Lipid Biosynthesis Flashcards
biosynthesis requires
malonyl-CoA
breakdown of lipids occurs in: Biosynthesis occurs in:
mitochondria cytosol
catalyzes the irreversible formation of malonyl-CoA from acetyl-CoA
Where does this reaction occur?
Contains what group?
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
catalyzes assembly of long carbon chains of fatty acids in the cytosol through a repeating four-step sequence
Begins with:
Elongation:
fatty acid synthase
begins with malonyl-CoA and acetyl-CoA
each sequence elongates chain by two carbons
Fatty Acid Synthesis
The Cofactor and Activating Groups in Fatty Acid Breakdown and Biosynthesis
- In β oxidation:
- in fatty acid synthesis:
- 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
Fatty acid synthase I (FAS I) found in mammals
- 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
= 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
acyl carrier protein (ACP)
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
The Mammalian Fatty Acid Synthase Has Multiple Active Sites
the intermediates remain covalently attached as thioesters to one of two thiol groups:
- the —SH group of a Cys residue in β-ketoacyl-ACP synthase
- the —SH group of acyl carrier protein
Fatty acid synthase receives the _______ and ________ groups
acetyl and malonyl group
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
malonyl/acetyl-CoA–ACP transferase (MAT) domain
The fatty acid synthase reactions are repeated to form ______
Production of _______ marks completion of one pass through the fatty acid synthase complex
Palmitate
butyryl-ACP
hydrolyzes the thioester linkage between palmitate and ACP to release free palmitate
thioesterase (TE)
The Overall Reaction for the Synthesis of Palmitate
8 acetyl-CoA + 7ATP + 14NADPH + 14H+ →
palmitate + 8CoA + 7ADP + 7Pi + 14NADP+ + 6H2O
biosynthesis of fatty acids requires:
- acetyl-CoA
- ATP to make malonyl-CoA
- the reducing power of NADPH to reduce
- the β-keto group
- the double bond
fatty acid synthesis occurs in the
cytosol
catalyzes the reversible formation of pyruvate and CO2 from malate
malic enzyme
the energy cost per acetyl-CoA transported into the cytosol
2 ATP
Shuttle for Transfer of Acetyl Groups from Mitochondria to the Cytosol
= transports malate into the matrix where it is reoxidized to oxaloacetate by malate dehydrogenase
malate-α-ketoglutarate transporter
transports pyruvate into the matrix where it is converted to oxaloacetate by pyruvate carboxylase or oxidized to acetyl CoA
pyruvate transporter
Fatty Acid Biosynthesis Is
Tightly Regulated
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
Regulation of Acetyl-CoA Carboxylase By Covalent Modification
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
Pathways are also regulated at the level of
gene expression
fatty acid synthesis and β oxidation do/do not occur simultaneously
do not
during fatty acid synthesis, malonyl-CoA inhibits fatty acid import into the mitochondria
shuts down β oxidation
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
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
linoleate may be converted to:
- γ-linolenate
- eicosatrienoate
- arachidonate (eicosatetraenoate)
α-linolenate may be converted to:
- eicosatetraenoic acid (EPA)
- docosahexaenoic acid (DHA)
must be obtained from dietary plant material
linoleate and α-linolenate for mammals
essential fatty acids
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
Cyclooxygenase (COX) Reaction
linear eicosanoids
leukotrienes
Glycerol 3-Phosphate Is Formed from
glycerol 3-phosphate dehydrogenase:
glycerol kinase:
DHAP and glycerol
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
Formation of Phosphatidic Acid
Formation of Triacylglycerol and glycerophospholipids from Phosphatidic Acid
Triacylglycerol biosynthesis in animals is regulated by
hormones
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)
Phospholipids remodel via the __________ facilited by lysophosphatidyl-choline acyltransferases (LPCATs)
Lands cycle
Contains characteristic double bond
Plasmalogens
along with platelet-activating factor both use similar synthetic pathways
Biosynthesis of Sphingolipids
Cholesterol Is Made from Acetyl-CoA in Four Stages:
- condensation of three acetate units to form mevalonate
- conversion of mevalonate to activated isoprene units
- polymerization of six isoprene units to form the 30-carbon linear squalene
- cyclization of squalene to form the four rings of the steroid nucleus
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
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
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
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
Cholesterol Synthesis and Transport Are Regulated at Several Levels
five modes of regulation:
- covalent modification of HMG-CoA reductase
- transcriptional regulation of HMG-CoA gene
- proteolytic degradation of HMG-CoA reductase
- activation of ACAT, which increases esterification for storage
- transcriptional regulation of the LDL receptor
- 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
Lipoproteins and Lipid Transport
- 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). - 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. - 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. - 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,
- 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 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. - 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.
- LDL also delivers cholesterol to macrophages, sometimes converting them into foam cells .
- LDL not taken up by peripheral tissues and cells returns to the liver and is taken up via LDL receptors in the hepatocyteplasma membrane.
- 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. - 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
Cholesterol Esters Enter Cells by Receptor-Mediated Endocytosis
