Ch. 16 Flashcards
(82 cards)
1
Q
What purposes do fatty acid oxidation and fatty acid synthesis serve in animals?
A
- Fatty acid oxidation: provides energy to cells when glucose levels are low
- Fatty acid synthesis: liver and adipose tissue convert excess acetyl-CoA into fatty acids that can be stored or exported as TAGs
2
Q
What are the net reactions of fatty acid degradation and synthesis for the typical C16 fatty acid palmitate?
A
- Fatty acid oxidation
Palmitate + 7 NAD+ + 7 FAD + 8 CoA + 7 H2O + ATP –> 8 Acetyl-CoA + 7 NADH + 7 FADH2 + AMP + 2 Pi + 7 H+
- Fatty acid synthesis
8 Acetyl-CoA + 7ATP + 14 NADPH + 14 H+ –> Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O
3
Q
What are the key enzymes in fatty acid metabolism?
A
- Fatty acyl-CoA synthetase
- Carnitine acyltransferase I (CAT1)
- Acetyl-CoA carboxylase
- Fatty acid synthase
4
Q
What are examples of fatty acid metabolism in everyday biochemistry?
A
Kangaroo rat and camel: survive in deserts for long periods of time without drinking water
5
Q
What is fatty acyl-CoA synthetase?
A
Set of 3 enzymes responsible for formation of fatty acyl-CoA molecules
- Catalyzes priming reaction
6
Q
What is carnitine acyltransferase I (CAT1)?
A
Mitochondrial outer membrane enzyme that converts fatty acyl-CoA to fatty acyl-carnitine for transport into mitochondria
7
Q
What is acetyl-CoA carboxylase?
A
Cytosolic enzyme that carboxylates acetyl-CoA
- 1st step in fatty acid synthesis (commitment step)
8
Q
What is fatty acid synthase?
A
Multi-functional protein (euks) or multienzyme complex (proks) that’s responsible for synthesis of fatty acids like palmitate
9
Q
Where does fatty acid β-oxidation occur?
A
Mitochondria
10
Q
What are the steps of the formation of fatty acyl-CoA?
A
- Fatty acyl-CoA synthetase catalyzes the adenylation of a fatty acid to form fatty acyl-adenylate (enzyme-bound
intermediate) - Fatty acyl-adenylate is attacked by the thiol group of CoA, forming the thiolester fatty acyl-CoA product and releasing AMP
11
Q
What are the 2 possible fates of fatty acyl-CoA? (hint: has to do with energy charge)
A
- Low energy charge: fatty acid degradation is favored
- High energy charge: fatty acid synthesis is favored
12
Q
What is the carnitine transport cycle?
A
3-step process that translocates fatty acids across the inner mitochondrial membrane
13
Q
What is this?
A
Carnitine
14
Q
What are the steps of the carnitine transport cycle?
A
-
CAT1 replaces CoA with carnitine to form palmitoylcarnitine
- Inhibited by malonyl-CoA when fatty acid synthesis is favored - Carnitine-acetylcarnitine translocase exchanges palmitoylcarnitine for carnitine
- Conversion of palmitoylcarnitine back to palmitoyl-CoA
- Catalyzed by CAT2
15
Q
What are the 2 important functions of the carnitine transport cycle in regulating cell metabolism?
A
- Provides mechanism to control flux of fatty acids into degradation or TAG/membrane lipid synthesis
- Maintains separate pools of CoA (cytosolic and mitochondrial)
16
Q
What is the β-oxidation pathway?
A
Fatty acid oxidation pathway that removes 2-carbon units from a fatty acid chain
- Produces FADH2, NADH, and acetyl-CoA
17
Q
What is hypoglycin A?
A
Amino acid derivative found in high concentrations in unripe ackee fruit
- Inhibitor of liver mitochondrial acyl-CoA dehydrogenases
- Jamaican vomiting sickness
18
Q
What is the net reaction of the β-oxidation pathway?
A
Palmitoyl-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O –> 8 Acetyl-CoA + 7 FADH2 + 7 NADH + AMP + 2 Pi + 7 H+
19
Q
What are the steps of electron transfer in β-oxidation?
A
- Acyl-CoA dehydrogenase donates electrons from the first fatty acid oxidation reaction to enzyme-bound FAD in ETF
- Electron pair is passed to Fe-S center in ETF-Q oxidoreductase
- Electron pair is passed from Fe-S center to coenzyme Q
20
Q
What are the auxiliary pathways for fatty acid oxidation?
Note: β-oxidation usually uses even-numbered and fully saturated fatty acids
A
- Degradation of monounsaturated fatty acids (ex. oleoyl-CoA)
- Degradation of unsaturated fatty acids (ex. cis-Δ9, cis-Δ12-linoleoyl-CoA
21
Q
What is ketogenesis? Where does it occur?
A
- Conversion of excess acetyl-CoA into ketone bodies
- Liver cell mitochondria
22
Q
List ketone bodies.
A
Acetoacetate and D-β-hydroxybutyrate
23
Q
What are the steps of ketogenesis?
A
- β-ketoacyl-CoA thiolase condenses 2 molecules of acetyl-CoA to form acetoacyl-CoA
- HMG-CoA synthase adds another acetyl-CoA to form HMG-CoA
-
HMG-lyase converts HMG to acetoacetate
4 & 5. Acetoacetate is exported directly or converted to acetone
24
Q
What uses ketone bodies to generate acetyl-CoA?
A
- Skeletal and cardiac muscle
- During extreme starvation: brain
25
What is ketoacidosis?
Side effect of excess ketone body formation, resulting in low blood pH
26
Diagram the carbon flow from glucose to fatty acids.
1. Citrate synthase combines oxaloacetate and acetyl-CoA to form citrate, which is shuttled to the cytosol where it is cleaved by citrate lyase back into acetyl-CoA and oxaloacetate
2. Cytosolic acetyl-CoA is converted to malonyl-CoA by acetyl-CoA carboxylase
3. Liver cells: fatty acids and glycerol are combined to form TAGs, which are packed in VLDLs
27
What is citrate lyase?
Cytosolic enzyme that **cleaves the acetyl group from citrate to form acetyl-CoA and oxaloacetate**
28
Fatty acid synthesis and degradation are complementary pathways. Compare and contrast them.
Both
- Require 4-step reaction cycle
- Involve removal or addition of C2 units attached to CoA
Differences prevent futile cycling
- Different locations
- Different reductants/oxidant
- Degradation needs multiple enzymes but synthesis only needs 1 multifunctional enzyme
- Degradation uses CoA as acetyl group anchor vs. synthesis uses ACP as hydrocarbon anchor
29
What is ACP?
Protein with serine linked phosphopantetheine group that serves as the **attachment site for intermediates during fatty acid synthesis**
30
Where does fatty acid degradation occur?
Mitochondrial matrix
31
What are the oxidants for fatty acid degradation?
FAD and NAD+
32
What is the rate-limiting step for fatty acid degradation?
**Carnitine-mediated transport** into the mitochondrial matrix
33
Where does fatty acid synthesis occur?
Cytosol
34
What is the reductant for fatty acid synthesis?
NADPH
35
What is the rate-limiting step for fatty acid synthesis?
Generation of **malonyl-CoA**
36
What are the 3 activities of acetyl-CoA carboxylase?
1. Biotin carboxylase
2. Biotin carrier
3. Carboxyltransferase
37
What are the 4 conserved reactions of fatty acid synthesis?
1. Condensation
2. Reduction
3. Dehydration
4. Reduction
38
Info on mammalian fatty acid synthase
- ~2500 amino acids (~275 kDa)
- 7 protein functions encoded in a single polypeptide chain
- Dimeric protein with each monomer containing 2 functional lobes
- Upper lobe contains the 3 modifying functions (KR, DH, ER)
- Lower lobe contains the 2 condensing functions (KS, MAT)
39
What is the net reaction of fatty acid synthesis?
8 Acetyl-CoA + 7 ATP + 14 NADPH + 14 H+ --> Palmitate + 8 CoA
40
Where do the enzymes that elongate palmitate exist?
Mitochondria and as membrane components of the ER
41
What are mixed-function oxidases?
Group of desaturating enzymes that **convert fatty acyl-CoA into longer fatty acids**
- Membrane-bound ER proteins that use molecular oxygen (O2) as oxidant
42
What is the citrate shuttle?
Mechanism for **transporting acetyl-CoA groups (via citrate) from mitochondria to cytosol**
- Provides mechanism to stimulate fatty acid synthesis in the cytosol when acetyl-CoA accumulates in the mitochondria (buildup occurs when glucose levels are high and the citrate cycle is feedback-inhibited by high energy charge in cell)
43
What is the primary control point of fatty acid synthesis?
Modulation of **acetyl-CoA carboxylase** activity
44
In what form is acetyl-CoA carboxylase active?
Hompolymer
45
What activates acetyl-CoA carboxylase?
Citrate
46
What inactivates acetyl-CoA carboxylase?
Palmitoyl-CoA
47
How is fatty acid synthesis hormonally controlled?
Shifts equilibrium between polymeric and monomeric forms as a function of **phosphorylation state**
- Phosphorylated by glucagon: monomeric (inactive)
- Dephosphorylated by insulin: polymeric (active)
48
What is AMPK?
AMP-sensitive regulatory protein that functions as a **key regulator of numerous metabolic pathways, including fatty acid synthesis**
49
What is AMPK activated by?
Lower energy charge (high AMP)
50
What regulates AMPK activity?
**AMP-binding** (induces conformational change, facilitating its phosphorylation at a regulatory threonine residue)
51
How are fatty acid synthesis and degradation allosterically controlled by metabolites?
1. Feedback inhibition of the citrate cycle under high energy charge leads to citrate export to cytosol, where it stimulates activation of acetyl-CoA carboxylase (**citrate in cytosol promotes synthesis**)
2. High levels of malonyl-CoA inhibit CAT1, which prevent mitochondrial import and degradation of fatty acyl-CoA molecules at the same time that fatty acid synthesis is favored (**malonyl-CoA inhibits degradation**)
3. High levels of faty acyl-CoA inhibit acetyl-CoA carboxylase by fatty acyl-CoA binding (**fatty acyl-CoA inhibits synthesis**)
52
What is LDL?
Class of cholesterol-transporting molecules that moves cholesterol from liver through blood to
peripheral tissue
53
What is cholesterol synthesized from?
Acetyl-CoA
54
Is cholesterol an essential lipid?
No, because of de novo synthesis
55
What is Stage 1 of cholesterol biosynthesis?
Generation of mevalonate from acetyl-CoA
56
What is Stage 2 of cholesterol biosynthesis?
Conversion of mevalonate to isopentanyl pyrophosphate dimethylallyl
pyrophosphate
57
What is Stage 3 of cholesterol biosynthesis?
Formation of squalene from 4 isopentanyl pyrophosphates & 2 dimethylallyl
pyrophosphates
58
What is Stage 4 of cholesterol biosynthesis?
Cyclization of squalene & lanosterol modification to form cholesterol
59
What is mevalonate?
Intermediate in cholesterol biosynthesis, formed by the condensation of 3 acetyl-CoA molecules
60
What is HMG-CoA reductase?
Enzyme responsible for formation of mevalonate from
acetyl-CoA
61
What are the 3 steps of Stage 1 of cholesterol biosynthesis?
1. 2 acetyl-CoA condensed to form acetoacetyl-CoA
2. 3rd acetyl-CoA added to form HMG-CoA
3. Rate-limiting step: HMG-CoA reductase converts
HMG-CoA to mevalonate in reduction reaction that
uses 2 NADPH releases CoA
62
What are the 3 primary functions of cholesterol?
If esterified...
- Stored in intracellular lipid droplets
- Packaged into lipoproteins and exported into circulatory system
- Secreted into small intestine or bile duct during digestion
63
What is cholate?
Major bile acid formed in liver by conversion of cholesterol
64
What are the major classes of lipoproteins?
- Chylomicrons
- VLDL
- IDL
- LDL
- HDL
65
All lipoproteins consist of...
- Phospholipid monolayer
- 1 or more apolipoproteins on the surface (serve as signal molecules that activate enzymes or bind to cell surface receptors)
66
What is HDL?
Class of cholesterol-transporting molecules that transport cholesterol from peripheral tissues to liver
67
What determines the steady-state levels of circulating cholesterol?
The balance of cholesterol input (diet and de novo synthesis), cholesterol recycling (returning tissue cholesterol to liver), and cholesterol output (loss of bile acids by excretion)
68
What does LDL transport cholesterol to?
From liver to peripheral tissues and arteries
69
What does HDL transport cholesterol to?
From peripheral tissues and arteries to liver
70
How do HDL particles function in reverse transport?
1. apoA-I activates lecithin-cholesterol acyltransferase
2. Lecithin-cholesterol acyltransferase esterifies cholesterol
3. HDL takes up cholesterol esters
4. HDL transports cholesterol back to liver
71
What is atherosclerosis?
Arterial blockage due to accumulation of fibrous tissue (rich in cholesterol, fat, a foam cells) in arterial walls
72
What is a myocardial infarction?
Heart attack
73
What is coronary artery bypass surgery?
Surgical procedure where veins are grafted to ther myocardium to restore blood flow to regions of the heart suffering from decreased oxygen due to atherosclerosis
74
What is familial hypercholesterolemia (FH)?
Recessive genetic disorder where individuals have reduced numbers of LDL receptors, resulting in high levels of serum LDL and associated cardiovascular disease
75
What happens if a person has mutations in both copies of the LDL receptor gene?
- No LDL receptors on cell surface
- Serum LBL levels are 5x higher than normal
- Severe atherosclerosis
- Die of heart attacks or strokes in early childhood
76
What happens if a person has only 1 mutant LDL receptor gene?
- Serum LDL IeveIs are 2-3x higher than normal
- Often have 1st heart attack before 30
77
What are the biochemical processes by which LDL receptors control serum LDL levels?
- LDL binds to receptor through apoB-100 occurs at specific sites in PM (clathrin-coated
pits)
- Low cholesterol levels stimulate HMG-CoA reductase activity
78
What are statin drugs?
Class of drugs that bind to and **inhibit HMG-CoA reductase**, indirectly resulting in **decreased serum cholesterol levels and decreased risk of cardiovascular disease**
79
What is the benefit of statin-mediated inhibition of HMG-CoA reductase activity?
Indirect effect of **stimulating LDL receptor expression through activation of SREBP**
- Lowering cholesterol levels in the liver --> LDL receptor expression is stimulated, resulting in elevated LDL endocytosis and a concomitant decrease in atherosclerotic disease
80
What are sterol regulatory element binding proteins (SREBPs)?
Dimeric DNA-binding protein **that binds to SREs & regulates gene expression**
81
Flux through lipid metabolism is regulated based on what 3 cellular demands?
1. Changing **energy needs** of the cell
2. Requirement for **membrane components** in rapidly dividing cells
3. Need to **synthesize cholesterol derivatives**
82
How are precursor SREBPs activated?
