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118 Cards in this Set

  • Front
  • Back
How are fatty acids activated for oxidation?
acyl-coA synthetases attach them to Coenzyme A (CoA-SH)
What defect causes Leigh syndrome?
no PDH --> pyruvate cannot be converted to acetyl-coA --> can't start TCA cycle

feed fatty acids as alternate source of acetyl-coA
What is the first step in fatty acid activation?
R-COO- + ATP --> R-COO-AMP + PPi

FA displaces PPi on ATP

PPi + H2O --> 2 Pi
PP hydrolysis drives rxn forward.
What is the second step in fatty acid activation?
R-COO-AMP + CoA-SH --> acyl-coA + AMP

CoA-SH displaces AMP.
How are fatty acids liberated from triacylglycerides?
LIPASE ENZYME cleaves fatty acids from glycerol backbone.
How is Lipase regulated?
Epinephrine/glucagon --> G protein cascade --> make cAMP

Lipase activated by cAMP dependent kinase (protein kinase A)
What happens to glycerol from breakdown of fats?
goes to gluconeogenesis
What happens to fatty acids from breakdown of fats?
transport thru blood with ALBUMIN

goes to liver
What are the major characteristics of most fatty acids found in the human body?
-even # of carbons (16, 18, 20)
-cis double bonds separated by -CH2-
-usually has unbranched carbon chain
What is the first step in β oxidation of fatty acids?
acyl-coA dehydrogenase (AD)

oxidize FA with FAD; make FADH2

trans double bond forms between α and β carbons

product: trans-Δ2-Enoyl-CoA
What is the second step in β oxidation of fatty acids? (What do we do with the enoyl-coA?)
enoyl-CoA hydratase (EH)

hydration of double bond --> β hydroxyl

product: 3-L-Hydroxyacyl-CoA
What is the third step in β oxidation of fatty acids?
3-L-hydroxyacyl-CoA dehydrogenase (HAD)

oxidizes 3-hydroxyl --> keto group

product: β-ketoacyl-CoA
What is the fourth step in β oxidation of fatty acids? What do we do with the β-keto acyl-coA?
β-ketoacyl-CoA thiolase (KT) + CoA-SH

CoA-SH attacks β carbonyl, displaces acyl coA.

products: Acetyl-CoA + fatty acyl-coA (2 C's shorter)
18 C fatty acid name?
stearate
16 C fatty acid name?
plamitate
20 C fatty acid name?
arachidonate
What is the difference between the Δ and ω fatty acid numbering systems?
Δ counts α-carbon as C1

ω counts end carbon as C1
Numbering scheme for fatty acids?
(name) A:B ΔC

(name) A:B ωD

A = # of C's in chain
B = # of double bonds
C = location of first C in double bond, counting from α carbon
D = location of first C in double bond, counting from ω carbon
What is the first step in fatty acid elongation?
Attachment to Acyl Carrier Protein

Malonyl-CoA --> Malonyl-ACP
Why cannot one simply hydrate the double bond in a cis-unsaturated fatty acid and skip the cis --> trans isomerization step?
need L-isomer of the beta-OH FA!

Hydration of the cis form yields D-isomer
What happens in MCAD deficiency?
no Medium Chain Acyl-CoA Dehydrogenase --> cannot generate trans β-γ alkene
Where are the FA oxidation enzymes located?
mitochondrial matrix
Where are the FA synthesis enzymes located?
cytosol/in mitochondria outside matrix
How many ATP produced per acyl coA cleaved from a FA?
1 FADH2 --> 1.5 ATP
1 NADH --> 2.5 ATP
1 Acetyl-CoA --> 10 ATP in TCA

total 14 - 2 for activation of whole FA = 12
Where does ketogenesis take place?
LIVER ONLY.
Why can't the liver utilize the ketone bodies it produces?
lacks CoA transferase enzyme:

acetoacetate + succinyl-coA --X--> AA-coA + succinate
What is the energy "cost" for utilizing acetoacetate in tissues except liver?
acetoacetate + succ.-coA --> AA-coA + succinate

bypasses GTP producing step of TCA cycle! "costs" a GTP.
Why can the liver carry out ketogenesis efficiently under starvation conditions? Why doesn't TCA cycle just eat up all the acetyl-coA from fatty acid degradation like it does in other tissues?
gluconeogenesis is also occurring --> oxaloacetate is being siponed off for use in GNG!

no OAA --> acetyl-coA cannot enter TCA cycle

accumulate acetyl-coA --> combine to make KB's
What is the efficiency of FA oxidation?
~33%
What controls the rate of acetoacetate to hydroxybutyrate in the last step of ketogenesis?
availability of NADH from FA oxidation!
What is the first step in ketogenesis?
THIOLASE

2 Acetyl-CoA --> acetoacetyl-CoA + CoA-SH
What is the second step in ketogenesis?
HMG CoA SYNTHETASE

Acetoacetyl-CoA + Acetyl-coA --> HMG-CoA + CoA-SH

incoming Acetyl-CoA attacks γ-keto group
What is the third step in ketogenesis? (what do we do with HMG coA?)
HMG CoA LYASE

HMG-CoA --> Acetoacetate + Acetyl-CoA

γ-OH on HMG-CoA collapses into keto group, ejects Acetyl-CoA
What are the two fates of acetoacetate ofter it is formed?
1. reduction by D-β-OH butyrate DeHase:
acetoacetate + NADH --> D-3-β-OH butyrate + NAD+

2. decarboxylation to acetone by Acetoacetate Decarboxylase:
Acetoacetate --> acetone + CO2
How do tissues other than the liver utilize ketone bodies?
convert back to Acetyl-CoA and run TCA cycle.

Acetoac + Succinyl-coA --> succinate + acetoacetyl coA

aa-CoA + CoA-SH --> 2 acetyl-coA
What is the first step in FA biosynthesis?
Acetyl-CoA Carboxylase (ACC)

2 step formation of malonyl-coA:

Biotin-ACC + HCO3- + ATP --> ACC-Biotin-COO- + ADP + Pi

ACC-Biotin-COO- + Acetyl-coA --> malonyl-coA + ACC-Biotin
What is the second step in FA biosynthesis?
Transacylase

attachment of malonate to ACP

malonyl-CoA + ACP-SH --> malonyl-ACP + CoA-SH

rxn ΔG ~ 0
What is the third step in FA biosynthesis? (after malonyl grp is attached to ACP)
KS

decarboxylation/condensation with Acetyl-CoA

malonyl-ACP + Acetyl-CoA --> Acetoacetyl-ACP + CO2 + CoA-SH
What is the fourth step in FA biosynthesis? (after acetoacetate gets attached to ACP)
β-ketoacetyl-ACP reductase (KR)

Reduction with NADPH

Acetoacetyl-ACP + NADPH --> D-3-OH butyryl-ACP + NADP+
What is the fifth step in FA biosynthesis? (after reduction of keto group)
β-OHacyl-ACP dehydrase (DH)

Dehydration to trans alkene

D-3-OH butyryl-ACP --> a/b-alkenyl-ACP + H2O
What is the sixth step in FA biosynthesis? (after alkene formation)
enoyl-ACP reducase (ER)

Hydrogenation of double bond

a/β-alkenyl-ACP + NADPH --> alkyl-ACP + NADP+
Describe the cycle of FA elongation.
ACP's acyl tail transferred back to enzyme
gets stolen by a NEW malonyl-ACP.
new C2 units added to point of attachment to ACP, not at end of tail.
What promotes activation of ACC (acetyl-coA carboxylase)?
-citrate (plentiful after a meal; carries acetyl-coA from matrix to cytosol)
-polymerization of ACC into active filamentous form
-dephosphorylation of enzyme by phosphatase 2
What promotes deactivation of ACC (acetyl-coA carboxylase)?
-AMP-dependent kinase (phosphorylates ser 79)
-AMP levels
-high palmitate levels (end product feedback)
oleate
18:1 Δ9
linoleate
18:2 Δ9, Δ12
linolenate
18:3 Δ9, Δ12, Δ15
palmitoleate
16:1 Δ9
arachidonate
20:4 Δ5, Δ8, Δ11, Δ14
What is the difference between synthesis of neutral and negative phospholipids?
neutral: activate polar head group with CTP for attachment to diacylglycerol

negative: activate phosphatidate with CTP (1,2-diacyl glycerol-3-phosphate)
What provides the glycerol for triacylglycerol backbones?
DHAP from glycolysis + NADH --> glycerol-3-P ---> glycerol + Pi

to make phosphatidate:
glycerol + ATP --> glycerol-3-P + ADP
What reaction in gluconeogenesis is the major drain on the cell's supply of oxaloacetate?
PEP Carboxykinase

Oxaloacetate + GTP --> PEP + CO2 + GDP
What enables ACC2 to make malonyl coA that suppressess CAT I (when ACC1 makes the same thing that doesn't repress)?
ACC2 has homing peptide that targets it to CAT I complex

--> makes malonyl coA very close to CAT I

ACC1 floating free in cytosol so its malonyl coA doesn't repress CAT I
What is the function of ACC?
carries out carboxylation of acetyl coA to malonyl coA with CO2-biotin-ACC.
What is the significance of phosphopantetheine?
It is the prosthetic group on ACP to which malonate is attached.
Which enzymes involved in fatty acid synthesis use biotin as a cofactor?
Acetyl-coA Carboxylase (makes malonyl-coA)
What is the tricarboxylate transport system?
method for getting Acetyl-coA from FA oxidation out of mito. matrix into cytosol.

pyruvate --> OAA (pyruvate carboxylase)
OAA + acetyl-coA --> citrate
citrate --> acetyl-coA + OAA
OAA --> pyruvate
What two processes in the cell utilize pyruvate carboxylase?
PC-biotin-CO2 + pyruvate --> oxaloacetate

1. gluconeogenesis
2. tricarboxylate transport of acetyl-coA
What is the first committed step of fatty acid synthesis?
Formation of malonyl coA by Acetyl-CoA Carboxylase.
Why can't humans synthesize ω-3 fatty acids?
We can't make <ω-7 FA's because desaturase can only reach C9 of palmitate.
How is arachidonate converted into prostaglandins?
cyclooxygenase (COX) adds heterocyclic bridge to molecule.
Why are nonspecific COX inhibitors likely to cause gastrointestinal upset?
They inhibit COX-1 which is necessary for maintaining organ homeostasis.

COX-2 is the one that makes prostaglandins that cause inflammation.
What is the mechanism of aspirin (acetylsalicylic acid) on COX enxymes?
acylates ser on cyclooxygenase --> deactivate
What is the mechanism of ibuprofen on COX enzymes?
substrate analog --> competitive inhibition
What is the difference between an oxidase and an oxygenase?
oxidase: does not incorporate O into product; O is just e- acceptor

oxygenase: O incorporated into product.
What is the major source of arachidonate for prostaglandin synthesis?
often hydrolyzed from C2 of phospholipids.
How do phospholipids function as precursors to second messengers in cell signaling pathways?
cleavage of head group from phospholipid by phospholipase C

produces diacylglycerol (Protein Kinase C) + head group (can mediate other processes--ex. inositol/ion channels)
What is the importance of phospholipids as detergents/surfactants?
keep surfaces slippery

prevent alveolar lung collapse or adhesion of other cavity walls to one another
What is the difference between synthesis of a neutral vs. negatively charged phospholipid?
neutral: activate head group w/CDP

negative: activate backbone (phosphatidate) w/CDP
What is the cofactor of ACC?
biotin
What is the cofactor of 3-ketosphinganine synthase?
PLP

pyridoxal phosphate
How are triacylglycerols synthesized (summary)?
-attach FA's 1 and 2 to glycerol-3-P
-dephosphorylate
-attach FA #3.
What does inositol 1,4,5 triphosphate regulate?
Ca2+ channels
What is the net charge on phosphatidylcholine?
neutral
What are the steps in activating head groups or phosphatidates during the last steps of phospholipid biosynthesis?
1. X + ATP --> X-P + ADP
2. X-AMP + CTP --> X-CDP + PPi

phosphorylate then attach CMP
Where do phospholipase A1 and A2 cut?
cleave FA esters from C1 and C2 on phospholipid
Where does phospholipase C cut?
cleaves phosphoryl head group --> generate DIACYLGLYCEROL
Where does phospholipase D cut?
cleaves just the head group --> generates PHOSPHATIDATE.

differs from PLC b/c it leaves phosphate on
Step 1 in synthesis of sphingosine?
ser + palmitoyl-coA --> dehydrosphingernine + CO2

enzyme has PLP cofactor
ser's α-C displaces coA-SH
Step 2 in synthesis of sphingosine?
deydrophingernine + NADPH --> dihydrosphingosine

reduce keto grp --> -OH
Step 3 in synthesis of sphingosine?
dihydrosphingosine + FAD+ --> SPHINGOSINE + FADH2

oxidize to alkene between what were the α&β carbons of palmitoyl-coA
How do you make ceramide?
attach acetylcoA to amino group of sphingosine.
How do you make sphingomyelin?
attach choline-CMP to terminal -OH of ceramide
How do you make a cerebroside?
attach sugar-UDP to terminal -OH of ceramide.
How do you make a glycosphingolipid?
attach an oligosaccharide to terminal -OH of ceramide.
What is the major function of gangliosides?
have n-acetyl-neuraminic (sialic) acid in their oligosaccharide chains

function as cell antigens: ceramide embedded in membrane, oligo waving in the breeze like a name tag/cell ID marker
Where are sphingolipids degraded?
lysozomes
What is special about lysozomal enzymes?
only function at low pH.

lysozome pumps H+ into itself to maintain optimal pH

prevents enzymes from eating cell if lysozome accidentally bursts.
What is the function of hexosaminidase A?
degrades ganglioside GM2 --> ganglioside GM3
What is the defect in Tay Sachs disease?
sphingolipidosis

no hexosaminidase A --> GM2 and GM3 accumulate in neurons, which swell

death by 4 y/o :(
What is the building block of cholesterol?
acetyl coA
What is the function of cholesterol in cell membranes?
regulate membrane fluidity with temperature fluctuations
How do we get cholesterol?
liver makes it in cytoplasm under well-fed conditions.

intestines absorb dietary cholesterol.
What is the difference between cytoplasmic and mitochondrial HMG-CoA?
cytoplasmic is made as choesterol precursor out of extra acetyl coA.

mitochondrial one made under starvation conditions with xs acetylcoA from FA oxidation.
What enzyme catalyzes the first committed step in cholesterol synthesis?
HMG-coA Reductase

uses NADPH to reduce HMG-coA to mevalonate.
What happens to mevalonate during cholesterol synthesis?
ATP used to add PP: yields 5-pyrophospho-mevalonate.
What happens to 5-pyrophosphomevalonate?
ATP-mediated decarboxylation to isopentenyl pyrophosphate.
What happens to isopentenyl pyrophosphate?
polymerize to geranyl-PP

geranyl-PP + isopentenyl-PP --> farnesyl-PP

2x farnesyl-PP --> SQUALENE
What general changes are made to convert squalene to cholesterol?
-cyclization
-double bond migration
-formation of epoxide that is later reduced to hydroxide
-some double bonds get reduced
-3 methyl groups removed
How are cholesterol + other lipids transported in the blood?
lipoproteins

"oil droplet" of TAG's and cholesterol esters

enclosed by phospholipid monolayer membrane with apoproteins and unesterified cholesterol in it.
What is the function of apoproteins?
interact with lipoprotein lipases on adipocyte surfaces.

Lipoprotein lipase tethered to surface by oligosaccharide chain, lyses lipoprotein, liberates FA's from TAG's and takes them into the cell.
What happens to empty chylomicrons?
endocytosed by liver cells for degradation.
How is cholesterol transported from the lipoprotein membrane into the interior of the droplet?
Lecithin Cholesterol Acyl Transferase (LCAT):

esterifies FA on C2 of lecithin (phos. choline) to -OH on cholesterol to increase hydrophobicity
How is cholesterol converted in an inert form for storage in the cell?
Acyl-coA Cholesterol Acyl Transferase (ACAT):

esterifies palmitoleoyl-coA or oleyl-coA to cholesterol.
How does the liver export cholesterol it makes to other parts of the body?
VLDL particles

Very Low Density Lipoproteins

28-70 nm diameter
How do intestinal cells transport dietary cholesterol to other parts of the body?
chylomicrons

80-500 nm diameter
How is blood [cholesterol] regulated?
-cells take up cholesterol for their own use (membrane, steroids)
-endothelial surface of cell has clathrin coated pit with LDL receptors that trigger endocytosis of LDLs.
How is cholesterol synthesis regulated by SREBP?
HMG-coA reductase = major control pt

low cholesterol --> transcriptional activation by Sterol Regulating Element Binding Protein (SREBP)

high cholesterol --> SREBP prevented from reaching nucleus (no transcriptional activation)
How is cholesterol synthesis regulated aside from SREBP?
HMG-coA reductase = major control pt

high [cholesterol]/derivatives: destabilize HR

AMP-dependent kinase: phosphorylate HR to turn off during low energy state

-regulate # of membrane LDL receptors to modulate cholesterol levels in cell
How are atherosclerotic plaques formed?
monocytes enter lesions in arteries and become macrophages that scavenge LDL's

macrophages accumulate cholesterol and become foam cells --> plaque.
What is another name for ceramide?
N-Acyl sphingosine.
VLDL's
-Liver packages TAG's it makes in VLDL's
-Carries TAG's to other parts of body
-covered in apo C-II (trigger Lipoprotein Lipase on adipocyte)
-becomes LDL after TAG's removed
What happens to excess cholesterol in the body?
-forms atherosclerotic plaques
-ideally, packaged into HDL's, sent to liver, & converted to bile salts for excretion
LDL's
-more cholesterol rich (40% by weight) than VLDL
-covered in apoprotein B-100
-cholesterol transporter
HDL's
-scavenge cholesterol from LDL, chylomicron remnants, dying cells
-esterify cholesterol and transfer to core of particle using LCAT
-transport xs cholesterol back to liver for excretion via bile salts.
Where do HDL's come from?
made by liver
How is cholesterol taken up by cells?
-Apo B-100 on LDL encounters clathrin coated pit --> binds LDL TM receptor
-cell does LDL endocytosis
-LDL degraded in lysosome to liberate cholesterol.
Chylomicrons
-intestinal cells package dietary fats, cholesterol in chylomicrons
-covered in apoprotein C-II
-encounters LPL on adipocyte surface, TAG's get hydrolyzed and taken up by cell