Biochemistry Block 3

Front 1

Catabolism involves oxidizing and burning to get energy from _______.

Back 1

(energy production, carbohydrates, lipid and protein)

and store it in ATP, NADH, NADPH

Front 2

Anabolism you spend energy and use high energy carrier to make ___, ____, ____.

Back 2

ADP, NAD+, NADP+;

(Synthesis of macromolecules, muscle contraction, active ion transport, thermogenesis)

Front 3

Energy requirements of your body are determined by the _____________ and _________________.

Back 3

basal energy expenditure (BEE);
body mass index (BMI)

Front 4

Energy is extracted from food molecules by a process of _______ oxidation (_______ burning).

Back 4

gradual; controlled;

Controlled oxidation occurs on simple monomeric fuels and energy is stored in activated carrier molecules (ATP).

Front 5

Energy is produced within cells by ________ of simple monomeric fuels (carbs, fatty acids, amino acids).

Back 5

oxidation

For sequential reactions ∆G values are additive!

Front 6

Energetically favorable reaction of ATP hydrolysis can be coupled to otherwise _______ reactions.

Back 6

unfavorable;

Front 7

Glycogen is the storage form of _____.

Back 7

glucose (primary carb for metabolic fuel in mammals)

Glucose --> pyruvate (glycolysis)--> acetyl CoA oxidized in TCA

Front 8

Mobilizable protein is protein that is converted into _________.

Back 8

amino acids

Front 9

Triacylglycerols are _____.

Back 9

fats

So, fat is by far the largest fuel source in mammals.

Front 10

Most of ATP from glucose metabolism from reduction of ____ and ___ to ___ and ____, and their reducing power in the electron transport chain.

Back 10

NAD+, FAD, NADH, FADH2

Electron flow generates proton gradient in mitochondrion that drives oxidate phosphorylation and ATP production. (full oxidation of glucose ~36 ATP)

NADH and FADH2 from TCA cycle = energy carriers - store tremendous amount of energy and mainly electrons (goes through oxidation chains)

Front 11

Like glucose, __________ can be completely oxidized in TCA cycle via conversion to ________. Complete oxidation of palmitate yields 129 ATP.

Back 11

fatty acids, acetyl CoA

Front 12

Amino acids can be oxidized by conversion to their corresponding _____, via class of enzymes called ________.

Back 12

keto-acids; transaminases;

many keto-acid products are intermediates in TCA or glycolysis

In addition to oxidation, amino acids used in gluconeogenesis (very imp. in starvation)

Front 13

Integration of Metabolic Pathways

Back 13

1. Metabolic intermediates can enter multiple pathways and serve as points of integration.

2. One pathway can affect another.

3. Organs/tissues have diffferent forms of key enzymes/proteins for integration in organ systems.

4. Genes for proteins in pathway are coordinately regulated.

5. Regulation by the “anabolic” hormone insulin and the “catabolic” hormone glucagon

Front 14

How do insulin and glucagon control metabolism?

Back 14

Front 15

Sugar has how many carbons in it?

Back 15

6

Front 16

The hydrolysis of _________ to glucose and galactose is catalyzed by the enzyme _________.

Back 16

lactose; lactase;

e.g. milk

Front 17

________ is the name given to a number of enzymes that catalyze the hydrolysis of sucrose to ________ and glucose.

Back 17

Sucrase; fructose;

e.g. cane sugar or syrup

Front 18

Digestion and ________ are required for uptake of dietary carbohydrates.

Back 18

absorption

Front 19

Amylase is in saliva and secreted by the ______, as the major luminal enzyme. The membrane enzymes hydrolyze products of amylase action and other poly and disaccharides to glucose, galactose and fructose.

Back 19

pancreas

Front 20

A critically important feature of absorption of substances across the epithelium is the requirement for a __________ cell.

Back 20

polarized

Front 21

____________ and ___________ can be transported via secondary active transport with Na+ with _____ proteins - couples ion transport with sugar transport.

Back 21

Glucose; galactose; SGLT1

Front 22

In contrast, to glucose and galactose, fructose is absorbed by a distinct apical membrane protein called GLUT5 in a process termed _____________.

Back 22

facilitated diffusion

Front 23

Once inside the cell, each monosaccharide is transported across the basolateral membrane by the same protein, _______, in a facilitated transport manner .

Back 23

GLUT2

Front 24

Mammals express two classes of glucose carrier: 1) ____________ and 2) ________________.

Back 24

Na+ dependent cotransporter; facilitated glucose transporters;

Front 25

High affinity for glucose, these transporters are _______ and _____.

_______ does erythrocyte transport, BBB, and transformed (cancerous cells).

_____ is the predominant brain isoform.

Back 25

GLUT-1;GLUT-3; GLUT-1; GLUT-3

Front 26

GLUT2 is a ____ affinity and _____-capacity glucose transporter. It is mostly expressed in ____ and _____.

Back 26

low; high;

liver; pancreatic B-cell;

glucose transport ~ [glucose] --> allows sensing for insulin secretion

low affinity allows allocation to brain when glucose is low.

liver - act as glucose buffer, can regulate storage as glycogen or triglyceride - the high Km allows liver to only act when blood glucose is high

Front 27

Glucose transport in muscle or fat tissues requires ________ while transport of glucose into liver or brain is largely independent of _______.

Back 27

insulin; insulin;

Front 28

_______ is translocated from the inside of the cell to the plasma membrane in response to insulin administration.

Back 28

GLUT4

blood glucose clearance for maintaining good level;

stored in either glycogen (muscle) or fat (adipose)

Front 29

Hexokinases I-III have a _____ affinity for glucose, a _____ tissue distribution, ______ specificity and strong _____ inhibition by _____.

Back 29

high; wide; limited; allosteric; G-6-P.

The G-6-P (product) inhibition of HK prevents tying up cell inorganic phosphate (depleting ATP).

Front 30

Hexokinase IV is also known as ______, and it has a ___ affinity for glucose, ____ tissue distribution (liver, islets, pituitary), and no ________ regulation by G-6-P.

Back 30

glucokinase; lower; limited; allosteric;

Front 31

Liver and islets are the two glucose sensing tissues that have specialized proteins _______ and _______ for handling glucose.

Back 31

GLUT-2; glucokinase;

Islets sense glucose by secreting insulin;

Liver is an organ of glucose storage at high glucose;

Front 32

G-6-P has multiple fates such as _______, ______, and ________.

Back 32

storage (G1P to UDP glucose to glycogen - short term storage in muscle); DNA,RNA via ribose production (6C to 5C); Energy (glycolysis for pyruvate to lactate)

Front 33

Glycolysis: __ Glucose = __ Lactate + __ ATP

Back 33

1; 2; 2;

Front 34

Fermentation under anaerobic conditions recycles NAD+ from NADH (oxidation) through the action of ______________ in the production of lactate.

Back 34

lactate dehydrogenase (reduces pyruvate to lactate)

NAD+/NADH ratio determines cell redox state

Front 35

There is an oxygen requirement for pyruvate dehydrogenase (PDH) plus _____ activity.

Back 35

TCA cycle;

(produces acetyl CoA and CO2)

Front 36

Metabolic fates of pyruvate?

Back 36

Front 37

Galactose can be made from _____ or from diet as part of ______. It is transported, like ______, with a Na+ linked transporter.

Back 37

glucose; lactose (milk); glucose;

Gal important in glycoproteins (e.g. N-acetyl galactosamine)

Front 38

3 enzymes are required for galactose utilization:

1) _______
2) _______
3) _______

Back 38

1) Galactokinase (phosph. C1 - not C6 like gluco/hexokinase; almost exclusive to liver)

2) Uridyl transferase (xfers UDP from Glu to Gal)

3) UDP-Galactose-4-Epimerase (UDP-Gal to UDP-Glu; requires NAD - reversible rxn which is why Gal is not essential)

Front 39

Hereditary problems in galactose metabolism lead to acccumulation of Gal and Gal-1-P. Gal is reduced to polyalcohol _______ by aldolse reductase.

Accumulation of these leads to eye lens damage and ______ in diabetic and ______ individuals.

Back 39

galactitol; cataracts; galactosemic;

(can also have non-enzymatic glycosylation of proteins)

(in babies have mental retard. and death from liver damage)

Front 40

Fructose is metabolized very efficiently in _____, but rarely in other tissue. Fructokinase is analogous to ______________ in phosphorylating C1.

Back 40

liver; galactose kinase;

F1P Aldolase gives DHAP and glyceraldehyde

in muscle and adipose tissue, it enters glycolysis as F6P via hexokinase

Front 41

The pathway of fructose metabolism in the liver bypasses ____ and its regulation of glycolysis.

Back 41

PFK;

this is most important control of glucose metabolism and you will use up all inorganic phosphate;

remember liver has special enzymes for glucose, galactose and fructose.

Front 42

______________ is an uncommon (1 in 130,000) autosomal recessive disorder that involves fructose kinase deficiency. It has no pathological effects because the kidney is capable of excreting the excess fructose efficiently.

Back 42

Essential fructosuria

Front 43

_____________________ has a higher incidence and caused by deficiency in F1P aldolase.

Back 43

Hereditary Fructose Intolerance;

(nausea, vomiting, and failure to grow)

fructose intake can lead to hypoglycemia (ATP and Pi depletion since fructose is phosph. but stalls there)

Front 44

Metabolism of Fructose in extrahepatic tissues

Back 44

Fructose is synthesized from glucose in the seminal vesicles by a combination of two oxidoreductases and the intermediate formation of the polyalcohol sorbitol.

Glucose + NADPH → Sorbitol + NADP

Sorbitol + NAD → Fructose + NADH

Front 45

____________, the synthesis of glucose from pyruvate in liver and kidney is essential for maintenance of blood glucose levels.

Back 45

Gluconeogenesis;

most other tissues including the brain almost exclusively use glucose (RBC = glucose only)

liver maintains glucose level by stimulating glycolysis and glycogen deposition OR gluconeogenesis when starved

Front 46

In gluconeogenesis, the pyruvate kinase reaction is reversed by _________ and ___________.

The PFK reaction is reversed by __________.

Hexo/Glucokinase reaction is reversed by __________.

Back 46

pyruvate carboxylase; phosphoenolpyruvate carboxykinase;

F1,6,BPase (F2,6,BPase activates PFK also inhibits F1,6,BPase so it is a good way to activate glycolysis and block gluconeogenesis)

G6,Pase (in lumen of ER, non-specific hexose phosphohydrolase - specificity by G6P translocase in ER membrane);

Front 47

Gluconeogenic precursors include ________ & ________, __________, and __________.

Back 47

lactate and pyruvate (Cori cycle - exercising muscle and erythrocytes - convert glucose to 3C metabolites in extrahepatic tissue and regenerate glucose in liver --> +2 ATP - 6 ATP); amino acids(need transaminase reaction to remove amino group - only subset of AA have this ability to enter TCA or glycolysis); fatty acids (propionyl --> OAA --> Glu);

cancer uses glycolysis as energy source leading to lactate buildup and severe liver burden

Front 48

Key enzymes are heavily regulated at the ___________ step.

Back 48

rate-limiting

Front 49

For enzyme regulation, the TF regulation can regulate ______ at a time (group of genes for metaoblism).

Back 49

many

Front 50

Modes of regulation are:

Back 50

1) Allosteric
2) Protein localization
3) Covalent modification
4) Gene expression

Front 51

Glucose phosphorylation is an example of _________.

Back 51

protein localization;

Front 52

Hexokinases 1-3 are _____-hepatic, __________ inhibited to prevent import of excess glucose and are _____ affinity.

Back 52

extra; product; high;

Front 53

Hexokinases 4 or _______ is found in the liver, NOT __________ inhibited - but instead inhibited by F-6,P, to prevent import of excess glucose and is _____ affinity.

Back 53

glucokinase; product; low;

note that F-6,P is in equilbrium with G-6,P

Front 54

_______ and __________ have low affinities for glucose that allow the liver to buffer blood glucose levels.

Back 54

GLUT2 and Glucokinase

Front 55

Glucokinase is regulated by _______ since when circulating glucose concentration is low then liver glucose concentration is low, and the glucokinase would be sequestered in the nucleus.

After a meal, the plasma glucose levels increase and enter liver via GLUT2 which leads to dissociation of _____ from GKRP which allows the GK to go to the _________.

Back 55

Glucokinase regulatory protein (GKRP);

Glucokinase; cytosol;

Front 56

Allosteric regulation involves the _____ which is the MOST regulated enzyme of the body, as it catalyzes the committed step.

The regulation of PFK by many stimuli is called the _______ effect.

Back 56

PFK; Pasteur;

Front 57

________ is the major regulator of PFK in liver as it antagonizes ATP ________ of PFK, ______ the Km of PFK for F-6,P.

Back 57

F-2,6,BP (imp. in regulation gluconeo vs. glycolysis); inhibition; lowers;

Front 58

The bifunctional protein is the ___________ interconverts F-6,P and F-2,6,BP.

Back 58

6-PF-2K/Fru-2,6Pase;

Front 59

A fasting state is catabolic (insulin/glucagon ___) and activates PKA (cAMP dep.), activates the phosphatase and inactivates the _____ (slowing glycolytic flux).

Back 59

low; kinase;

Front 60

A fed state is anabolic that activates a phosphatase which activates kinase and inactivates __________, which increases glycolytic flux.

Back 60

phosphatase;

Front 61

_______ and __________ have low affinities for glucose that allow the liver to buffer blood glucose levels.

Back 61

GLUT2 and Glucokinase

Front 62

Glucokinase is regulated by _______ since when circulating glucose concentration is low then liver glucose concentration is low, and the glucokinase would be sequestered in the nucleus.

After a meal, the plasma glucose levels increase and enter liver via GLUT2 which leads to dissociation of _____ from GKRP which allows the GK to go to the _________.

Back 62

Glucokinase regulatory protein (GKRP);

Glucokinase; cytosol;

Front 63

Allosteric regulation involves the _____ which is the MOST regulated enzyme of the body, as it catalyzes the committed step.

The regulation of PFK by many stimuli is called the _______ effect.

Back 63

PFK; Pasteur;

Front 64

________ is the major regulator of PFK in liver as it antagonizes ATP ________ of PFK, ______ the Km of PFK for F-6,P.

Back 64

F-2,6,BP (imp. in regulation gluconeo vs. glycolysis); inhibition; lowers;

Front 65

The bifunctional protein is the ___________ interconverts F-6,P and F-2,6,BP.

Back 65

6-PF-2K/Fru-2,6Pase;

Front 66

A fasting state is catabolic (insulin/glucagon ___) and activates PKA (cAMP dep.), activates the phosphatase and inactivates the _____ (slowing glycolytic flux).

Back 66

low; kinase;

Front 67

A fed state is anabolic that activates a phosphatase which activates kinase and inactivates __________, which increases glycolytic flux.

Back 67

phosphatase;

Front 68

When Pyruvate Kinase is phosphorylated, it is ______, and when PK is ___________ it is more active.

Back 68

inactive; dephosphorylated;

(-) effectors of PK = ATP, Alanine
(+) effectors of PK = F-1,6,BP

Front 69

An example of transcriptional regulation is the ____ and the ____ effect.

Back 69

HIF; Warburg (high aerobic glycolysis in cancer);

low O2 enhances glycolysis, forms heterodimer with ARNT (target glyc. enzymes and gluc. transporters)

Front 70

HIF upregulates expression of:

Back 70

1) F-2,6BP (iPFK-2 increase F-2,6BP, it is bifunctional but phosphatase domain is removed)
2) GLUT 1,3
3) CAiX (increase pH in response to acidosis)
4) LDHA (make lactate to recycle NADH to NAD+)
5) PDKinase (inhibit Acetyl CoA production since not useful)

Front 71

ChREBP = glucose mediated induction of gene expression.

Here, high sugar levels mean dephosphorylated sites leading to nucleus entry and TF binding.

Back 71

short term (sugars) --> reduced fuels for long term (fats)

citrate --> triglyceride with ACL, ACC, and FAS prots.

Xu5P-->PP2A-->PF2K/Pase -->F6P/F26P ratio (short term)

or PP2A-->ChREBP-->triglycerides (long term)

Front 72

Regulation of gluconeogenesis occurs at several sites:

Back 72

1) FA oxidation (via lipase) stimulates gluconeogenesis (Acetyl CoA activates pyruvate carboxylase, inhibits PDH)

2) glucagon/insulin ratio regulates gluconeogenesis by PK, bifunctional enzyme (phosph. state)

3) glucagon regulates CREB by PKA which upregulates PEPCK (same with insulin)

Front 73

Glucose can go through:

Back 73

1) Glycolysis
2) Storage (muscle/liver glycogen)
3) Pentose phosphate (NADPH - red. power, protection from oxidative stress & 5C sugars)

Front 74

Glycogen = glucose polymer with a1,4 and a1,6 linkages to form helix configuration. Helices allow reduction of _______, increased ___________, rapid release of glucoso monomers.

Back 74

osmotic effect; solubility;

Front 75

Glycogen in muscle not available to other cells as it is in liver, since muscles lack _____.

Back 75

G-6Pase

Front 76

Glycogen, instead of fat is used since fat is not as rapidly ___ in skeletal muscle.

Also fat can not be _____ to produce energy anaerobically.

It also requires ____ input.

Fat also can not be converted into _____.

Back 76

mobilized; oxidized; energy; glucose;

Front 77

UDP glucose makes glycogen formation favorable, and the irreversible hydrolysis of __________ drives the reaction forward.

Back 77

pyrophosphate

Front 78

Glycogen synthase requires a primer substrate. ______ is responsible for making the short polymer.

Back 78

Glycogenin (it is self-glycosylating)

Front 79

_______ enzyme breaks a1,4 bond and makes a1,6 link.

Back 79

Branching;

Glycogen synthesis is efficient (only consumes 1 ATP but full oxidation of glycogen yields 37 ATP)

Front 80

______________ is the rate-limiting enzyme of glycogen degradation.

Back 80

Glycogen phosphorylase;

G1P to G6P via phosphoglucomutase

it can not cleave a1,6 bonds, so a separate enzyme "debranching enzyme" cleaves these.

Front 81

Glycogen breakdown is initiated by falling glucose in liver through action of _____ and in muscles by flight/fight response via epinephrine (they lack glucagon receptors).

Back 81

glucagon;

Front 82

Three enzymes affect the conversion of phosphorylase a and b:

Back 82

(1) phosphorylase kinase (phosphorylates glycogen phosphorylase)

(2) cAMP- dependent protein kinase, which phosphorylates (thereby activating) phosphorylase kinase

(3) phosphoprotein phosphatase-1, which dephosphorylates and deactivates glycogen phosphoylase a.

Front 83

Phosphorylase kinase has four subunits:

2 inhibitory: _____, ______

1 catalytic: ______

1 Ca2+ sensitive: _______

Back 83

alpha, beta (these are phosphorylated when active);

gamma;

delta (calmodulin, significant since glycogen breakdown is coupled with muscle contraction due to Ca2+ influx);

Front 84

cAMP signaling is stimulated by glucagon or ______, and it also inhibits ______ phosphatase.

Back 84

epinephrine; phosphoprotein;

Front 85

Regulation of Liver and Muscle Glycogen Stores:

Back 85

Front 86

Glycogen phosphorylase can be in either the "T" or "R" state, where the "R" state binds glycogen and is stimulated by ____, and inhibited by ATP and ____.

Back 86

AMP; G6P;

Front 87

Phosphorylase a and b are controlled both ______ and allosterically.

Back 87

covalently;

Front 88

Phosphorylation of _____________ inactivates the enzyme, from a to b form.

Back 88

glycogen synthase

Front 89

Glycogen synthase phosphorylation is induced by ____, cAMP, and ____.

Back 89

Ca2+; DAG

phosphoprotein phosphatase is inactivated by PKinase A

Front 90

Glucagon inhibits glycolysis at ____ and _____.

Back 90

PFK, pyruvate kinase;

Front 91

Epinephrine leads to ____ release from ER and inactivates synthase, and activates phosphatase.

Back 91

Ca2+;

Note that Epinephrine in muscle leadsto increased glycolysis (since muscle don't have glucose transporters)

Front 92

The production of __________ and the generation of ______ are the most significant consequences of the pentose shunt pathway.

Back 92

pentoses; NADPH;

Front 93

Pentose phosphate pathway

Back 93

Production of NADPH for a variety of intracellular processes

Production of the pentose – ribose

Production of various 5- and 7-carbon carbohydrates

Primarily located in the cytosol

Front 94

Where does the pentose phosphate pathway occur?

Back 94

1. FA and steroid synthesis tissues (e.g. liver)

2. RBCs

3. The eye - high ROS and NADPH demand

note: Glucose-6-phosphate dehydrogenase is specific for NADP+ in mammals and is considered to be the rate- limiting step in the pentose shunt pathway.

Front 95

______ is highly regulated since it is committed step in carbohydrate to lipid synthesis or TCA.

Back 95

Pyruvate Dehydrogenase (PDH)

Front 96

_________ is product of fatty acid oxidation or PDH.

Back 96

Acetyl CoA

Front 97

Pyruvate can be converted into:

Back 97

- lactate (reduction)

- alanine (transamination)

- oxaloacetate (carboxylation)

- Acetyl CoA (oxidative decarboxylation)

Front 98

PDH consists of three subunits: _________, _______, __________.

It is irreversible which is why ____ can not be converted into carbohydrate.


It is analogous to alpha-___________ DH.

Back 98

decarboxylase,transacetylase,dehydrogenase;

fat;

ketoglutarate;

Front 99

RARE FACT: PDH is NOT regulated by ______.

Back 99

cAMP

Front 100

PDH controls TCA, gluconeogenesis and _____________.

Back 100

glucose to fat conversion

Front 101

Pyruvate is charged and therefore needs a _______ to move through membrane.

Back 101

transporter;

Front 102

PDH _________ inactivates PDH.

PDH _________ activates PDH.

Back 102

kinase; phosphatase;

Insulin and Ca2+ stimulate phosphatase activity;

Front 103

When starving, FA oxidation yields __________ and ____.

Back 103

acetyl CoA; ATP;

(also inhibits PDH via kinase)

Acetyl CoA also activates pyruvate carboxylase.

Front 104

TCA is most of the tissue CO2, NADH, precursors (amphobolic).

There are __ carbons in and __ carbons out.

Back 104

2; 2;

excess energy used for FA synthesis; oxaloacetate primes the cycle;

Front 105

Enzymes in steps of TCA.

Back 105

1. citrate synthase (irreversible, -ve ATP/ADP, reg'd by OAA availability)

2. aconitase

3. isocitrate DH (+ve ADP, -ve NADH,ATP); gives NADH and CO2

4. alpha-ketoglutarate DH (-ve ROS); gives NADH

5. succinyl-CoA synthetase (only rxn to make GTP)

6. succinate DH (integral membrane protein); make NADH

7. Fumarase

8. Malate DH (makes NADH and OAA)

Front 106

Succinate DH is sensitive to changes in levels of ___.

Back 106

OAA

Front 107

TCA cycle = source of biosynthetic intermediates

alpha-ketoglutarate goes to _________.

___________ --> replenish TCA intermediates

Back 107

amino acids; Anaplerosis

Front 108

Quinones act as electron and proton carriers.

Can be reduced by one and two electrons. (semi or hydro)

Carrier is _______ in semiquinone form.

Back 108

negative

Front 109

Flavoproteins = ___ e- acceptors and ___ e- donors.

Back 109

2; 1;

Front 110

Fe-S prots = carriers only transfer __ e-

Back 110

one;

Front 111

Heme proteins = 1e- carriers, protect heme iron from molecular ______.

Back 111

O2

Front 112

Respiratory Chain has Complex I,II,III,IV.

Only complex ___ does not transport protons across membrane.

Back 112

II; (this is succinate reductase from TCA)

Front 113

CoQ = hydrophobic and restricted to membrane.

Redox energy of NADH converted to _____ gradient.

Back 113

proton;

Front 114

Complex I

Back 114

FMN bound NADH DH and Fe-S

- Complex I CoQ turns QH2 form to diffuse into hydrophobic membrane

HIGHLY exergonic, enough for ATP production

Front 115

Complex II

Back 115

succinate and FADH2, BUT NOT EXTRUSION OF PROTONS

Front 116

Complex III

Back 116

relocates electrons from QH2 to oxidized cyt c.

transfer from 2e- carrier to 1e- carrier is most efficient

Front 117

Complex IV

Back 117

transfer cyt c electrons to O2.

Front 118

Chemiosmotic Hypothesis

Back 118

- e-transport/ATP synthesis are coupled

- vectorized protein distribution

- need intact membrane

equilibrium of ATP synthase

Front 119

F1F0 ATP Synthase

Back 119

F1 = trimer of heterodimers alpha-beta

proton motive force

Front 120

O2 regulated by need for ___ (except in brown adipose tissue).

Measure of control = ratio of O2 used with ADP, and without.

Back 120

ATP;

Front 121

Uncouplers of O2 phosphorylation =

Back 121

DNP, CCCP, Valinomycin

Front 122

Thermogenin allow return of ___, as in brown fat.

Back 122

H+

Front 123

Need specific metabolic shuttles.

Malate-aspartate shuttles:

Back 123

NADH in cytosol reduce OAA (NADH-->NAD+) --> malate --> malate oxidized to OAA in matrix (NAD+ --> NADH) --> OAA transaminated with glutamine to alpha-ketoglutarate

Front 124

Alcohol DH uses cytosolic ______.

Aldehyde DH in mitochondria uses _____.

Back 124

NAD+; NAD+;

So shuttle is dead, inhibition of gluconeogenesis and FA oxidation.

Leads to fatty liver (NADH increases pyruvate to lactate)

Cancer = problems in succinate DH, isocitrate DH, fumarase

Front 125

Insulin resistance due to

(INFLAMMATION is big time in reduced insulin sensitivity)

Back 125

1) obesity

2) cachexia (cancer-associated)

3) congenital/acquired lipodystrophies

Front 126

Adipose tissue depots respond in __________ fashion to metabolic challenges (unlike donor organs).

Back 126

coordinated

Sexual dimorphism (male = central fat pad/visceral/apple; female = subcutaneous, lower extremity pear)

fat pads also respond differently

Front 127

________ shuttles FA to adipocytes for storage.

Back 127

Insulin

"ideal adiposity"

adipose = protective and deleterious (inflammation)

Front 128

Pancreas = insulin and glucagon

Liver and Kidney = gluconeogenesis

Glucose consumers = _________ and _________

Heart runs on _______.

Central regulation by brain.

Back 128

Brain; muscle;

Fatty acids

Front 129

Glucose tolerance test = oral or IV (bypass digestive tract)

Track plasma clearance of glucose.

Back 129

OGTT > HOMA-IR > FSIVGT > Euglycemic clamp

(more complex means more specific info)

Front 130

Excessive reduction in insulin sensitivity leads to ________ in pregnancy.

Back 130

gestational diabetes;

(precursor to diabetes)

Front 131

Diabetes is a disease of the beta-cell but is complex:

Back 131

insulin resistance in liver and muscle leads to inappropriate deposition of lipid in wrong tissues

Front 132

Islet has 3 cell types:

Back 132

alpha - glucagon

beta - insulin

delta - somatostatin

diabetes = loss of beta, alpha remain

islets highly vascularized to ensure rapid delivery of hormones into blood stream

loss of glucagon opposition is problem, so if you antagonize glucagon you would actually be OK

Front 133

C-peptide indicates secretion, so a C-peptide/insulin ratio shows insulin ______ and ________.

Back 133

release; clearance;

Front 134

Preproinsulin --> proinsulin (3 disulfide bonds, cleaved by peptidase) --> insulin --> _______________

Back 134

secretory granules

Front 135

GLUT2 uptake of glucose increases ATP/ADP ratio which inactivates ___ channel to open ___ channel for Ca2+ influx, which releases ___ from their storage granule.

Back 135

K+, Ca2+, insulin

Front 136

Insulin release is a ____ process.

Back 136

biphasic

(readily released pool and sustained slow release from reserve pool)

Front 137

An incretin, such as GLP-1 potently stimulates _______ release. It is a major accessory factor for beta-cell to respond to increases in carbohydrates.

Back 137

insulin

Front 138

Insulin resistance affects different organs in different ways:

In liver, it increases gluconeogenesis, and ___________, increasing plasma glucose.

In muscle and fat, glucose uptake is reduced which ________ plasma glucose.

Adipocyte increases lipolysis and increases FA release, which is used for gluconeogenesis by the ________.

Back 138

glycogenolysis; increases; liver;

Front 139

Insulin receptor has an alpha and beta subunit. The beta is the _______ kinase.

Back 139

tyrosine;

Insulin binds, TK gets autophosphorylated then cross; IRS-1 binds, PI3K, then PDK1 and then Akt

Front 140

You have the TM, JM and Tyr 972 which binds PTB of ____ and ___.

Back 140

IRS-1 and Shc

Front 141

Insulin increases levels of _____ for glucose transport.

Back 141

GLUT4

Front 142

___ in liver and kidneys breaks down blood insulin.

Back 142

insulinase;

Front 143

additional effects of insulin = ras pathway

there is regulation of pro-mitogenic action of insulin

Back 143

IRS phosphorylates Shp2 (SH2 which is a tyrosine phosphatase) then Grb2 (SH3) then SOS1 then Ras.

Front 144

Overexpression of Grb14 leads to hyperphosphorylation of IR and a decrease in _____ phosphorylation leading to insulin resistance.

Back 144

IRS-1

Front 145

SOCS proteins bind phosphotyrosine on IR, then blocks _____.

Back 145

IRS-1

Front 146

Counterregulatory hormons (back up glucagon) are:

Back 146

From Adrenal Gland - Catecholamines (Epi, Norepi - special because block insulin and stimulate glucagon), and Hydrocortisone

From pituitary - GH

Front 147

T2DM leads to ______ resistance and inability to dispose of glucose into muscle and adipose.

Back 147

insulin

It is also linked to the ability of liver to listen to the insulin (insulin-resistance)

Front 148

Insulin also regulates release of FA, so insulin resistant cells will inappropriately release ____.

Back 148

FFA;

Depot specifity is important.

Front 149

Subclinical inflammation leads to increase in ____, which affects macro and microvasculature.

Back 149

CRP;

IL-6 from fat triggers CRP;

Front 150

FA, ketones, AA can stimulate insulin release.

AA can also stimulate _______.

Back 150

glucagon;

Front 151

Defense against hypoglycemia is:

Back 151

liver and kidney gluconeogenesis;

liver glycogenolysis;

1/2 of glucose used by brain, rest of body lipid economy; FA oxidation leads to ketones (not full oxidized so brain can still use)

Front 152

Defense against hyperglycemia is:

Back 152

insulin (insulin resistance leads to polyuria)

Front 153

T1DM problem is diabetic _________.

Back 153

ketoacidosis

Front 154

Diabetic = uncontrolled _______, like uncontrolled fasting.

Back 154

catabolism;

insulin deficiency and excess glucagon;

Front 155

Early stage/non-emergent diabetes is:

Back 155

elevated blood glucose, polyuria, increased thirst and food intake (hypertriglyceridemia and hypercholestermia)

Weight loss in T1DM

Weight gain in T2DM

Front 156

Emergent diabetes:

Back 156

T1DM = diabetic ketoacidosis

T2DM = non-ketotic hyperosmolar coma (clots especially in brain)

Front 157

Late complication syndrome is:

Back 157

retionopathy, neuropathy, nephropathy (microvascular) and MI, stroke, gangrene, amputation (macrovascular)

Front 158

Symptoms of hypoglycemia are _________ and _________.

Back 158

neurogenic (2* to ANS activity - tremor, sweat, hunger, anxiety, tachy)

neuroglycopenia (low glucose in CNS - confusion, dizzy, vision blur, difficult speaking, loss of conscious, convulsion)

Front 159

Measurement of _____________ is accepted as a method for long-term glucose control in patients with diabetes mellitus.

Back 159

hemoglobin A1c (HbA1c)

Front 160

Major classes of diabetic medications are:

Back 160

1. Thiazolidinediones/Biguanides(decrease insulin resistance by making muscle and adipose cells more sensitive to insulin, also suppress hepatic glucose production); Side effect of TZD is weight gain (higher fat mass for insulin sensitivity)

biguanide example is metformin

2. Drugs that stimulate the pancreas to make more insulin: Sulfonylureas Meglitinides (concern that SU's cause hypoglycemia and CV disease, exhaust beta-cell function)

3. Drugs that slow the absorption of starches: Alpha-glucosidase inhibitors

4. DPP IV inhibitor (incretin)

Front 161

________ plays a critical role in the adipogenic transcriptional cascade

Back 161

PPARγ

PPAR isoforms share a common domain structure and molecular mechanism of action

PPARγ activity can be modulated by many different additional factors that include co-activtors and co-repressors.

Front 162

Iron overload can lead to generation of ______ _______ species, that damage various tissues when uncontrolled.

Back 162

reactive oxygen (ROS)

Fenton rxn, ad microbial infections

"tug of war" between host and bacteria (lactoferrin in breast milk chelates and sequesters iron, just like transferrrin away from bacterial hemolysin)

PROBLEM: iron availability is increased in acidity or iron overload

Front 163

Iron works as a cofactor in _____, Fe-S, and dioxygenases (HIF).

Back 163

heme

Front 164

The body needs to sense and regulate Fe, so the _____ are storage depot for RBCs and recycle it.

Some Fe floats around, but it is bounded to _______.

The loss of Fe is ___________.

Back 164

macrophages;

transferrin;

UNREGULATED;

recycled iron is main source of need;

Front 165

_______ is the primary protein expressed in intestine, main way for Fe uptake. Fe needs to be ____________ to be taken up.

Back 165

DMT-1; REDUCED (dietary factors can help reduce);

Front 166

You do not want Fe in cytosol (ROS), so if it is not in Heme or Fe-S, excess iron is ___________ and put into ________.

Back 166

oxidized; ferritin (shell keeps Fe hidden and good depot);

Front 167

Tissues that would need to export iron are liver, intestinal cells and macrophages.

_________ exports Fe2+ which is oxidized by _______ or _________.

Back 167

Ferroportin; hephaestin; ceruloplasmin;

Front 168

Non-intestinal cells have transferrin receptors which allow Fe3+ entry via ________, so Fe3+ is reduced then released via ______ into cytosol.

Back 168

endosome (acidic); DMT-1;

Front 169

_______ regulation of iron coordinates intestinal iron absorption and iron storage in liver and macrophage with iron consumption and O2 demand.

Back 169

Systemic

Front 170

_______ is produced by liver, which binds ferroportin (leading to its internalization and destruction via lysosome or Ub).

Back 170

Hepcidin

It can be upregulated or downregulated.

conditions favoring reduced Fe mobilization --> hepcidin release (for iron overload, infection/inflammation)

conditions of high iron demand (anemia, hypoxia, erythropoesis) downregulate hepcidin expression, allowing Fe export

Front 171

There is also a need to regulate gene products coordinately at a cell level.

A post translational modification used is IRE (either in 5' UTR or 3' UTR), which are binding sites for _______.

Back 171

IRPs (regulated by iron availability; IRP1 forms Fe-S cluster and IRP2 degraded in high iron state)

When Fe is low, IRP binds 5' UTR of ferritin (downregulate iron storage), and 3' UTR of transferritin receptor (upregulate iron uptake)

Front 172

Misregulation of iron homeostasis leads to:

Back 172

Fe overload syndromes (hemochromatosis - HFE involved in hepcidin regulation, hemosiderin accumulation; liver-cirrhosis, heart failure, CNS-Parkinsons)

Fe deficiencies (anemia, hypochromic microcytic anemia)

Front 173

Heme is generated from succinyl CoA and glycines. Heme biosynthesis needs mitochondrial and cytosolic enzymes.

Here, the first step is catalyzed by ______.

Back 173

ALA-synthase (in mito)

uses vit B6 and activity regulated by feedback inhibition by heme and by repression of synthesis by heme

Front 174

Intermediates of heme biosynthesis can generate ROS.

___________ controls rate limiting step of first step (feedback by heme).

Back 174

ALA synthase;

build up of intermediates lead to porphyrias (hepatic most common - e.g. acute intermittent porphyria (AIP) deficiency in uroporphyrinogen I synthase)

lack of control of ALA synthase by heme increases production and excretion of ALA and porphobilinogen (symptoms brought about by drugs)

Front 175

Heme degradation involves:

Back 175

Recycle iron; process hydrophobic products of porphyrin ring cleavage

initial reaction in degradation catalyzed by heme oxygenase (requires O2 and NADPH) and produces CO and biliverdin

biliverdin reductase acts to make bilirubin pigment

Front 176

Bilirubin binds ________ which helps increase solubility then transport to liver.

Conjugation of bilirubin to ____ by UDP glucoronyltransferase occurs in the liver.

Back 176

albumin; glucuronic acid (solubilizes in liver and exrete into bile and large intestine);

Glucuronides cleave by b-glucuronidase in intestine releasing bilirubin, which is reduced (oxidation of this produces stool color)

Front 177

Kernicteris = bilirubin toxicity

Back 177

excess amounts of bilirubin circulating in the blood stream dissolve in the subcutaneous fat causing a yellowish appearance of the skin and the whites of the eyes

Front 178

Bilirubin in the plasma is carried either as the diglucuronide or bound to serum albumin.

The van den Berg reaction only detects _____ bilirubin.

Back 178

"free"

direct = diglucuronide that is soluble without albumin

indirect = freed from albumin by methanol

Front 179

If jaundice is due to hemolysis, liver can not form glucuronides for all heme, and the _____ form of bilirubin will increase.

With biliary obstruction, glucuronide not secreted properly which will lead to increase in _______ form of bilirubin with lower fecal content of bile pigments. Both direct/indirect if obstruction is prolonged.

Cirrhosis/hepatitis fails to conjugate bilirubin which will decrease bile secretion and increase ______ form of bilirubin.

Neonatal hyperbilirubinemias have increase unconugated bilirubin (low UDP-glucouronyltransferase activity). Treated with ___ light to break down bilirubin.

Back 179

indirect;

direct;

indirect;

UV;

Front 180

Erythropoiesis accounts for nearly 80% of the daily iron and heme demands in humans.

____ is a glycoprotein hormone that regulates red blood cell production

Back 180

Erythropoietin (Epo)

1. Discovery and therapeutic applications (anemia)
2. Regulation: Hypoxia Inducible Factor


HIF induction is regulated by both oxygen and iron availability at multiple levels (including the presence of an IRE within the the 5’ UTR of the HIF-2α subunit)

Front 181

Amino acids usually used for protein synthesis or for synthetic purposes. The excess is degraded.

_________ is a waste product of amino acid breakdown.

Back 181

Ammonia;

especially in amino purines (AMP)

Most excreted as urea

No storage form for AA except tissue protein.

AA breakdown are substrates for gluconeogenesis.

Front 182

Common reactions that involve AA: (all use pyridoxine or vit b6)

Back 182

1. transamination (transaminases highest in liver and muscle, equilibrium near 1 - no energy needed)

e.g. pyr --> ala; OAA-->Asp; 2-ketoglutarate-->Glu

2. Decarboxylation (produce corresponding amines; many produce NTs, decarb of Glu makes GABA)

3. Deamination (most are oxidative, i.e ser-->pyr)

Front 183

Aldehydes are able to combine with amino groups non-enzymatically and form a covalent compound called a ____________.

The enzymes that carry out these reactions are called ___________.

Back 183

Schiff's base

Forms with lysine chain, which can be displaced by an AA. Once bound tautomeric shifts can activate different bonds to reactive. (all of this is reversible)

aminotransferases; (aspartate or alanine (elevations in AST or ALT for liver or muscle damage - MI))

Front 184

Glutamate is a source of NH3 (deamination) - uses ATP (reg'd)

Glutamate and NH3 form glutamine (glutamine synthetase) - uses ATP (reg'd)

__________ releases NH3

Back 184

Glutaminase;

Glutamine = Most abundant free amino acid in blood (Transports “ammonia” among organs, buffer moderates hyperammonemia)

Front 185

Deficiencies in the conversion of amino groups to urea result in elevated ammonia levels, or __________.

Back 185

hyperammonemia;

elevated glutamine is a marker of this, its amino is also imp. in synthetic rxns

Front 186

After amino group removal via transamination or deamination, the carboxylic acid (2-ketoacid usually) makes stuff to be converted to glucose via __________.

Back 186

gluconeogenesis; (glucogenic)

substrates for gluconeo = pyruvate and TCA intermediate (2-keto, succinate, fumarate, OAA)

ketogenic (acetyl CoA not convertable to glucose, in liver if acetyl CoA made faster than it is oxidized you make ketones, which do energy but no glucose)

Front 187

Excess glutamine release can deplete muscle of TCA intermediates, inhibiting ____ metabolism.

Back 187

aerobic;

(amido nitrogen of glutamine - one added by synthetase is imp. source of amino group in synthetic reactions)

breakdown of aminopurines gives ammonia (adenine for muscle in exercise)

Front 188

Ammonia from glutaminase used in kidney to establish ______ balance and in liver it provides ammonia for ____ cycle.

Back 188

acid-base (urine); urea;

Front 189

5 enzymes are required to make urea

Back 189

1. Carbamylphosphate synthetase 1

2. Ornithine transcarbamylase

3. Argininosuccinate synthetase

4. Argininosuccinate lyase

5. Arginase

Liver is ONLY organ with full urea cycle.

Front 190

Urea cycle regulation

Back 190

1. Rate of urea synthesis regulated at CPS1 step

2. N-acetylglutamate is required activator

3. Urea cycle enzyme activities induced by starvation and high protein meals.

Front 191

Ammonium is generated by glutamate dehydorgenase and allosterically inhibited by ___ and ____. ADP and GDP are activators.

Back 191

ATP; GTP;

Front 192

Urea Cycle

Back 192

Front 193

Arginine in Urea Cycle

Back 193

- Only UC intermediate used in protein synthesis

- Synthesized in intestine and kidney

- Liver not involved in arginine synthesis

- Used in synthesis of creatine

- Used in synthesis of nitric oxide

- Becomes an essential aa in urea cycle defects

Front 194

All patients who are hyperammonemic have elevated levels of glutamine and alanine.

OTC deficiency has a hallmark as excreted orotic acid and ______.

AL and AS enzyme deficient patients become symptomatic when they run out of ________.

Back 194

uracil; (b/c CPS is in pyrimidine synthesis too)

arginine;

Front 195

AL deficiency leads to ASA accumulation, and is solved by giving ______.

AS deficiency is addressed by arginine, but not enough to prevent hyperammonemia. Sodium benzoate conjugates with glycine (formed by ammonia) which is excreted, but replenishing of glycine depletes ammonia.

Back 195

arginine

Front 196

CPS and OTC deficiency do not accumulate AA in blood, but arginine not helpful. Instead PAA conjugate with glutamine. Since it smells, inow we use ______.

Back 196

phenylbutyrate

Front 197

Ornithine not in diet, but can be made from arginine or glutamate and is source of proline (another non-essential).

Back 197

All enzyme defects except arginase deficiency have same symptoms!

Front 198

PKU

Back 198

Deficiency in Phe hydroxylase (uses O2 and cofactor BH4)

makes tyrosine (catecholamines, melanin, thyroxine)

no Phe transaminase (reason high levels of PhePyr indicate PKU)

pts treated with phenylacetate (UC issues) smell like PKU

Tyr becomes essential AA

need to lower Phe (low prot)

Phe hydroxylase = homotetramet (compact form with BH4, opens up with Phe)

Front 199

BH4 deficiency

Back 199

BH4 synthesized denovo from GTP

BH2 recycled to BH4 by DHPR

problem with DHPR or 3 enzymes leads to BH4 deficiency

leads to issues with Phe degradation, L-DOPA, catecholamine, serotonin precursor, NO, 5-hydroxytrp

PKU = normal biopterin

BH4 deficiency = low levels

DHPR defect = normal biopterin, but low BH4

BH4 oral therapy fix Phe levels, but not NT so need NT therapy as well

BH4 responsive PKU?

Front 200

MSUD

Back 200

Hydroxy derivatives of ketoacids corresponding to valine, isoleucine, leucine massively excreted.

All three branched chain amino acids (valine, leucine, isoleucine) share a common keto-acid decarboxylase.

Deficient in branched chain ketoacid DH --> ketoacid formed by transamination giving ketoacidosis. The AA's also build up since transamination reversible. possible hypoglycemia.

Restrictintake of 3 branched AAs and low protein with protein formula without branched chains. Dialyze in acute situation, some respond to thiamine (E1 subunit)

newborn screen test for elevated leucine

Front 201

Propionyl-CoA carboxylase deficiency leads to

Back 201

Proprionic acidemia

major symptoms are acidosis, compensated for by rapid deep breathing (Kussmaul respirations)

Proprionyl-CoA normally converted to methylmalonyl-CoA (biotin is cofactor)

Proprionyl-CoA is exclusively intracellular, when it accumulates you see metabolic effects (form methylcitrate instead of citrate, odd ketons, proprionylglycine)

Ile, Val, Thr, Met NOT elevated (unlike PKU and MSUD proprionic acidemia is not a primary amino acidopathy), may have high Gly

proprionyl-CoA = competitive substrate for acetyl-CoA which is why hyperammonemia (N-acetylglutamate interference for CPS in UC) and hypoglycemia (interference with pyr carboxylase activation by acetyl-CoA inhibiting gluconeogenesis)

Carnitine non-essential that acyl transfers (so see lot of poprionyl-carnitine in their tissues)

Some with multiple carboxylase (holocarboxylase synthetase issues = recurrent ketoacidosis and hypoglycemia) or biotinidase (remove biocytin issues = scaly skin) deficiencies resspond to large doses of biotin.

Front 202

Methylmalonic acidemia (just like prioprinic acidemia)

Back 202

lethargy, ketoacidosis, rapid repsiration, massive excretion of methylmalonic acid, lesser excretion of metabolites of proprionyl-CoA

racemase needed for D to L methylmalonyl-CoA; then methylmalonyl-CoA mutase deficiency or defect in vit B12 metabolism (coenzyme B12 and methylcobalamin (for homocytinuria) are active forms). Many with B12 issues have higher homocysteine levels.

Addition of B12 may help.

Front 203

Homocystinuria (Methionine and Cysteine Metabolism)

Back 203

THF is good, homocysteine goes round and round, you gotta make methyl groups

eye lens dislocation, abnormal blood clots, thin bones, mental retardation

classical homocystinuria = deficiency in cystathionine beta-synthase (homocysteine degraded to cysteine and 2-ketobutyrate); pts have high homocysteine and methionine and low cysteine (but cause is high homocysteine); treated with pyridoxine, or low methionine diet with betaine or folic acid? (methylate homocysteine to get methionine, pts will have high met)

with one carbon metabolism, and deficient 5,10 MTHFR you get high homocysteine with normal or low methionine (methyl group comes from 5-methyltetrahydrofolic acid); This leads to neurologic issues (seizure, mental retard) and higher CV disease. Remethylation of homocysteine requires methyl-B12 (second B12 requiring rxn in humans). B12 metabolism defect or deficiency can increase homocystein, low methionine and increase methylmalonic acid.

5,10 MTHF acid from degradation of Gly,Ser

Front 204

Hypoxanthine, xanthine and uric acid contain ____, _____, and _____ oxygens respectively and are known as oxopurines.

Back 204

one, two and three

Hypoxanthine is the initial product of de novo purine synthesis in the body.

Uric acid is the end product of purine degradation and is excreted in the urine.

Front 205

If one hydroxyl in hypoxanthine or xanthine is replaced by an amino group, the aminopurines ________ and _______ are produced.

Back 205

adenine and guanine

Front 206

Initial product of pyrimidine biosynthesis is _______.

Back 206

orotic acid (precursor of other pyrimidines, no other role)

decarboxylate orotic acid --> uracil (amino for keto substitution = cytosine; methylation of uracil = thymine)

Front 207

Hypoxemia increases the proportion of nucleotide mono and di-phosphates.

_______ are synthesized as ribonucleotide monophosphates rather than as free bases.

Back 207

Purines;

Make IMP:
1st committed step = PRPP -> phosphoribosylamine
+ PPi
(inhibited by IMP, AMP, GMP; it is irreversible since hydrolysis of 2 phosphate bonds)

Form rings using Gly, Asp, Gln, formyl-THF

Front 208

IMP --> -->AMP

Back 208

Uses GTP
Inhibited by AMP

De novo purine synthesis consumes lot of energy, so have feedback inhibition of initial two enzymes PRPP synthetase and glutamine PRPP amidotransferase.

Front 209

Guanylate is also made by a two step process:

Back 209

IMP --> XMP --> GMP

First rxn inhibited by GMP.
ATP consumed in 2nd rxn.

Front 210

The synthesis of AMP and GMP is kept in balance by _______ activation and inhibition.

Back 210

reciprocal;

If cellular levels of both nucleotides are high, IMP is degraded and excreted as uric acid instead of being used for further AMP or GMP synthesis.

Front 211

Purine base salvage

Back 211

HGPRT
- Hypoxanthine + PRPP --> IMP
- Guanine + PRPP --> GMP
(guanine/hypoxanthine from purine nt degradation)
- Deficiency = Lesch-Nyhan syndrome = Hyperuricemia, brain dysfunction (high uric acid responds to allopurinol)

APRT
- Adenine + PRPP --> AMP
(adenine from S-adenosylmethionine)

Enzymes of purine synthesis do not act on native bases. Purines are synthesized as ribonucleotides.

Front 212

Other purine reactions:

Back 212

Adenosine kinase (Adenosine + ATP --> AMP + ADP, no kinase for guanine/hypoxanthine)

Various deaminases:
AMP-->IMP
GMP-->IMP
Adenosine-->Inosine

Nucleotidases and Nucleoside phosphorylases (nt --> ns --> base)

Front 213

Guanine can be deaminated to form Xanthine.

Adenine cannot be deaminated.

It must be recycled to its nucleotide and be deaminated to form ____ before it can be excreted.

Back 213

IMP

Front 214

Synthesis of pyrimidines:

Back 214

- synthesized as bases
- nts made by adding PRPP
- from Asp (to form ring) and Gln (as carbamylphosphate from CPS2)
- Orotate is first synthesized

CAD polypeptide makes dihydroorotate

The next reactions make UMP from dihydroorotate (dihydroorotate dehydrogenase and UMP synthase)

UTP + NH3 --> CTP

CPS2 inhibited by UTP and activated by PRPP, carbamoylphosphate destined to form orotate

Front 215

dTMP is made from dUMP (thymidylate synthase; methyl from methylene-THF, THF oxidized to dihydrofolate)

Back 215

dUDP is produced by reduction of UDP by ribonucleotide reductase or by deamination of CDP (reductase uses NADPH and inhibited by dATP, balance controlled by other dNTPs)

dUMP is produced by phosphate transfer from dUDP

Front 216

_______ and _________ are not excreted as such. The pyrimidine rings are oxidized
and opened, releasing β-amino acids, CO2 and ammonia.

Back 216

Uracil and thymine

Front 217

PRPP synthesis

Back 217

PRPP synthetase
- Ribose-5-P + ATP ---> PRPP + AMP
- Inhibited by purine nucleotides
- Ex. excess synthesis-->gout
-- Allopurinol also inhibits PRPP synthetase
-- Allopurinol also inhibits phosphoribosylamine synthesis

Front 218

Methotrexate inhibits dihydrofolate reductase

Back 218

Stops thymidine synthesis (methylene THF issues) and also stops recycling of dihydryofolate reductase (makes it DNA specific drug)

decreases purine synthesis (formyl THF)

lowers methionine synthesis (methyl THF)

Front 219

Acyclovir

Back 219

Guanosine analog

Acyclovir is inactive

Acyclovir triphosphate inhibits Herpes Simplex Virus (HSV) DNA polymerase

No guanosine kinase in human, means that you can identify which cells express Herpes Simplex Virus (they will have a thymidine kinase to phosph. acyclovir)