Lipid Biosynthesis Flashcards
(81 cards)
1
Q
biosynthesis requires
A
malonyl-CoA
2
Q
breakdown of lipids occurs in: Biosynthesis occurs in:
A
mitochondria cytosol
3
Q
catalyzes the irreversible formation of malonyl-CoA from acetyl-CoA
Where does this reaction occur?
Contains what group?
A
acetyl-CoA carboxylase
reaction occurs in the cytoplasm
contains a biotin prosthetic group covalently bound in amide linkage to the ε-amino group of a Lys residue
acetyl-CoA + CO2 + ATP → malonyl-CoA + ADP + Pi
4
Q
catalyzes assembly of long carbon chains of fatty acids in the cytosol through a repeating four-step sequence
Begins with:
Elongation:
A
fatty acid synthase
begins with malonyl-CoA and acetyl-CoA
each sequence elongates chain by two carbons
5
Q
Fatty Acid Synthesis
A
6
Q
The Cofactor and Activating Groups in Fatty Acid Breakdown and Biosynthesis
- In β oxidation:
- in fatty acid synthesis:
A
- in β oxidation:
- NAD and FAD serve as electron acceptors
- the activating group is the thiol (–SH) group of coenzyme A
- in fatty acid synthesis:
- the reducing agent is NADPH
- the activating groups are two different enzyme-bound –SH groups
7
Q
Fatty acid synthase I (FAS I) found in mammals
A
- seven active sites are in separate domains within a single multifunctional polypeptide chain
- two polypeptide chains function independently, but as a homodimer
- forms a single product
8
Q
= shuttles the acyl group from one active site to another in sequence
is covalently linked to the acyl group
is part of the single FAS I polypeptide
A
acyl carrier protein (ACP)
9
Q
The Overall Process of Palmitate Synthesis
carbons C-16 and C-15 of the palmitate are derived from the methyl and carboxyl carbon atoms, respectively, of an acetyl-CoA used to prime the system at the outset
A
10
Q
The Mammalian Fatty Acid Synthase Has Multiple Active Sites
the intermediates remain covalently attached as thioesters to one of two thiol groups:
A
- the —SH group of a Cys residue in β-ketoacyl-ACP synthase
- the —SH group of acyl carrier protein
11
Q
Fatty acid synthase receives the _______ and ________ groups
A
acetyl and malonyl group
12
Q
catalyzes two reactions:
the transfer of the acetyl group of acetyl-CoA to ACP (which is then transferred to β-ketoacyl-ACP synthase (KS))
the transfer of the malonyl group from malonyl-CoA to the —SH group of ACP
A
malonyl/acetyl-CoA–ACP transferase (MAT) domain
13
Q
The fatty acid synthase reactions are repeated to form ______
Production of _______ marks completion of one pass through the fatty acid synthase complex
A
Palmitate
butyryl-ACP
14
Q
hydrolyzes the thioester linkage between palmitate and ACP to release free palmitate
A
thioesterase (TE)
15
Q
The Overall Reaction for the Synthesis of Palmitate
A
8 acetyl-CoA + 7ATP + 14NADPH + 14H+ →
palmitate + 8CoA + 7ADP + 7Pi + 14NADP+ + 6H2O
16
Q
biosynthesis of fatty acids requires:
A
- acetyl-CoA
- ATP to make malonyl-CoA
- the reducing power of NADPH to reduce
- the β-keto group
- the double bond
17
Q
fatty acid synthesis occurs in the
A
cytosol
18
Q
catalyzes the reversible formation of pyruvate and CO2 from malate
A
malic enzyme
19
Q
the energy cost per acetyl-CoA transported into the cytosol
A
2 ATP
20
Q
Shuttle for Transfer of Acetyl Groups from Mitochondria to the Cytosol
A
21
Q
= transports malate into the matrix where it is reoxidized to oxaloacetate by malate dehydrogenase
A
malate-α-ketoglutarate transporter
22
Q
transports pyruvate into the matrix where it is converted to oxaloacetate by pyruvate carboxylase or oxidized to acetyl CoA
A
pyruvate transporter
23
Q
Fatty Acid Biosynthesis Is
Tightly Regulated
A
excess metabolic fuel is generally converted to fatty acids and stored as lipids, such as triacylglycerols
the reaction catalyzed by acetyl-CoA carboxylase is the rate-limiting step in the biosynthesis of fatty acids
24
Q
A
25
Regulation of Acetyl-CoA Carboxylase By Covalent Modification
## Footnote
phosphorylation inactivates the enzyme
* triggered by the hormones glucagon and epinephrine or by high [AMP]
* reduces sensitivity of citrate activation and slows fatty acid synthesis
* causes polymerization of ACC into long, inactive filaments
26
Pathways are also regulated at the level of
gene expression
27
fatty acid synthesis and β oxidation do/do not occur simultaneously
do not
## Footnote
during fatty acid synthesis, malonyl-CoA inhibits fatty acid import into the mitochondria
shuts down β oxidation
28
catalyzes an oxidative reaction that introduces a double bond into a fatty acid chain
is a mixed function oxidase
requires:
fatty acyl-CoA desaturase
NADPH, cytochrome b5, and cytochrome b5 reductase
29
humans cannot desaturate beyond:
plants can, to produce:
Delta 9
* linoleate 18:2(D9,12) :ω-6 fatty acid
* a-linolenate 18:3 (D9,12,15) :ω-3 fatty acid
30
linoleate may be converted to:
* γ-linolenate
* eicosatrienoate
* arachidonate (eicosatetraenoate)
31
α-linolenate may be converted to:
* eicosatetraenoic acid (EPA)
* docosahexaenoic acid (DHA)
32
must be obtained from dietary plant material
## Footnote
linoleate and α-linolenate for mammals
essential fatty acids
33
lengthen palmitate to form long saturated fatty acids
Where is it present?
What is the most common product?
fatty acid elongation systems
Present in smooth ER and mitochondria
Stearate (18:0) is the most common product
34
Eicosanoids Are Formed from
from 20- and 22-Carbon Polyunsaturated Fatty Acids
35
eicosanoid hormones
prostaglandins,
leukotrienes, and
thromboxanes
36
Prostaglandin synthesizing enzymes convert ________ to prostaglandins
cyclooxygenase (COX) =
arachidonate
prostaglandin H2 synthase
catalyzes the formation of prostaglandin H2 (PGH2)
37
Cyclooxygenase (COX) Reaction
38
Prostaglandin H2 Synthase Has
Two Isoforms
* COX-1 = catalyzes synthesis of prostaglandins that regulate gastric mucin secretion
* COX-2 = catalyzes synthesis of prostaglandins that mediate pain, inflammation, and fever
39
irreversibly inactivates the cyclooxygenase activity of both COX isozymes
acetylates a Ser residue and blocks the enzyme’s active site
inhibits the synthesis of prostaglandins and thromboxanes
aspirin
NSAIDs
40
converts PGH2 to thromboxane A2,
thromboxane A2 is precursor to other series 2 thromboxanes
present in blood platelets (thrombocytes)
thromboxane synthase
41
linear eicosanoids
leukotrienes
42
fatty acids synthesized or ingested have one of two fates
## Footnote
both pathways begin with the formation of fatty acyl esters of glycerol
* incorporation into triacylglycerols for the storage of metabolic energy
* incorporation into the phospholipid components of membranes
43
triacylglycerols and glycerophospholipids share two precursors:
* fatty acyl–CoA
* L-glycerol 3-phosphate
44
Glycerol 3-Phosphate Is Formed from
## Footnote
glycerol 3-phosphate dehydrogenase:
glycerol kinase:
DHAP and glycerol
## Footnote
**glycerol 3-phosphate dehydrogenase**
catalyzes the formation of glycerol 3-phosphate from dihydroxyacetone phosphate (DHAP)
cytosolic NAD-linked enzyme
**glycerol kinase**
catalyzes the formation of small amounts of glycerol 3-phosphate from glycerol
in liver and kidney
45
Fatty Acyl-CoAs are formed from :
acyl-CoA synthetases:
Free fatty acids
* catalyzes the formation of fatty acyl-CoAs from free fatty acids
* the same enzymes responsible for the activation of fatty acids for β oxidation
46
Formation of Phosphatidic Acid
47
Formation of Triacylglycerol and glycerophospholipids from Phosphatidic Acid
48
Triacylglycerol biosynthesis in animals is regulated by
hormones
49
people with severe diaetes mellitus fail to
synthesize fatty acids
50
Assembly of phospholipids occurs primarily:
on the surfaces of the smooth ER and the inner mitochondrial membrane in eukaryotic cells
51
Attaching the Phospholipid Head Group requires activation by
cytidine diphosphate (CDP) nucleotide
52
Strategies for Forming the Phosphodiester Bond
* strategy 1
* CDP is attached to diacylglycerol, forming the activated phosphatidic acid **CDP-diacylglycerol**
* strategy 2
* CDP is attached to the hydroxyl of the head group
(ie activated polar headgroup)
53
Phospholipids remodel via the __________ facilited by lysophosphatidyl-choline acyltransferases (LPCATs)
Lands cycle
54
Contains characteristic double bond
Plasmalogens
along with platelet-activating factor both use similar synthetic pathways
55
four stages of sphingolipid biosynthesis:
1. synthesis of the 18-carbon amine sphinganine from palmitoyl-CoA and serine
2. attachment of a fatty acid in amide linkage to yield N-acylsphinganine
3. desaturation of the sphinganine moiety to form N-acylsphingosine (ceramide)
4. attachment of a head group to produce a sphingolipid such as a cerebroside or sphingomyelin
56
Glycolipids
* cerebrosides
* globosides
* the head-group sugar is attached directly to the C-1 hydroxyl of sphingosine in glycosidic linkage
* the sugar donor is a UDP-sugar
* gangliosides
* Contains sialic acid residue in the polar head group
* Sialic acid donor is CMP-sialic acid
57
Biosynthesis of Sphingolipids
58
Cholesterol Is Made from Acetyl-CoA in Four Stages:
1. condensation of three acetate units to form mevalonate
2. conversion of mevalonate to activated isoprene units
3. polymerization of six isoprene units to form the 30-carbon linear squalene
4. cyclization of squalene to form the four rings of the steroid nucleus
59
Stage 1: Synthesis of Mevalonate from Acetate
**Formation of acetylacetyl CoA**
* acetyl-CoA acetyl transferase = catalyzes the condensation of two acetyl-CoA molecules
**Formation of β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)**
* HMG-CoA synthase = catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)
**Formation of mevalonate**
* HMG-CoA reductase = an integral membrane protein of the smooth ER that catalyzes the reduction of HMG-CoA to mevalonate
* the major point of regulation on the pathway to cholesterol
* catalyzes the committed step
* requires 2 molecules of NADPH
60
Stage 2: Conversion of Mevalonate to Two Activated Isoprenes
**Phosphorylation of mevalonate**
* three phosphate groups are transferred from three ATP molecules to mevalonate to form 3-phospho-5- pyrophosphomevalonate
**Formation of ∆3-isopentenyl pyrophosphate**
* CO2 and Pi leave to produce a double bond in ∆3-isopentenyl pyrophosphate
* the first activated isoprene
**Formation of dimethylallyl pyrophosphate**
* isomerization of ∆3-isopentenyl pyrophosphate yields dimethylallyl pyrophosphate
* the second activated isoprene
61
**Stage 3: Condensation of Six Activated Isoprene Units to Form Squalene**
* the two activated isoprenes undergo head-to-tail condensation to form geranyl pyrophosphate
* geranyl pyrophosphate undergoes head-to-tail condensation with isopentenyl pyrophosphate to form farnesyl pyrophosphate
* two molecules of farnesyl pyrophosphate join head-to-head to form squalene
62
Stage 4: Conversion of Squalene to the Four-Ring Steroid Nucleus (1 of 2)
**Formation of squalene 2,3-epoxide**
* squalene monooxygenase = adds one oxygen atom from O2 to the end of the squalene chain to form squalene 2,3-epoxide
* mixed-function oxidase
* requires NADPH
**Formation of lanosterol**
* cyclization of squalene 2,3-epoxide forms lanosterol
* a series of ~20 reactions converts lanosterol to cholesterol
63
Cholesterol Synthesis and Transport Are Regulated at Several Levels
five modes of regulation:
1. covalent modification of HMG-CoA reductase
2. transcriptional regulation of HMG-CoA gene
3. proteolytic degradation of HMG-CoA reductase
4. activation of ACAT, which increases esterification for storage
5. transcriptional regulation of the LDL receptor
64
HMG-CoA Reductase is Most Active When
Dephosphorylated
* covalent modification provides short-term regulation of HMG-CoA reductase
* AMPK phosphorylates HMG-CoA to decrease its activity in response to rising AMP levels
* insulin promotes dephosphorylation (activation)
* glucagon and epinephrine promote phosphorylation (inactivation)
65
Cholesterol Has Several Fates
cholesterol is synthesized primarily in the \_\_\_\_\_\_\_
most of it is exported as:
liver
* most of it is exported as
* bile acids
* biliary cholesterol
* cholesteryl esters
* formed in the liver by acyl-CoA-cholesterol acyltransferase (ACAT)
66
plasma lipoproteins
* macromolecular complexes of:
* apolipoproteins
* phospholipids
* cholesterol
* cholesteryl esters
* triacylglycerols
67
different combinations of lipids and proteins produce particles of different densities
can be separated by
ultracentrifugation
68
the largest and least dense of the lipoproteins
contains a high proportion of triacylglycerols
chylomicrons
69
very-low-density lipoprotein (VLDL)
* lipoproteins that carry cholesteryl esters or triacylglycerols
* the liver to muscle
* the liver to adipose tissue
* apoC-II activates lipoprotein lipase to release FFAs from triacylglycerols
70
formed by triacylglycerol loss in VLDL
rich in cholesterol and cholesteryl esters
carries cholesterol to extrahepatic tissues and macrophages
low-density lipoprotein (LDL)
71
receptors in the hepatocyte plasma membrane that take up LDL not taken up by peripheral tissues and cells
LDL receptors
72
* lipoproteins that originate in the liver and small intestine as small, protein-rich particles
* contain lecithin-cholesterol acyltransferase (LCAT) to catalyze the formation of cholesteryl esters
* mediates cholesterol scavenging and transport back to the liver
high-density lipoprotein (HDL)
carries out reverse cholesterol transport
73
Lipoproteins and Lipid Transport
1. Chylomicrons are synthesized from dietary fats in the ER of enterocytes, epithelial cells that line the small intestine. The
chylomicrons then move through the lymphatic system and enter the bloodstream via the left subclavian vein. The apolipoproteins of chylomicrons include apoB-48 (unique to this class of
lipoproteins), apoE, and apoC-II (Table 21-2).
2. ApoC-II activates lipoprotein lipase in the capillaries of adipose, heart, skeletal muscle, and lactating mammary tissues, allowing the release of free fatty acids (FFA) to these tissues. Chylomicrons thus carry dietary fatty acids to tissues where
they will be consumed or stored as fuel.
3. The remnants of chylomicrons, depleted of most of their
triacylglycerols but still containing cholesterol, apoE, and apoB-48, move through the bloodstream to the liver. Receptors in the liver bind to the apoE in the chylomicron remnants and mediate uptake of these remnants by endocytosis.
4. In the liver, the remnants release their cholesterol and are degraded in lysosomes. This pathway from dietary cholesterol to the liver is the exogenous pathway When the diet contains more fatty acids and cholesterol than are needed immediately as fuel or precursors to other molecules,
5. they are converted to triacylglycerols or cholesteryl esters in the
liver and packaged with specific apolipoproteins into very-low-density lipoprotein (VLDL). Excess carbohydrate in the diet can also be converted to triacylglycerols in the liver and exported as VLDL. In addition to triacylglycerols and cholesteryl esters, VLDL contains apoB-100, apoC-I, apoC-II, apoC-III, and apoE (Table 21-2). VLDL is transported in the blood from the liver to muscle and adipose tissue.
6. 6 In the capillaries of these tissues, apoC-II activates lipoprotein lipase, which catalyzes the release of free fatty acids from triacylglycerols in the VLDL. Adipocytes take up these
fatty acids, reconvert them to triacylglycerols, and store the products in intracellular lipid droplets; myocytes, in contrast, primarily oxidize the fatty acids to supply energy. When the insulin level is high (after a meal), VLDL serves primarily to convey lipids from the diet to adipose tissue for storage. In
the fasting state between meals, the fatty acids used to produce VLDL in the liver originate primarily from adipose tissue, and the principal VLDL target is myocytes of the heart and skeletal muscle.
7. LDL carries cholesterol to extrahepatic tissues such as muscle, adrenal glands, and adipose tissue. These tissues have plasma membrane LDL receptors that recognize apoB-100 and mediate uptake of cholesterol and cholesteryl esters.
8. LDL also delivers cholesterol to macrophages, sometimes converting them into foam cells .
9. LDL not taken up by peripheral tissues and cells returns to the liver and is taken up via LDL receptors in the hepatocyteplasma membrane.
10. A fourth major lipoprotein in mammals, high-density lipoprotein (HDL), originates in the liver and small intestine as small, protein-rich particles that contain relatively little cholesterol and no cholesteryl esters. HDLs contain primarily apoA-I and
other apolipoproteins. They also contain the enzyme lecithin-cholesterol acyltransferase (LCAT), which catalyzes the formation of cholesteryl esters from lecithin (phosphatidylcholine) and cholesterol. LCAT on the surface of nascent (newly forming) HDL particles converts the cholesterol and phosphatidylcholine of chylomicron and VLDL remnants
encountered in the bloodstream to cholesteryl esters, which begin to form a core, transforming the disk-shaped nascent HDL to a mature, spherical HDL particle.
11. Nascent HDL can also pick up cholesterol from cholesterol-rich extrahepatic cells (including macrophages and foam cells, formed from macrophages).
* 12 Mature HDL then returns to the liver, where the cholesterol is
unloaded via the scavenger receptor SR-BI.
* 13 Some of the cholesteryl esters in HDL can also be
transferred to LDL by the cholesteryl ester transfer protein. The HDL circuit is reverse cholesterol
transport . Much of this cholesterol is converted to bile salts by
enzymes sequestered in hepatic peroxisomes; the bile salts are stored in the gallbladder and excreted
into the intestine when a meal is ingested.
* 14 Bile salts are reabsorbed by the liver and recirculate
through the gallbladder in this enterohepatic circulation
74
HDL
* reverse cholesterol transport
* the HDL circuit where HDL picks up cholesterol from cholesterol-rich extrahepatic cells and returns it to the liver for unloading
* much of this cholesterol is converted to bile salts and stored in the gallbladder
75
Cholesterol Esters Enter Cells by Receptor-Mediated Endocytosis
76
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Cardiovascular Disease (CVD)
is Multifactorial
```
very high LDL-cholesterol levels tend to correlate with atherosclerosis
low HDL-cholesterol levels are negatively associated with heart disease
77
Dysregulation of Cholesterol Metabolism Can Lead to \_\_\_\_\_\_\_\_
## Footnote
the obstruction of blood vessels from the pathological accumulation of cholesterol (plaques)
Cardiovascular disease
Atherosclerosis
78
Reverse Cholesterol Transport by HDL Counters ______ and \_\_\_\_\_\_\_
Plaque formation and Atherosclerosis
## Footnote
process by which HDL removes cholesterol from peripheral tissues and carries it to the liver
protects against atherosclerosis
79
* drug class used to treat patients with elevated serum cholesterol
* resemble mevalonate
* are competitive inhibitors of HMG-CoA reductase
80
familial hypercholesterolemia
* characterized by extremely high blood levels of cholesterol
* due to a defective LDL receptor
* cholesterol accumulates in foam cells and contributes to the formation of atherosclerotic plaques
81
Familial HDL Deficiency and
Tangier Disease
familial HDL deficiency:
Tangier disease:
* **familial HDL deficiency** = HDL levels are very low
* **Tangier disease** = HDL levels are almost undetectable
* both are the result of mutations in the ABCA1 protein
* apoA-I in cholesterol-depleted HDL cannot take up cholesterol from cells that lack ABCA1 protein
* apoA-I and cholesterol-depleted HDL are rapidly removed from the blood and destroyed
