth phase (used as a biosynthetic pathway), can make no more glycogen and is hyperglycemic

Front 112

formation of ribulose-5-phosphate for the HMPS

Back 112

1. glucose-6-phosphate + NADP+ -> lactone + NADPH
a. catalyzed by glucose-6-phosphate dehydrogenase
b. in this reaction the C1 aldehyde is oxidized to an acid to give the necessary energy to form an NADPH
2. lactone actually enters an intermediary ring form, remove from the ring form and keep into the straight form through lactonase (it hydrolyzes the internal ester that forms from the ring formation), this forms 6-phosphogluconic acid
3. 6-phophogluconic acid + NADP+ -> ribulose-5-phosphate + NADPH + CO2
a. catalyzed by 6-phosphogluconic acid dehydrogenase

Front 113

what is the overall reaction of the degradation of one glucose molecule when entering HMPS

Back 113

6 C6 + 12 NADP+ -> 6 C5 + 12 NADPH + 6 CO2

Front 114

how does one regulate the entrance of glucose-6-phosphate into the HMPS?

Back 114

it is controlled by the availability of glucose-6-phosphate and NADP+, the [NADP+] is the rate limiting step of HMPS

Front 115

uses for NADPH

Back 115

used for biosynthetic reactions, it has reducing power
1. reduction of Fe+++ -> Fe++ (which allows for proper hemoglobin function)
2. keep Cys-SH in a reduced state and not as a disulfide bond (either as individual cysteines or in proteins)
3. reduce ribose into deoxyribose for DNA
4. fatty acid biosynthesis, reduces the acetyl CoAs for fatty acid biosynthesis
5. cholesterol synthesis, use acetates and NADPH as reducing power

Front 116

formation of glyceraldehyde-3-phosphate and 2 fructose-6-phosphate from 3 ribulose-5-phosphate

Back 116

all these reactions are very reversible
1. ribulose-5-phosphate -> ribose-5-phosphate
a. catalyzed by isomerase
2. ribulose-5-phosphate -> xylulose-5-phosphate
a. catalyzed by epimerase
3. ribose-5-phosphate + xylulose-5-phosphate -> C10 -> glyceraldehyde-3-phosphate (C3) + sedoheptulose-7-phosphate (C7)
a. C10 -> two products catalyzed by transketolase, requires thiamine pyrophosphate (vitamin B1)
4. glyceraldehyde-3-phosphate + sedoheptulose-7-phosphate -> C10 -> erthrulose-4-phosphate (C4) + fructose-6-phosphate (C6)
a. C10 -> two products catalyzed by transaldolase, removal of aldehyde involved
5. erythrulose-4-phosphate + xylulose-5-P (from the 3rd ribulose-5-phosphate) -> C9 -> glyceraldehyde-3-phosphate + fructose-6-phosphate
a. catalyzed by transketolase

Front 117

stoichiometry of HMPS

Back 117

3 C5 -> 2 C6 + 1 C3
or
6 C5 -> 4 C6 + 2 C3 (these 2 C3, which are GAP, can form 1 GAP and 1 DHAP, which can form ribose 1,6 bisphosphate with aldolase which can form ribose-6-phosphate with ribose 1,6, biphosphate phosphatase to give:
6C5 -> 5 C6

Front 118

why go through the trouble of HMPS if it just makes intermediates of glycolysis

Back 118

take 6 glucose-6-phosphates to form 6 ribose-5-phosphates + 6 CO2 + 12 NADPH, 6C5 -> 5C6, basically to make 12 NADPH from 1 glucose-6-phosphate for reducing power

Front 119

what controls glucose-6-phosphate dehydrogenase

Back 119

amount of enzymes in the reactions and the availability of glucose-6-phosphate and NADP+

Front 120

scenarios where HMPS is used

Back 120

1. need NADPH and Ribose-5-phosphate (say for DNA and RNA synthesis)-would go through first part of HMPS and make ribose-5-phosphate and NADPH, but then take ribose-5-phosphate and make DNA and RNA, all the other cycles would be non-existent
2. need NADPH only-basically use the shunt as detailed above forming fructose-6-phosphate and glyceraldehyde-3-phosphate (these are recycled)
3. need ribose but not NADPH-run the shunt backwards turning GAP and fructose-6-phosphate into ribose
4. need NADPH and C2 units for fatty acid or cholesterol synthesi-run the HMPS as outlined and drive the process down glycolysis
5. ingested and metabolized RNA-take ribose and degrade it down the HMPS

Front 121

glucose-6-phosphate dehydrogenase deficiency

Back 121

leads to a reduction in NADPH (reducing power) and ribose synthesis which makes synthesis of fatty acids and cholesterol difficult, found in 10-12% of blacks, what does this lead to:
1. lose about 50% of the ability to make NADPH
2. growth problems (in children)
3. impaired reduction of proteins, especially in RBC membrane proteins, leads to hemolytic anemia
4. Fe++ oxidation in hemoglobin is more difficult, leads to Hb-met (Fe+++) (an oxidized form), leads to hypoxia

Front 122

Wernicke-Koraskov Syndrome

Back 122

is associated with a defective transketolase and low vitamin B1 (as found in alcoholics), many people actually have a defective transketolase (one that does not bind B1 as well as a normal one), but a good diet INC [B1] and pushes the binding of B1 to transketolase forward, bad nutrition and defective transketolase leads to neurological and muscular defects (i.e. walking properly is affected)

Front 123

formation of alpha-glycerol-phosphate

Back 123

1. DHAP + NADH -> alpha-glycerol-phosphate + NAD+
a. catalyzed by DHAP dehydrogenase
2. alpha-glycerol-phosphate -> glycerol
a. catalyzed by glycerol kinase

Front 124

formation of triglycerides

Back 124

take alpha-glycerol-phosphate (which has two OH groups and one O-PO4 attached to three Cs) and place a fatty acid on each one (esterify it) to form a triglyceride, can kinate a glycerol with glycerol kinase to form alpha-glycerol-phosphate

Front 125

adipocytes and alpha-glycerol-phosphate formation

Back 125

glycerol kinase is absent in adipocytes so they cannot take in glycerol and turn it into alpha-glycerol-phosphate, rely solely on glycolysis as a source of DHAP for making triglycerides, need insulin to take in glucose

Front 126

pyruvate conversion to alanine

Back 126

alpha-amino-acid + pyruvate -> alanine + alpha-keto-acid
catalyzed by a transaminase

Front 127

three-phosphoglycerate conversion to serine

Back 127

1. 3-PGA + NAD+ -> 3-phosphopyruvate + NADH
2. 3-phosphopyruvate + alanine -> 3-phosphoserine + pyruvate
3. 3-phosphoserine -> serine + Pi

Front 128

The Bohr Effect

Back 128

a means of switching from anaerobic to aerobic, tells Hb to let go of O2 because it is running anaerobic, hemoglobin bound to O2 (Hb(O2)) can be placed in an acidic environment and can preferentially bind to the excess H+ releasing O2
Hb(O2)4 + H+ -> H+Hb + 4 O2
proton sources:
1. lactic acid -> lactate + H+
2. CO2 + H20 -> H2CO3 -> HCO3- + H+

Front 129

Bisphosphoglyceric acid and anaerobic to aerobic conditions

Back 129

secondary (to the Bohr Effect) means of telling hemoglobin to release O2, RBCs go through glycolysis and produce lactate (35-40 gms/day), during anaerobic conditions, muscle also produces lactate greatly increasing [lactate] in blood, this causes lactate in the RBC to go backwards and it does leading to an accumulation of 1,3 bisphosphoglyceric acid (PGA) and 3-PGA -> 2,3 bis-PGA, which is catalyzed by a transferase, 2,3 bis-PGA begins to accumulate in RBC to tell the hemoglobine to release O2, it wedges itself noncovalently between the 2 beta chains causing the O2 to be released

Front 130

amino acids, pyruvate and its entrance into glycolysis

Back 130

glycine, cystein, serine, thronin and tryptophane can turn into pyruvate and enter glycolysis or gluconeogenesis

Front 131

ethanol synthesis in bacteria/yeast

Back 131

1. pyruvate -> acetaldehyde + CO2
a. catalyzed by pyruvate decarboxylase
2. acetaldehyde + NADH -> ethanol + NAD+
a. in an anaerobic conditions
3. acetaldehyde + NAD+ -> acetic acid + NADH
a. in aerobic conditions

Front 132

ethanol degradation in humans

Back 132

1. ethanol + NAD+ -> acetaldehyde + NADH
a. catalyzed by alcohol dehydrogenase
2. acetaldehyde + NAD+ -> acetic acid + NADH
a. catalyzed by acetaldehyde dehydrogenase
3. acetic acid + CoAsh -> acetyl CoA
1 molecule of ethanol yields 1 acetyl CoA (12 ATP) + 2 NADHs (6 total ATP)

Front 133

alcohol intolerance

Back 133

found in 1/3 of the oriental population, have a diminished amount of acetaldehyde dehydrogenase, [acetaldehyde] thus INC to toxic levels, forms X-linked proteins which causes liver problems, this causes individuals to become extremely sick

Front 134

Anabuse and alcoholism

Back 134

thought to work in a mechanism similar to alcohol intolerance, blocks acetaldehyde dehydrogenase and makes individuals sick when they consume alcohol, one way to treat alcoholism

Front 135

pyruvate and its movement into the mitochondria

Back 135

glycolysis occurs in the cytosol of cells, pyruvate enters the mitochondria for the TCA cycle without restriction

Front 136

pyruvate to acetyl CoA

Back 136

pyruvate + NAD+ + CoASH -> Acetyl CoA (C2) + CO2 + NADH
catalyzed by pyruvate dehdyrogenase

Front 137

pyruvate dehydrogenase (PDH)

Back 137

properties of include
1. large-M.Wt of 3-4 million (about 35-40,000 aa)
2. multiple subunits (E1 = 24, E2 = 24, E3 = 12
3. uses 5 cofactors
a. thiamine pyrophosphate (vitamin B1)
b. lipoic acid (lipoate)
c. panthothenic acid (for CoA)
d. riboflavin (vitamine B2 for FAD)
e. niacin (VitB3 for NAD)
body needs 14 vitamins and 5 are found here

Front 138

shape and mechanism of PDH (oxidative decarboxylation)

Back 138

E1 outside, responsible for decarboxylation, mechanism:
pyruvate + E1 + TPP -> CO2 + E1*C2
E2 form a concentric sphere inside E1, responsible for transacetylation, mechanism:
E1*C2 + E2 -> E2*lipoate*C2
E2*lipoate*C2 + CoASH -> E2*lipoate (with reduced SH) + acetyl CoA
E3 found inside of E2, responsible for dehydrogenation, makes NADH, mechanism:
E3*FADH2 + NAD+ -> E3*FAD + NADH
involves decarboxylation, transacetylation and dehydrogenation, E1 distributes to E2 which distributes to E3

Front 139

structure of CoA

Back 139

adenine-pantoic acid-beta alanine-thioetahnolamine

Front 140

general reactions of TCA (tricarboxylic acid cycle) (Krebs cycle) (citric acid cycle)

Back 140

C2 + C4 -> C6 -> C6 -> C6 -> C5 -> C4 -> C4 -> C4 -> C4 -> C4 (the one that binds to a C2 at the beginning), so a total of 1 C2, 3 C6, 1 C5, and 5 C4

Front 141

compounds of TCA cycle

Back 141

oxaloacetate (C4, OAA) + acetyl CoA (C2) -> citrate (C6) -> aconitate (C6) -> isocitrate (C6) -> alpha ketoglutarate (C5) -> succinyl-CoA (C4) -> succinate (C4) -> fumarate (C4) -> malate (C4) -> oxaloacetate (C4 at beginning)

Front 142

energetics of TCA cycle and total energetics from one glucose

Back 142

from 1 turn of TCA get:
3 NADH -> 9 total ATP
1 GTP -> 1 ATP
1 FADH2 -> 2 total ATP
so get a total of 12 ATP/turn, 2 turns from 1 glucose, so a total of 24 ATP
total energetics (8 from aerobic glycolysis, 6 from PDH, and 24 from TCA = 38 total ATP from a single glucose)

Front 143

reactions of TCA cycle

Back 143

1. acetyl CoA + oxaloacetate -> citrate
a. catalyzed by citrate synthase (the condensing enzyme)
2. citrate -> aconitate + H2O
a. catalyzed by aconitase, treats symmetrical molecule asymmetrically
3. aconitate + H2O -> isocitrate
a. catalyzed by aconitase
4. isocitrate + NAD+ -> alpha-ketoglutarate + CO2 + NADH
a. catalyzed by isocitrate dehydrogenase
5. alpha-ketoglutarate + NAD+ CoASH -> succinyl-CoA + NADH + CO2
a. catalyzed by alpha-ketoglutarate dehydrogenase, analogous to PDH
6. succinyl-CoA + GDP -> succinate + CoASH + GTP
a. catalyzed by succinyl-CoA thiokinase
7. succinate + FAD -> fumarate + FADH2
a. catalyzed by succinate dehydrogenase
8. fumarate + H2O -> malate
a. catalyzed by fumarase
9. malate + NAD+ -> oxaloacetate + NADH
a. catalyzed by malate dehydrogenase

Front 144

pyruvate and metabolism

Back 144

pyruvate is the foal point of metabolism going in various directions, glucose, acetyl CoA, gluconeogenesis, fermentation, lactate, amino acids

Front 145

where are the various enzymes of the TCA cycle found

Back 145

succinate dehydrogenase is found on the inner mito. membrane while all others are found in the matrix

Front 146

purposes of the TCA cycle

Back 146

1. oxidize acetyl CoA to CO2
a. 1CHO + 5CH2OH -> C)2
2. produce high energy rich compounds (NADH, FADH2, GTP)
3. integrate metabolism (carbohydrates and amino acids)
4. synthetic reactions, fatty acids, amino acids

Front 147

citrate synthase mechanism

Back 147

utilizes a Histidine for binding, forms a citroyl-CoA intermediate

Front 148

citrate synthase energetics

Back 148

reaction is driven by the hydrolysis of citroyl CoA derivative, this high energy thioester drives the reaction forward and makes it irreversible, delta G = -8 kcal/mol

Front 149

citrate syntahse control

Back 149

inhibited by high [ATP] or energy charge, ATP can bind to histidine and blocks the CoA to bind and get transferred, INC Km of the reaction and thus needs more acetyl CoA to go forward

Front 150

tracing carbons from glucose through the TCA cycle

Back 150

from glucose, # 3 and 4 are lost before the TCA cycle, C1 and C6 are metabolized the same and C2 and C5 are metabolized the same, there is no loss of C1,2,5,6 during the first turn of TCA cycle, during the second turn all the C2 and C5 are loss during the isocitrate dehydrogenase step, from that point on ½ the remaining C1 and C6 carbons are loss on each subsequent turn, succinate is symmetrical and metabolized symmetrically while citrate is symmetrical but metabolized asymmetrically

Front 151

committed and irreversible steps of TCA cycle

Back 151

committed (& irreversible) step: acetyl CoA + OAA -> citrate (through citrate synthase), (has a delta G of about -9, energy comes mostly from splitting of the thioester)
other irreversible steps: isocitrate -> alpha-ketoglutarate (delta G of about -7) & alpha-ketoglutarate -> succinyl CoA (delta G of about -7)

Front 152

citrate and its other pathways

Back 152

can be release from the mito, into the cytosol and used to make fatty acids and cholesterol or can be used to inhibit glycolysis (PFKI)

Front 153

alpha-ketoglutarate and its other pathways

Back 153

can be used to make glutamic acid

Front 154

succinyl-CoA and its other pathways

Back 154

can be used to make Heme

Front 155

malate and its other pathways

Back 155

can leave the mito and enter the cytosol and act in gluconeogenesis, can turn into OAA in the cytosol, join with pyruvate to form PEP and continue along making glucose, found mostly in the liver

Front 156

energetics of the malate -> OAA reaction

Back 156

delta G of +7, goes forward if there is acetyl-CoA present to drive it forward, organs such as the heart, muscle, and adipocytes release other various C2 molecules to pull it forward, the reaction stops at malate unless there is some C2s present to make it present, otherwise it goes backwards all the way to succinyl-CoA

Front 157

regulation of TCA cycle

Back 157

1. availability of acetyl CoA
2. availability of oxaloacetate-this is the most important of the intermediates in the cycle, it determines the rate of the reaction
3. energy charge-in terms of the availability of NAD+, FAD, GDP
4. allosteric regulation of citrate synthase-includes inhibition of citrate synthase by succinyl-CoA and GTP
5. product inhibition of ICDH and alpha-ketoglutarate by NADH (this acts by blocking the active site directly
6. ADP stimulation of ICDH and alpha-ketoglutarate and inhibition by ATP-these two act allosterically and compete for the same site

Front 158

aconitase and its ability to act asymmetrically on citrate

Back 158

citrate is symmetrical but is acted upon asymmetrically due to aconitase and its 3-point attachment, by having 3 points for attachment it allows the enzyme to properly orient the citrate and always add the C=C in the same spot, succinate on the other hand is symmetrical and is acted upon as such (uses a 2-point attachment scheme)

Front 159

malonate and succinate dehydrogenase

Back 159

malonate inhibits SDH by plugging the active site, was the first competitive inhibitor discovered

Front 160

general reaction for oxidative phosphorylation

Back 160

NADH + H+ + ½ O2 -> NAD+ + H2O + energy
NADH gives 3 ATP, FADH2 gives 2 ATP

Front 161

substrate level phosphorylation

Back 161

a different form of ATP production, ex: PEP + ADP -> ATP

Front 162

cytosolic NADH (how is it utilized during oxidative phosphorylation)

Back 162

NADH intact cannot just enter the mitochondria without some help, must utilize a shuttle to move the reducing power into the mito and regenerate the NAD+ for glyceraldehyde-3 phosphate dehydrogenase

Front 163

aspartate-malate shuttle

Back 163

used to shuttle the reducing power of cytosolic NADH into the mito and to regenerate NAD+ in the cytosol, OAA can become reduced to malate by NADH (this does two things, (1) produces NAD+ and (2) produces malate which can enter the mito and act as a means of transferring the reducing power), malate enters the mito and becomes OAA, OAA can join with glutamate and form aspartic acid and alpha-ketoglutarate (both of which can leave the mito), when in the cytosol, aspartic acid regenerates the above OAA and alpha-ketoglutarate becomes glutamate which goes back inside the mito., important in the liver

Front 164

energetics and reversibility of the asparatate-malate shuttle

Back 164

1. complete conservation of energetics from the reducing power in cytosol to the reducing power in the mito, therefore the NADH in the cytosol still produces 3 ATP each and this leads to a total of 38 ATP per glucose
2. very reversible reaction-each of the steps are very reversible, this allows for communication between glycolysis and the TCA cycle using some of their intermediates (OAA and NADH from glyceraldehyde-3-phosphate dehydrogenase) as points of determing whats happening upstream and downstream

Front 165

alpha glycerol phosphate shuttle

Back 165

used to shuttle the reducing power of cytosolic NADH into the mito and regenerate NAD+ in the cytosol, NADH reduces DHAP into alpha glycerol phosphate to (1) regenerate NAD+ and (2) transfer the reducing power (via alpha glycerol phosphate) to the mito, alpha glycerol phosphate enters the mito and regenerates DHAP which goes back to the cytosol, reduces FAD to FADH2, important in the heart, brain and muscle

Front 166

energetics and reversibility of the alpha glycerol phosphate shuttle

Back 166

1. since FADH2 is made instead of NADH, the NADH from the outside is converted to only 2 ATP as opposed to 3, so a total ATP production of 36 ATP
2. irreversible-what to make sure that the heart, muscle and brain constantly undergo glycolysis, don’t want to drive the system backwards

Front 167

functions of the outer mito membrane

Back 167

fatty acid elongation and activation

Front 168

functions of the intermembrane space

Back 168

1. responsible for nucleotide transfers: use nucleotide diphosphokinase to turn GTP + ADP -> ATP + GDP
2. myokinase activity: responsible for the reaction ADP + ADP -> ATP + AMP
3. monoamine oxidase (MAO): play a role in degrading neurotransmitters (norepinephrine, dopamine), act as antidepressants

Front 169

functions of the inner membrane

Back 169

1. succinate dehydrogenase
2. carnitine acyl transferase and translocase-allows fatty acids to cross
3. electron transport chain
4. heme biosynthesis-from succinyl CoA

Front 170

functions of the matrix

Back 170

1. TCA cycle
2. beta-oxidation
3. transaminases (amino acids)
4. urea cycle
5. PDH enzyme complex

Front 171

half reactions and oxidation of NADH

Back 171

NADH + H+ + ½ O2 -> NAD+ + H2O
NAD+ + 2 e- + 2 H+ -> NADH (+15 kcal/mole)
½ O2 + 2 e- + 2H + -> H2O (-38 kcal/mole)
gives a total delta G for the forward reaction of -53 kcal/mole and at 40% efficiency that gives 21 kcal/mole, enough energy for 3 ATP
delta E = +0.50

Front 172

Nernst equation and some conventions

Back 172

delta Go’ = -n*F*deltaEo’; where n=# of moles of electrons and F = faraday’s constant (23,063 cal/mol of e-), can also have –RT ln Keq = -n*F*deltaE
some conventions used for this equation:
1. always write reactions as reductions
2. +deltaG = - deltaE and –delta G = +deltaE

Front 173

strategies for keeping energy from exploding (keeping e- under control)

Back 173

1. stepwise
2. close to equilibrium
3. couple reactions-so that it doesn’t become free
4. regulate the process (sensitive to what is going on downstream)

Front 174

generally, how does ETC work

Back 174

transfer elections to other molecules first who don’t really want the electrons themselves but not as bad as the previous one’s don’t want them, allows electrons to be gradually transferred, do reach certain spots where the next molecule in line is pretty willing to take up the e- and gives of a deltaG of -7, this energy is coupled to ATP production

Front 175

FMN, FeS-proteins and CoQ

Back 175

order of these molecules found on the inner mito membrane:
FMN -> FMNH2 -> Fe+++ -> Fe++ -> CoQ -> CoQ:H2
basically, once the oxidized forms become reduced, they are oxidized again to their original form while the next form downstream is reduced, allows for a stepwise manner of electron transfer

Front 176

electron transport on the inner mito membrane

Back 176

electron is reduced all the way down, NADH -> FMN -> FMNH2 -> Fe+++ -> Fe++ -> CoQ -> CoQ:H2, small deltaG at NADH -> FMN -> Fe stages, this is released as heat and energy, at FeS++ -> CoQ, gives off a deltaG of -7 which can be used for the production of ATP, another site further downstream with a deltaG of -7 for another ATP, then at the final electron acceptor (O2-), there is a large delta G (-24) which is coupled to another ATP made, total of three sites of ATP production, note: the molecules don’t need to touch to transfer electrons, e- can actually jump form molecule to molecule

Front 177

why is the delta G at the final e- acceptor (O2) so large?

Back 177

pulls the electrons down real fast which ensures that the reaction and ETC is not reverse

Front 178

types of electron carriers

Back 178

1. NAD-electrons attack at the C next to the attached group opposite the N in the ring
2. FMN-flavinmononucleotide, e- attack at the two N’s with conjugated double bonds
3. FeS-iron sulfure proteins, proteins are cysteine rich, can be monomeric (one Fe, found in mito), dimeric (has 2 Fe, found in humans) or tetrameric (4 Fe), e- bind to the Fe itself
4. CoQ-coenzyme Q, are quinones (two O on opposite sides?), e- are accepted at the two O sites, also has a hydrophilic tail

Front 179

heme-iron vs. non-heme-iron proteins

Back 179

1. heme-iron proteins-has central Fe bounded by 4 N, hydrophobic type of molecule, found in hemoglobin and myoglobin, protein + heme is called a cytochrome, absorbs light and is red, there are different types of cytochromes (B, C1, C, A, A3), cytochromoes have a + deltaE
2. non-heme-iron proteins-are the iron sulfur proteins

Front 180

A A3 cytochromes

Back 180

has Fe and Cu, found in mito membrane

Front 181

oxygen toxicity

Back 181

one of the functions of the electron transport chain is to prevent molecules of O2 from picking up only 1 or 3 e-, these form very reactive, toxic superoxide and peroxide forms, can occur from giving too much O2 as well

Front 182

total sequence of electron carriers

Back 182

NADH -> FMN -> FMNH2 -> Fe+++ -> Fe++ -> CoQ -> CoQ:H2 -> Fe+++ -> Fe++ -> Cyto B -> Cyto C1 -> Cyto C -> Cyto A,A3 -> O2, delta G for ATP synthesis occurs from FeS -> CoQ, from Cyto C1 -> Cyto C and from Cyto A,A3 -> O2

Front 183

where do NADH and FADH2 enter the ETC and what accounts for the amount of ATP they produce

Back 183

1. NADH enters right at the beginning at FMN and encounters all three ATP production sights where delta G is atleast -7
2. FADH2 enters at the CoQ level after the first deltaG = -7 area, accounts for why FADH2 only makes 2 and not 3 ATP

Front 184

Complexes found in the ETC

Back 184

complexes are a group of proteins that are formed together on a polypeptide
1. complex 1-composed of FMN and FeS
2. complex 2-composed of succinyl dehdyrogenase
3. complex 3-cytochrome Fe, B, C1
4. complex 4-cyochrome A, A3
not only need all 4 complexes to reduce O2, but also need all the individual molecules in there proper places as well, if missing something ETC won’t work

Front 185

pH, charge gradients and the ETC

Back 185

found that protons were being pumped from the lumen into the intermembrane space at the sites of large deltaG during the ETC (remember it was 3 specific spots), protons jump and shuttle to the intermembrane space, the directionality of the H+ movement is determined by the delta G of the membrane molecule, can change pH to change directionality (and make NADH) but large delta G at O2 acceptance prevents reversibility at this site (reversible at other carrier proteins), this movement of H+ creates
1. a pH gradient-high [H+], low pH (6.8) in the intermembrane space and low [H+], high pH (7.8) in the lumen, gradient is about 1.1.4 units or 10X more H+ outside than in the lumen
2. charge gradient-created since there is more H+ outside, outside therefore has a + charge while the inside is -, how big of a charge gradient (~1 e- volt)

Front 186

why don’t keep pumping H+, why is the gradient not bigger

Back 186

well the extra H+ in the intermembrane space are trying to push against the carrier proteins that brought them into the space and trying to get back into the lumen, but the for of NADH is pushing against that, that force pushes the H+ out, but only with a force enough to be a 10X difference from outside to inside of [H+], if have way too much [H+] in the intermembrane space, then they will go into the lumen and produce NADH

Front 187

proton pore

Back 187

found imbedded in the inner mito wall that allows for excess H+ to reenter the lumen, composed of an F0 stalk and an F1 knob, inside of the F0 stalk are lots of alternating aspartic acids which shuttle the proton down into the F1

Front 188

ATPase (an ATPsynthase)

Back 188

a pinwheel type confirmation that confines H+ and produces ATP through a mechanical type energy, 3 knobs are present in the ATPase each of which can form 1 of 3 conformations:
1. L-loose, can bind ADP and P and form ATP
2. T-tight, binds ATP tightly
3. O-open form, tight form turns into the open form and releases ATP when a new set of ADP and Pi binds
each of the subunits can make ATP independent of each other, phosphonium intermediate is formed (a Pi loses an H20 and becomes highly reactive connecting with ADP to form ATP)

Front 189

ADP/ATP translocase

Back 189

mechanism for getting ATP made from the ATPase inside of the mito outside of the cell, is a membrane bound protein that binds ADP and ATP, when both are bound at the same time, it spins so that ATP can exit and ADP can enter

Front 190

coupling concepts

Back 190

if low ADP (high [ATP]) then ATP can’t leave the mito and it plugs the ATPase, H+ thus does not enter, O2 is not reduced and NADH levels are high

Front 191

inhibitors of Ox-Phos

Back 191

1. amytal-can block right after complex III, everything upstream is reduced while everything downstream is oxidized
2. CO, CN and N3 (azide)-blocks O2 -> H2O and stops O2 consumption
3. bongkrekic and atractyloside-stops the rotation of the ADP/ATP translocase
4. DCCD and oligomycin-blocks the F0 from accepting H+
5. malonate-blocks the activity of SDH

Front 192

uncouplers of Ox-Phos

Back 192

are mito membrane hole pokers, allow protons to move into the lumen causing the gradient to collapse, O2 consumption increases because there is no resistance present, consumed fuels release there energy strictly as heat and no ATP is produced

Front 193

examples of Ox-Phos uncouplers

Back 193

1. dinitrophenol-once used in dieting
2. Ca++ ions-do so in a reversible and regulatory manner, can change the size of pores based on the [Ca]
3. valinomycin-an antibiotic, forms donut shaped holes that only allows for K+ (not H+) to go through, this disrupts the charge gradient to collapse
4. thermogenin-produced in hibernation conditions

Front 194

thyroxine and uncouplers

Back 194

not an uncoupler, found in individuals with hyperthyroid, it INC ATP consumption by INC the acitivity of 100 different enzymes generating heat

Front 195

what controls O2 consumption during Ox-Phos

Back 195

1. need ADP to make the reaction go forward, it INC O2 consumption, when ADP is all used up, then O2 consumption stops until more is added, this is done to ensure that O2 is not reduced unless ADP is present (which is really meaning that O2 is not consumed unless ATP is made)
2. uncouplers-dramatically INC O2 consumption, can stop this consumption if place an inhibitor upstream of where the uncoupler works at
3. inhibitors of Ox Phos-stop O2 consumption, stop all reactions downstream of where it acts

Front 196

succinate and Ox-Phos

Back 196

enters Ox-Phos at Complex II, if a Complex I inhibitor is given, it has no effect if succinate is the energy source, if have an inhibitor that acts downstream of succinate then there will be a stop to O2 consumption

Front 197

types of lipids

Back 197

fatty acids, simple lipids, compound (complex) lipids, derived lipids

Front 198

cell composition

Back 198

70% water
15% proteins
7% nucleic acids (1% DNA + 6% RNA)
2% carbohydrates
2-3% lipids
2-3% free amino acids-vitamins

Front 199

definition of lipids

Back 199

organic cellular components that are insoluble in water, or soluble in nonpolar substances

Front 200

functions of lipids

Back 200

1. energy (triglycerides)
2. membranes (structure, boundary between two aqueous compartments)
3. signals (messengers, hormones, prostaglandins)
4. cofactors (Vitamin A,D,E,K these are the lipid soluble vitamins)
5. transport
6. protection (insulation and abuse)
7. dolicohols (adding carbs to proteins)

Front 201

fatty acid info

Back 201

the simplest of the lipids, composed of an acid on the end of a long hydrocarbon chain, two types (saturated and unsaturated (has double bonds in hydrocarbon chain))

Front 202

names, structures and abbreviations of fatty acids we should know that are involved in lipid metabolism

Back 202

C1-formic, HCOOH, 1:0 (# carbons : # double bonds)
C2-acetic, CH3COOH, 2:0
C3-propionic, CH3CH2COOH, 3:0
C4-butyric, CH3(CH2)2COOH
C16-palmitic, CH3(CH2)14COOH, 16:0
C18-stearic
C20-arachidic

Front 203

what does INC the chain length of a fatty acid do?

Back 203

1. it INC its hydrophobicity
2. it INC its melting point temperature (mp), this is because the long chains interact with each other and an INC in interaction causes an INC in packing

Front 204

delta vs. omega nomenclature of amino acids

Back 204

delta-start with C1 at the most oxidized end (the COOH end) and count to the end
omega-start C1 at the opposite end from delta, this is because of elongation (elongation occurs at the COOH end and so omega nomenclature allows the Cs to stay the same number

Front 205

omega families for the unsaturated fatty acids

Back 205

these are metabolically related families of fatty acids, omega-7, 9, 6, and 3, this means that there is a double bond between C7-8, C9-10, C6-7, and C3-4

Front 206

rules for unsaturation (going from saturated to unsaturated fatty acid)

Back 206

1. desaturase works from delta1 C and reaches a maximum of 9 Cs
2. additional double bonds are not inserted past the 1st double bond
3. double bonds are methylene interrupted (meaning that each successive double bond is exactly 3 C’s away)
4. all double bonds are cis-this puts kinks into the fatty acid and these kinks are why we can’t have double bonds pass the 1st one placed on

Front 207

De novo synthesis of fatty acids

Back 207

can make the omega7 and omega9 families, start with palmitic (which can be made in the body), can either (1) desaturate to palmitoleic (16:1 omega7) or (2) elongate to stearic, stearic can then be desaturated to oleic (18:1 omega9), oleic can also be desaturated to linoleic (18:2 omega9)

Front 208

arachidonic acid (the omega6 family)

Back 208

(20:4 omega6), necessary to live (essential fatty acid), used to make prostaglandins and leukotrienes, can’t make it de novo but can eat it, not essential to eat it because can eat a precursor that can be turned into it, that fatty acid is linoleic acid (18:2 omega6)

Front 209

linoleic acid (omega6 form)

Back 209

(18:2 omega6), THE ESSENTIAL FATTY ACID, most important fatty acid and must be eaten (mainly from plants, corn, soy), can be desaturated, elongated then desaturated to form arachidonic acid

Front 210

omega3 family fatty acids

Back 210

must also be eaten (cannot be synthesized de novo), comes from fish oils (from the algae they eat), can be 20:5 omega3, 22:6 omega3 can promote good health but not necessary to live, prevents cardiac disease, reduces tumor growth and INC sensitivity to chemo, and is truly unsaturated, the enzymes that recognize arachidonic acid to make prostaglandins and leukotrienes may actually use omega3 families to make lots of leukotrienes

Front 211

unsaturated fatty acids, its properties and membrane fluidity

Back 211

INC kinks, DEC packing, INC fluidity, outer layer of bilayer is more saturated while the inner membrane is more unsaturated

Front 212

simple lipids

Back 212

fatty acids involved in ester bonds, ex: esters, waxes and mono-, di-, and triglycerides

Front 213

esters

Back 213

fatty acid (acid) + alcohol -> esters

Front 214

wax

Back 214

fatty acid (acid) + long chain hydrocarbon (maybe 30 C) -> wax

Front 215

acyl suffix

Back 215

means fatty acid

Front 216

mono-, di- and triacylglycerides

Back 216

formed from fatty acids binding to glycerol (mono-1 fa, di-2 fa, tri-3 fa), triglycerol normally put reduced fatty acids, reduced triglycerol can be retailored to unsaturated version via a deactylation-reactylation (2 enzyme step) at alpha-2 (middle OH on glycerol)

Front 217

thiolester formation

Back 217

fatty acid + acyl-CoA -> thiolester, has a deltaG of about -6 to -8 Kcal/mol

Front 218

compound/complex lipids

Back 218

fatty acid + some alcohol + something else, ex: glycerol lipids (phosphatidic acid, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl inositol, cardiolipin, plasmalogens), sphingolipids (sphingosine,

Front 219

phosphatidic acid (PA)

Back 219

important in metabolism, made from:
diacylglycerol + phosphate -> phosphatidic acid (the phosphate is attached to alpha1)
phosphatidic acid can be used to make triglycerides (by adding a fatty acid-CoA to it and releasing the phosphate) or phospholipids (by adding a alcohol to it and attacking the phosphate)

Front 220

phosphatidyl choline (PC) (AKA lecithin)

Back 220

phosphatidic acid + choline -> phosphatidyl choline + H2O
a phospholipid, is amphipathic (the choline is very polar while the two fatty acid chains are nonpolar)

Front 221

phosphatidyl ethanolamine (PE)

Back 221

PA + ethanolamine -> PE
amphiphatic, ethanolamine is interchangeable with choline (ethanolamine is the same as choline except it is missing the three methyl groups), can make PE from PC by using S-adenosyl-methionine (SAM) and ATP to add the methyl groups

Front 222

phosphatidyl serine (PS)

Back 222

PA + serine -> PS
amphiphatic, can decarboxylate PS to form PE which is interchangeable with PC

Front 223

phosphatidtyl inositol (PI)

Back 223

PA + inositol -> PI
can take PI (which has an abundant source of OH’s) and, with ATP, phosphorylate two spots to form phosphatidyl-inositol polyphosphate (PIP3), cleave PIP3 to form IP3 (these two are second messengers)

Front 224

cardiolipin

Back 224

2 PA + glycerol -> cardiolipin
found only in inner mito membrane, critical for humans, has 4 fatty acids, 2 phosphates and 3 glycerols, probably functions in complex II

Front 225

plasmalogens

Back 225

found in nervous tissue, tumor cells, acts as a second messengers (PAF, can cause aggregation of platelets)
1. DHAP (a monoacyl compound) + NADH -> intermediate
2. intermediate + long chain alcohol -> vinyl ether + FA
3. vinyl ether + choline -> plasmalogen
4. plasmalogen + FA-CoA -> PAF (platelet activating factor) + CoA

Front 226

spingolipids

Back 226

a complex lipid that uses serine as its building block, ex: sphingosine, ceramide

Front 227

sphingosine

Back 227

palmitoyl-CoA decarboxylates serine to form sphingosine

Front 228

ceraminde

Back 228

sphingosine + 24:0 FA -> ceramide

Front 229

sphingomyelin

Back 229

add a phosphorylated choline to ceramide to form spingomyelin, analogous to PC

Front 230

cerebrosides

Back 230

formed from adding a UDP-glucose or UDP-galactose to ceramide, two groups (those that have glucose and those that have galactose

Front 231

gangliosides

Back 231

formed from adding about 6-8C carbs to form gangliosides, can add N-acetyl Neuraminic Acid (NANA)

Front 232

Tay-Sachs disease

Back 232

hits between the cerebroside -> ganglioside

Front 233

sulfatides

Back 233

add S to cerebrosides

Front 234

brain type tissues

Back 234

cerebrosides, gangliosides, sulfatides

Front 235

derived lipids

Back 235

coming from some lipid (fatty acid), could be all the way back to acetyl-CoA as the building block, ex: prostaglandins, leukotrienes, phospholipases, sterols, lipid soluble vitamins, cholesterol

Front 236

prostaglandins

Back 236

use prostaglandin synthase (cyclo-oxgenase) to change the double bond arrangements found in arachidonic acid to form PG-H, can form different families from here (D2 (OH up), E2 (OH down), F2 (two OH), PG-I (found in capillaries and blood vessels, called prostacyclin and it decreases platelet aggregation), TBX (found in platelets, called thromboxane, it INC platelet aggregation, makes a thrombus)), important in the inflammatory response

Front 237

leukotrienes

Back 237

use 5-lipoxygenase, uses O2 to cause a shift in double bonds and end up with conjugated double bonds, three in a row and it can thus absorb light, forms leukotriene (LTA-4), LTA-4 can give rise to different families (LTB4 (chemotaxic for macrophages, inflammatory response), LTC4 (smooth muscle stimulator, found in asthmatics and anaphylactic shock), LTD4, LTE4)

Front 238

LTC4

Back 238

LTA4 + glutathione (small tripeptide, gamma-GLU-CYS-GLY) -> LTC4 (forms with the gamma carboxy group), can remove the gamma-GLU to form LTD4 and can then remove GLY to form LTE4

Front 239

autocoids

Back 239

classification of the prostaglandins and leukotrienes, biologically active, go to adjacent cells and work on those cells

Front 240

phospholipases

Back 240

act by cleaving the fatty acids in the cell membrane to free arachidonic acid or lineolic acid, different types of phospholipases:
1. Phospholipase A1-cleaves the 1st fatty acid (saturated)
2. Phospholipase A2-cleaves the second fatty acid (unsaturated), physiologically important
3. Phospholipase C-cleves between the third C (the one without a FA bound) and the PO4 on the choline (cleaves the ester bond), physiologically important
4. Phospholipase D-cleaves between the PO4 and the choline, found in plants only

Front 241

what would one do if he or she wanted to block the inflammatory response?

Back 241

1. block the availability of arachidonic acid with cortisol (probably has saved the most lives of any drug, a steroidal-anitinflammatory), this block phospholipase A2 inhibiting the ability of the cell membrane to release arachidonic acid
2. can also use NSAIDS (nonsteroidals, ex: aspirin, Tylenol) to block cyclo-oxygenase (aspirin irreversible acetylation, Tylenol in competitive way) and prevent production of prostaglandins

Front 242

cystic fibrosis

Back 242

found that there is an INC in 20:4 (arachadonic (ETA)) and a DEC in 22:6 (omega3, docosahexaneoic acid (DHA)), the lung, pancreas and intestine showed the changes in 20:4 and 22:6, found that they could INC DHA in the three tissues through dietary changes and clear up lung infections

Front 243

cholesterol structure

Back 243

4 rings, 3-6 membered rings, 1-5 membered rings, 27 Cs

Front 244

cholesterol esters

Back 244

actually a simple lipid, OH on C3 serves in the esterification, usually add to 18:2 omega6 FA, formation of cholesterol esters requires acylase and degradation requires esterase, uses include dietary (free C or C-E, transport (C-E) and storage (C-E))

Front 245

Lecithin Cholesterol Acyl transferase (LCAT)

Back 245

extracellular, one of the acylases used to make cholesterol esters, found in serum and binds lecithin (the 2nd fatty acid part of it) to cholesterol at the OH on C3, unsaturated normally found at the 2nd fatty acid (usually 18:2 or 20:4)

Front 246

acyl cholesterol acyl transferase (ACAT)

Back 246

intracellular, one of the acylases used to make cholesterol esters, looks for free fatty acyl-CoA (or also arachidonic acid) and binds it to cholesterol

Front 247

lysolecithin

Back 247

product formed after LCAT or phospholipase A2 cleaves the middle fatty acid from lecithin and places it on cholesterol, considered to be a strong detergent (has a hydrophobic end and a hydrophilic end), can be used to lyse cell membrane (also RBCs and LDL) called a lysophospholipid

Front 248

function of cholesterol

Back 248

fits between phospholipids, makes membrane more tight packed and makes it lose some fluidity (in lateral direction)

Front 249

bile salts and bile acids

Back 249

bulk of the cholesterols injested is used to make bile salts and bile acids, difference between bile salts and acids with cholesterol is three Cs, want to remove side chain as propionyl-CoA, bile acid has COOH in place of the C3 removed unit, esterify with glycine to form glycocholic acid (bile salt) or add a taurine (from cysteine) with a amide bond to form taurocholic acid (bile salt), can INC the polarity of cholesterol by adding OH groups to C7 and C12 of the bile acid (or also bile salt), liver busy making this stuff

Front 250

steroid hormones

Back 250

made from cholesterol, shortened cholesterols, most is 21 C, can make progesterone (C21) from cholesterol, progesterone can be used to make aldosterone, cortisol or androgens (C19, have to remove a C2), androgens can form estrogens (C18, have to remove a C), cholesterol can also form isocapraldehyde (proproic acid, C6) when making progesterone

Front 251

vvitamin D (cholecalciferol)

Back 251

formed from 7-dehydrocholesterol (an intermediate in the formation of cholesterol), has an extra double bond in the B ring, if light hits it, can cleave the B ring and make it swoop down, if add an OH group to two parts (one added in liver C25, and one added in kidney C1) can form vitamin D (1,3,25 trihydroxy cholecalciferol)

Front 252

vitamin A (beta carotene)

Back 252

4 isoprenes (5 Cs on each one) between two 6 membered rings, all trans double bonds, cleave at symmetrical point and form 2 retinoic acids, then through a reduction form retinal, and a 2nd reduction form retinol (for vision)

Front 253

vitamin E (alpha tocoherol)

Back 253

an antioxidant, has isoprenes on the end, when poly-unsaturated fatty acids are exposed to O2 can become rancid, form epoxides, endoperoxides and hydroperoxides (these propagate down affecting all the double bonds downstream), can lead to breakage of bonds which form products with smell, vitamin E give protection from rancid oxidation products, has an OH group that can donate protons and make hydroxyl groups disallowing the full O2 from attacking, use vitamin C to re-reduce OH that oxidized double bond to OH

Front 254

vitamin K (menadione)

Back 254

involved in blood clotting, different forms of vitamin K due to side chains that may be added to it, vitamin K is given to infants because it doesn’t cross placental barrier and newborn GI tract is sterile (since GI bacteria can make vitamin K)

Front 255

membrane formation

Back 255

add PC to H2O, FA will stick in the air and choline will face the H2O, if exceed the capacity for the surface to hold PC, then a micelle (monolayer) begins to form with the FAs pointing in the middle, bile acids lowers the critical micellar concentration (CMC, the amount of phospholipids needed to beginning forming a micelle)

Front 256

lipid bilayers

Back 256

start as a cyclindrical shape when keep adding PC into H2O after a micelle forms, eventually forms a spherical bilayer

Front 257

liposomes

Back 257

spherical bilayer structures

Front 258

phospholipid composition of membranes

Back 258

PC (50%) > PE (25%) > PS (2-10%) > PI (2-10%) > Sphingolipids (2-10%) > others (plasmalogens, cerebrosides, gangliosides, cholesterol) (1%)

Front 259

fatty acid composition of membranes

Back 259

position #1 usually saturated
PC-18:0
PE-16:0
PS-16:0, 18:0, 18:1
PI-16:0
Sph-16:1
position #2 usually unsaturated
PC-18:2, 20:4
PE-20:4
PS-18:2, 20:4
PI-18:2
Sph-16:0-26:0

Front 260

protein:lipid ratios

Back 260

RBC- 50% lipid 50% protein
plasma-50% lipid 50% protein
ER-40% lipid 60% protein
nuclear-35% lipid 65% protein
outer mito membrane- 45% lipid 55% protein
inner mito membrane-25% lipid 75% protein
myelin- 80% lipid 20% protein

Front 261

distribution of phospholipids across membranes

Back 261

outside-less fluid (dealing with lateral movement), more saturated, contains PC and Sphingomyelins
inside-more fluid (dealing with lateral movement), more unsaturated, contains PE, PS, and PI
flip-flop-very rare, slow

Front 262

lipid intake

Back 262

mostly triglycerides, some phospholipids, some cholesterol (free and esters), oils (sat and unsat) and vitamins

Front 263

lingual lipase

Back 263

found on the dorsal side of the tongue, some triglycerides can be broken down to diacylglycerol and 1 free fatty acid, works on either end only, fa composition determines how well the lingual lipase works

Front 264

gastric lipase

Back 264

found in the stomach, has about the same specificity as the lingual lipase, if have a triglyceride with a short or medium sized fatty acid (mostly from milk, more hydrophilic), those are cleaved preferentially and absorbed in the gastric mucosa (same for lingual lipase)

Front 265

pancreatic lipases

Back 265

secreted as a zymogen (so are phospholipases and cholesterol esterases) by the pancreas, a triglyceridase, cleaves both ends of the triglyceride and forms a beta-monoglyceride + 2 fatty-acids, amino acid fragments from the lipases create a C5 molecule that can tell the brain that we are full (called enterostatin), thought that CCK acts in the same way

Front 266

lipase function

Back 266

when it is released it binds to a globule but it becomes inactive just sticking on to the membrane of the globule, need to shrink it down (that is what bile does) and colipase (anchoring molecule, it is cosecreted with lipase) to become active, this makes a ternary complex (triglycerides, bile salts, lipase and colipase, allows the lipase to do its job)

Front 267

what does lipase do to the triglyceride after formation of ternary complex?

Back 267

it can break triglyceride down into:
1. a beta-monoglyceride + 2 fatty acids (~72%)
2. an alpha-monoglyceride + 2 fatty acids (~22%)
3. a glycerol + 3 fatty acids (~6%)

Front 268

bile salts function in absorption after breakdown

Back 268

forms little micelles that can interact with the mucosal cell villi, to bring in lipids (free fatty acid, alpha and beta monoglycerides and glycerol), glycerol and any leftover short and medium chain fatty acids can enter straight into the blood

Front 269

how do we get free fatty acids (long chain) out of the mucosal cell into the blood?

Back 269

we activate and esterify them with ATP and CoASH, forms 2 FA-CoA + beta-monoglyceride, do it to beta-monoglycerides as well and can form a triglyceride in the mucosal cell, can also make phospholipid and package them into another globule with the TGs (90%) and cholesterol (1-5%) on the inside and phospholipids (8-10%) on the outside

Front 270

Apo-proteins

Back 270

A, B48, C, D, and E forms, decorates the micelle and form chylomicrons (referred to as the exogenous lipids, the ones we take in) which go to the lymph

Front 271

breakdown of chylomicrons

Back 271

goes through the lymph system, through the heart, out the aorta, chylomicrons (through ApoCII) then bind to lipoprotein lipase (on the endothelian wall, through an ionic interaction), lipase leaches out the triglyceride and breaks it down into glycerol and 3 fatty acids, FFA and glycerol can go straight into the adipocyte, FFA is trapped as TG through phosphorylation and glycerol is released (no glycerol kinase) going back into the liver, chylo remnant also goes to liver for recycling into component pieces

Front 272

Apo A

Back 272

activates LCAT (needed to go from cholesterol to cholesterol ester)

Front 273

Apo B48

Back 273

aids chylomicron transport from mucosal cell to lymph

Front 274

Apo CII

Back 274

activates lipoprotein lipase

Front 275

Apo D

Back 275

activates LCAT, not really too sure

Front 276

Apo E

Back 276

uptake of chylomicron remnant by liver

Front 277

Triglyceride storage in adipocyte

Back 277

have FFA in the adipocyte but cannot store them because they are disruptive so they are esterified to FA-CoA, combine FA-CoA with alpha glucose phosphate (which comes from DHAP reduction) to form triglyceride in adipocyte

Front 278

insulins role on triglyceride storage in adipocyte

Back 278

1. acts as a necessary molecule for glucose to enter the adipocyte to act as a source of GAP and DHAP for triglyceride formation
2. also inhibits a hormone sensitive lipase that normally breaks down TG in the adipocyte to release glycerol and fatty acid

Front 279

Diabetes

Back 279

lack of insulin, can’t store TG in the adipocytes and breaks it down leading to high blood glucose levels, a lipid metabolism problem as well as carb problem

Front 280

7 different lipases

Back 280

lingual lipase, gastric lipase, pancreatic lipase, lipoprotein lipase, hormone sensitive lipase, phospohlipase, cholesterol esterase

Front 281

metabolism in amino acids

Back 281

90% used in protein synthesis, 2-10% for energy

Front 282

insulin and glucokinase

Back 282

can actually cause an INC in glucokinase (a long process though, cumulative)

Front 283

How do we degrade citrate?

Back 283

1. citrate -> OAA
a. catalyzed by citric acid lyase
2. citrate + CoASH + ATP -> acetyl-CoA (used to make fatty acids and cholesterol)
a. catalyzed by citric acid lyase

Front 284

What is the fate of the OAA made from citrate degradation?

Back 284

1. OAA + NADH -> malate + NAD+
a. catalyzed by malate dehydrogenase
two alternatives for the malate
1. malate enters the mito and enters the TCA cycle and regenerates OAA in the mito
2. malate + NADP+ -> NADPH + pyruvate + CO2
a. catalyzed by malic enzyme
b. produces 50% of NADPH in body, other 50% comes from HMPS
c. pyruvate goes back into mito

Front 285

C numbering in fatty acid synthesis

Back 285

acetyl-CoA-has C1 and C2, acetyl-CoA can become malonyl-S-protein with 3 carbons, the carbons here are number 3, 4, and 5, when acetyl-CoA binds with malonyl-SCoA, malonyl C3 attacks C2 of acetyl-CoA and carbon three is released, therefore the new C4 compound is numbered 1, 2, 4, 5, so when elongating always remove the first carbon off the malonyl and next two are numbered, so a C6 fatty acid is 1,2,4,5,7,8

Front 286

when making a fatty acid, there are ketones at every other carbon, what do we do?

Back 286

reduce it twice with NADPH before adding the next C2 unit, then reduce, reduce then add

Front 287

production of malonyl-SCoA

Back 287

acetyl-CoA + CO2 + ATP + biotin -> malonyl-SCoA
catalyzed by acetyl-CoA carboyxlase (ACC) AKA malonyl-CoA synthetase (it is a biotin-ATP dependent carboxylation
this step is the key committed step to making fatty acids, add malonyl-CoA to acetyl CoA then keep adding malonyl-CoA after reducing steps

Front 288

what stimulates and inhibits ACC

Back 288

stimulation-citrate, insulin, polymer active when well fed, insulin also activates phosphoproteinphosphatase so removes phosphate from monomeric units so they can form an active polymer
inhibit- palmytoyl-CoA (16:0-CoA, final product of fatty acid synthesis), glucagon, monomer is inactive during starvation state, phosphate on monomer so they do not collect to form an active polymer

Front 289

reaction in fatty acid synthesis

Back 289

1. Acetyl-S-Protein + Malonyl-S-acyl-carrier protein (ACP) -> aceto-acetate-SACP (AKA beta-ketobutyrate)
2. aceto-acetate-SACP + NADPH -> beta-hydroxybutyrate-SACP + NADP+
a. catalyzed by dehydrogenase (reductase), makes alcohol form
3. beta-hydroxybutyrate-SACP -> unsaturated SC FA-SACP + H2O
a. catalyzed by a dehydratase
4. unsaturated SC FA-SACP + NADPH -> saturated FA + NADP+
a. catalyzed by dehydrogenase
5. repeat until 16:0-SACP
6. 16:0-SACP -> 16:0 (palmitate) + H-S-ACP
a. catalyzed by thiolase

Front 290

Fatty-Acid Synthase complex (FAS, Acyl Carrier Protein)

Back 290

fatty acid synthesis occurs entirely on this complex, is a dimer so is able to give two enzymatic sites, two dimmers interact with each other (steps 1,2,3 on one and 4,5,6 on the other), a protein on the end of the protein with a ser bound to coenzyme of CoA, FAS consists of 7 enzymes:
1. load C2
2. load C3
3. condense
4. reduce
5. dehydrate
6. reduce
7. thiolase (once it gets to the length of 16 C units)

Front 291

coenzyme of CoA

Back 291

pantoic acid (can’t make) beta alanine (can make) and thioethanolamine (can make)

Front 292

what happens to 16:0 palmitate after it is released by thiolase

Back 292

it is activated with CoASH and ATP to form 16:0-SCoA (activated), catalyzed by acyl-CoA synthetase

Front 293

where does elongation and desaturation occur

Back 293

on the ER, has enzymes on it for the process, mito can also a little bit but we will ignore it

Front 294

properties of fatty acid synthesis

Back 294

1. large complex
2. begin with C2 and C3 units
3. NADPH is the reducing power used
4. it is strictly a cytosolic phenomenon
5. uses long arm (acyl carrier protein)

Front 295

what do we do with 16:0-SCoA

Back 295

can put it on a glycerol phosphate or alpha-glycerol phosphate, (which comes from DHAP) to esterify them, can form phosphatidic acid, which are the precursors for triglycerides and glycerolipids

Front 296

triglyceride synthesis

Back 296

phosphatidic acid + FA-SCoA -> triglyceride + Pi

Front 297

phospholipid synthesis (CDP-DAG method to PI or PC)

Back 297

1. phosphatidic acid -> diacylglycerol + Pi
2. diacylglycerol + CTP -> CDP-diacylglycerol + PPi
3. CDP-diacylglycerol + choline or inositol -> PC or PI + CMP

Front 298

phospholipid synthesis (via the activated choline pathway)

Back 298

1. phosphatidic acid -> diacylglycerol + Pi
2. activate choline or some other base to add to the DAG (can use ethanolamine too):
a. choline + ATP -> phosphorocholine + ADP
b. phosphorocholine + CTP -> CDP-choline + PPi
3. CDP-choline + DAG -> PC + CMP

Front 299

phosphatidyl serine synthesis

Back 299

PE (from above method) + serine -> PS + ethanolamine
a direct base exchange
can decarboxylate PS to form PE

Front 300

phosphatidyl choline synthesis with PE

Back 300

PE + 3 SAM (S-adenosylmethionine) -> PC (adding 3 methyl groups)

Front 301

spingolipid biosynthesis

Back 301

1. 16:0-SCoA + Serine -> sphingosine + CO2
a. condensation reaction
2. sphingosine + long chain fatty acid (16:0 – 22 or 24) -> ceramide

Front 302

sphingomyelin synthesis

Back 302

ceramide + CDP-choline -> sphingomyelin + CMP

Front 303

cerebroside formation

Back 303

ceramide + UDP glucose -> gluco-Cerebroside
ceramide + UDP galactose -> galacto-Cerebroside
found in brain tissue, can also add another UDP-glucose or UDP-galactose to either the gluco- or galacto-cerebroside, name dependent on what binds first
can also do this reaction:
gluco/galactocerebroside + N-acetyl Galactosamine -> elongated cerebroside

Front 304

ganglioside formation

Back 304

gluco/galactocerebroside + N-acetyl-neuraminic acid (NANA, sialic acid) -> gangliosides
different forms of gangliosides (GM 1, 2 or 3, G for ganglioside, M for mono (only one NANA, can be di-, tri-, quatro) and number for sequence of carbs)

Front 305

shingolipidoses

Back 305

diseases, such as Tay-Sachs, cannot degrade sphingolipids

Front 306

alternative route for C2 from citrate

Back 306

can be used in cholesterol biosynthesis, is a cytosolic process

Front 307

HMG-CoA synthesis

Back 307

1. acetyl-CoA + acetyl-CoA -> aceto-acetyl-CoA + CoA
a. catalyzed by a thiolase
2. aceto-acetyl-CoA + acetyl CoA -> 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) + CoA
a. catalyzed by HMG-CoA synthase
b. adds to C2 of aceto-acetyl-CoA
functions for HMG-CoA: building block for cholesterol (well-fed state), can make ketones (under starvation)

Front 308

mevalonic acid synthesis

Back 308

1. HMG-CoA, lose CoA making it an acid, reduce it with NADPH to an aldehyde and reduce again with NADPH to make a alcohol (REQUIRES 2 NADPH)
2. this reduced form is mevalonic acid
a. catalyzed by HMG-SCoA reductase
b. the key regulatory step for cholesterol synthesis, a two step reduction
c. this occurs under well-fed conditions (make cholesterol under well-fed conditions, therefore if hyperglycemic can also be hypercholesteremic)
d. membrane bound to the ER, active if on the ER

Front 309

HMG-CoA reductase regulation

Back 309

1. stimulated by insulin, inhibited by glucagon
2. glucagon -> INC protein kinase activity (through cAMP)
a. ATP to phosphorylate and activate a reductase kinase kinase which activates a reductase kinase which inactivates a reductase, reductase activated with insulin through PPP
3. cholesterol dissociates HMG-CoA reductase from E.R., inactivating it
4. cholesterol DEC transcription of HMG-SCoA reductase gene (DEC the total # of HMG-CoA reducatse)
5. mevolinic acid (drugs such as statins (lipitor)) block HMG-SCoA reductase, look like mevalonic acid and binds to HMG-CoA competitively

Front 310

isoprene production

Back 310

1. mevalonic acid + 3-ATP -> isopentenyl pyrophosphate (IPPP) + CO2
2. IPPP isomerizes with dimethyl allyl pyrophosphate (DMAPP) (just moving the double bond)
a. IPPP and DMAPP are the isoprenes (these are 5 C units)

Front 311

use for isoprene (make squalene and lanosterol)

Back 311

1. DMAPP + IPPP (in a head to tail fashion) -> geranyl pyrophosphate (C10, terpene) PPi
2. geranyl pyrophosphate + IPPP (head to tail) -> farnesyl pyrophosphate (C15) + PPi
3. farnesyl + farnesyl (tail to tail fashion) -> squalene (C30) + 2 PPi
4. squalene tends to fold up
5. squalene (folded) + O2 -> lanosterol
a. catalyzed by squalene oxidase (closes the ring structure forming 4 rings)

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cholesterol formation from lanesterol

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steps needed to turn lanesterol to cholesterol (C27)
1. remove 3 methyl groups
a. remove the CH3 through oxidation and removing them as CO2
b. use a mixed function oxidase (MFO, or methyl sterol oxidase) to oxidize
c. CH3 -> CH2OH -> CHO -> COOH -> CO2
d. need to split O2 into O with NADPH -> NADP+ + H20 to give the energy for the oxidation reactions (the reactive O attacks each of the steps
2. reduce delta24 double bond
a. use NADPH or NADH to reduce it
3. isomerizes delta7 -> delta5 bond
a. insert another double bond in lanosterol at C5 to form 7-dehydrocholesterol
b. 7-dehydrocholesterol can make vitamin D when exposed to light
c. 7-dehydrocholesterol can make cholesterol when reducing the delta7 double bond

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Very low density lipoprotein (VLDL) synthesis

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amino acids -> proteins -> apoproteins A, B, C, D, and E
glucose -> citrate -> acetyl CoA -> fatty acids -> triglycerides, gangliosides, sphingolipids and cholesterol
VLDL formed from FA, TG, GL, SpL and Chol on the inside of a phospholipid/apoprotein covered spherical compartment, made in the liver

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VLDL breakdown to IDL and LDL

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similar to the mechanism of how chylomicrons are broken down, VLDL composed of 50-60% TG and 40-50% chol and chol-ester, VLDL is broken down by lipoprotein lipase into FFA and glycerol and I.D.L., IDL (intermediate density lipoprotein, also leaches out some FFA) -> LDL (low density lipoprotein, C and CE rich, and has high protein content)

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storage of FFA

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FFA interact with alpha GP (which comes from DHAP) to form TG, HSL is inhibited by insulin (HSL wants to breakdown TG into FFA and glycerol

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leptin

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thought to be made in the adipoctyes when there is an INC in [TG], leptin is thought to leave the adipocyte and go to the hypothalamus where it is though to reduce appetite

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LDL metabolism

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LDL composed of cholesterol and cholesterol esters on the inside and Apo A, D and B100 on the outside, has two fates:
1. LDL is attracted to the adrenal cortex (has clathrin coated pits with B100 receptors on it), takes in LDL, eventually the membrane is recycled and B100 is released, LDL is kept inside and fuse with lysosomes to release free cholesterols, can be stored as cholesterol esters or produced into hormones (aldosterone and cortisol)
2. liver has been releasing HDL3 (which has associated LCAT and lecithin, stimulated by a little alcohol or exercise), HDL3 and LDL (cholesterol and Apo A and D) interact, HDL3 sucks cholesterol out of LDL and turn it into cholesterol ester, is now sphere shaped and called an HDL2, goes back to the liver and cholesterol is made into bile to be excreted, (HDL3 can also bind to membrane bound cholesterol as well

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lipid degradation

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occurs during fasting (starving) conditions, degrade triglycerides mostly, need to mobilize the TG through HSL, activate it with CoA derivatives, transport them into the mito for beta oxidation and formation of ketones

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three notes for lipid degradation

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1. carbs -> lipids, TG, fatty acids
2. fatty acids cannot be converted to carbs, not allowed transition
3. equivalences between starvation and diabetes

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how does hypoglycemia work to tell adipocyte to release FFA

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low blood sugar is the main signal, it causes INC in glucagon, epinephrine, ACTH (stress levels INC) and GH (in pituitary, GH and ACTH are adipo kinetic) while inhibiting insulin, causes glycogen to make glucose (in the liver), insulin normally blocks hormone sensitive lipase while glucagon, epinephrine, ACTH and GH normally stimulates it, causes degradation of TG into FFA and glycerol

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epinephrine and raising the blood glucose levels

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epinephrine causes glycogen breakdown and its use in the cycle, prevents the cell from using blood glucose but instead using its own stores

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adipocytes and alpha glycerol kinase

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lack it, good because it would just recycle the effect of hormone sensitive lipase in the adipocyte and produce TGs from FFAs and glycerol

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fate of FFA and glycerol in the adipocyte

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FFA will leave the adipocyte, enter the bloodstream and bind to albumin (atleast 3 hydrophobic binding sites), carries FFA to different tissues (liver, muscle, others, NOT brain, Alb-FA is too large to go in), when reach the liver, albumin lets go of FA, FA binds to FA binding protein to form complex, drives the FA in

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fate of FFA once inside different tissue

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FFA + CoASH + ATP -> acyl-CoA + AMP + PPi
catalyzed by acyl-CoA synthetase, found on outer mito membrane, activates the FFA

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sudden infant death syndrome (S.I.D.S.)

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may be due to a defect in the short chain and medium chain synthetases, babies can starve in between meals if they have this type of defect, milk is mostly SC and MC and they have difficulty in degrading SC and MC

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once we have activated FFA, what do we do with it?

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want to get it into the mito (need to cross both the outer and inner)
1. to go through the outer membrane-there is a carnitine acyl transferase (CAT1, AKA carnitine palmitoyl transferase (CPT)) found embedded in the outer ER membrane, carnitine is located in the intermembrane space, acyl binds with carnitine to form acyl-carnitine (and lose CoASH in the cytosol) in the intermembrane space
2. to go through the inner membrane-there is a translocase that brings in the acyl-carnitine to the matrix, carnitine and acyl-CoA are regenerated by CAT II which is bound on the inner mito memebrane, allows for acyl to gain a CoA to form acyl-CoA and for the carnitine to leave and reenter the intermembrane space for another reaction

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carnitine synthesis

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need MET and LYS