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Chapter 24 Lipid Biosynthesis Biochemistry by Reginald Garrett and Charles Grisham Outline 1. How Are Fatty Acids Synthesized? 2. How Are Complex Lipids Synthesized? 3. How Are Eicosanoids Synthesized, and What Are Their Functions? 4. How Is Cholesterol Synthesized? 5. How Are Lipids Transported Throughout the Body? 6. How Are Bile Acids Biosynthesized? 7. How Are Steroid Hormones Synthesized and Utilized? 24.1 – How Are Fatty Acids Synthesized? The Biosynthesis and Degradation Pathways are Different • As in cases of glycolysis/gluconeogenesis and glycogen synthesis/breakdown, fatty acid synthesis and degradation go by different routes • There are five major differences between fatty acid breakdown and biosynthesis The Differences Between fatty acid biosynthesis 1. 2. 3. 4. 5. and breakdown Intermediates in synthesis are linked to -SH groups of acyl carrier proteins (as compared to -SH groups of CoA) Synthesis in cytosol; breakdown in mitochondria Enzymes of synthesis are one polypeptide (fatty acid synthase) in animals Biosynthesis uses NADPH/NADP+; breakdown uses NADH/NAD+ & FAD Stereochemistry (D-b-hydroxyacyl) Activation by Malonyl-CoA • • • • • Acetate Units are Activated for Transfer in Fatty Acid Synthesis by Malonyl-CoA Fatty acids are built from 2-C units -- acetyl-CoA Acetate units are activated for transfer by conversion to malonyl-CoA Decarboxylation of malonyl-CoA and reducing power of NADPH drive chain growth Chain grows to 16-carbons (palmitate) Other enzymes add double bonds and more Cs The sources of Acetyl-CoA • Amino acid degradation produces cytosolic acetyl-CoA • Fatty acid oxidation produces mitochondrial acetyl-CoA • Glycolysis yields cytosolic pyruvate which is converted to acetyl-CoA in mitochondria • Citrate-malate-pyruvate shuttle provides cytosolic acetate units and reducing equivalents for fatty acid synthesis The reducing power: NAPDH • Produced by malic enzyme • Produced in pentose phosphate pathway (chapter 22) The "ACC enzyme" commits acetate to fatty acid synthesis Acetyl-CoA Carboxylase • Carboxylation of acetyl-CoA to form malonylCoA is the irreversible, committed step in fatty acid biosynthesis • ACC uses bicarbonate and ATP (& biotin) – E.coli enzyme has three subunits – Animal enzyme is one polypeptide with all three functions - biotin carboxyl carrier, biotin carboxylase and transcarboxylase Figure 24.2 (a) The acetyl-CoA carboxylase reaction produces malonyl-CoA for fatty acid synthesis. (b) A mechanism for the acetylCoA carboxylase reaction. Bicarbonate is activated for carboxylation reactions by formation of Ncarboxybiotin. ATP drives the reaction forward, with transient formation of a carbonylphosphate intermediate (Step 1). In a typical biotin-dependent reaction, nucleophilic attack by the acetyl-CoA carbanion on the carboxyl carbon of N-carboxybiotin a transcarboxylation yields the carboxylated product (Step 2). Malonyl-CoA Figure 24.3 In the acetyl-CoA carboxylase reaction, the biotin ring, on its flexible tether, acquires carboxyl groups from carbonylphosphate on the carboxylase subunit and transfers them to acyl-CoA molecules on the transcarboxylase subunits. Acetyl-CoA Carboxylase ACC forms long, active filamentous polymers from inactive protomers • As a committed step, ACC is carefully regulated • Palmitoyl-CoA (product) favors monomers • Citrate favors the active polymeric form Citrate Inactive protomers active polymer Acyl-CoA Figure 24.4 Models of the acetyl-CoA carboxylase polypeptide, with phosphorylation sites indicated, along with the protein kinases responsible. Phosphorylation at Ser1200 is primarily responsible for decreasing the affinity for citrate. Phosphorylation of ACC modulates activation by citrate and inhibition by palmitoyl-CoA • Unphosphorylated E has high affinity for citrate and is active at low [citrate] • Unphosphorylated E has low affinity for palmCoA and needs high [palm-CoA] to inhibit • Phosphorylated E has low affinity for citrate and needs high [citrate] to activate • Phosphorylated E has high affinity for palmCoA and is inhibited at low [palm-CoA] Figure 24.5 The activity of acetylCoA carboxylase is modulated by phosphorylation and dephosphorylation. The dephospho form of the enzyme is activated by low [citrate] and inhibited only by high levels of fatty acyl-CoA. In contrast, the phosphorylated form of the enzyme is activated only by high levels of citrate, but is very sensitive to inhibition by fatty acyl-CoA. The acyl carrier protein carry the intermediates in fatty acid synthesis • ACP is a 77 residue protein in E. coli - with a phosphopantetheine • The same functional group of CoA Fatty Acid Synthesis • • • • • • • Acetyl-CoA-ACP transacylases (ATase) Malonyl-CoA-ACP transacylases (MTase) b-ketoacyl-ACP synthase (KSase) b-ketoacyl-ACP reductase (KRase) b-hydroxyacyl-ACP dehydratase (DH) Enoyl-ACP reductase (ERase) Thioesterase (TEase) in animals Figure 24.7 The pathway of palmitate synthesis from acetyl-CoA and malonyl-CoA. Acetyl and malonyl building blocks are introduced as acyl carrier protein conjugates. Decarboxylation drives the b-ketoacyl-ACP synthase and results in the addition of two-carbon units to the growing chain. Concentrations of free fatty acids are extremely low in most cells, and newly synthesized fatty acids exist primarily as acyl-CoA esters. Fatty Acid Synthesis in Bacteria and Plants • The separate enzymes in bacteria and plants • Pathway initiated by formation of acetyl-ACP and malonyl-ACP by transacylases • Decarboxylation drives the condensation of acetyl-CoA and malonyl-CoA by KSase • Next three steps look very similar to the fatty acid oxidation in reverse • Only differences: D configuration and NADPH Fatty Acid Synthesis Acetyl-CoA + 7 malonyl-CoA + 14 NAPDH + 14 H+ Palmitoyl-CoA + 7 HCO3- + 14 NAPD+ + 7 CoA-SH The formation of malonyl-CoA: 7 Acetyl-CoA + 7 HCO3- + 7 ATP47 malonyl-CoA + 7 ADP3- + 7Pi2- +7H+ The overall reaction: 8 Acetyl-CoA + 7 ATP4- + 14 NAPDH + 14 H+ Palmitoyl-CoA + 14 NAPD+ + 7 CoA-SH + 7 ADP3- + 7Pi2- (213 KD) In yeast: a6b6 (203 KD) Figure 24.8 In yeast, the functional groups and enzyme activities required for fatty acid synthesis are distributed between a- and bsubunits. Fatty Acid Synthase in Animals Fatty Acid Synthase - a multienzyme complex • Dimer of 250 kD multifunctional polypeptides – Domain 1: AT, MT & KSase – Domain 2: ACP, KRase, DH, ERase – Domain 3: Thioesterase Figure 24.9 Fatty acid synthase in animals contains all the functional groups and enzyme activities on a single multifunctional subunit. The active enzyme is a headto-tail dimer of identical subunits. (Adapted from Wakil, S. J., Stoops, J. K., and Joshi, V. C., 1983.Fatty acid synthesis and its regulation. Annual Review of Biochemistry 52:537579.) Figure 24.10 Acetyl units are covalently linked to a serine residue at the active site of the acetyl transferase in eukaryotes. A similar reaction links malonyl units to the malonyl transferase. Further Processing of FAs Additional elongation & desaturation • Additional elongation occurs in mitochondria and the surface of ER • The reducing coenzyme for the second step is NADH, whereas the reductant for the fourth step is NADPH. • In ER, involving malonyl-CoA Figure 24.12 Elongation of fatty acids in mitochondria is initiated by the thiolase reaction. The b-ketoacyl intermediate thus formed undergoes the same three reactions (in reverse order) that are the basis of boxidation of fatty acids. Reduction of the b-keto group is followed by dehydration to form a double bond. Reduction of the double bond yields a fatty acyl-CoA that is elongated by two carbons. Note that the reducing coenzyme for the second step is NADH, whereas the reductant for the fourth step is NADPH. ( in mitochondria) Further Processing of FAs Introduction of cis double bonds • E.coli add double bonds during the fatty acid synthesis • After four normal cycles, b-hydroxydecanoyl thioester dehydrase forms a double bond b, g to the thioester • O2-independent Figure 24.13 Double bonds are introduced into the growing fatty acid chain in E. coli by specific dehydrases. Palmitoleoyl-ACP is synthesized by a sequence of reactions involving four rounds of chain elongation, followed by double bond insertion by bhydroxydecanoyl thioester dehydrase and three additional elongation steps. Another elongation cycle produces cisvaccenic acid. Further Processing of FAs • • • • • Introduction of cis double bonds Eukaryotes add double bond until the fatty acyl chain has reached its full length (usually 16 to 18 carbons) Desaturase Cytochrome b5 reductase & Cytochrome b5 All three proteins are ssociated with the ER membrane NADH & O2 are required; O2-dependent Figure 24.14 The conversion of stearoyl-CoA to oleoyl-CoA in eukaryotes is catalyzed by stearoyl-CoA desaturase in a reaction sequence that also involves cytochrome b5 and cytochrome b5 reductase. Two electrons are passed from NADH through the chain of reactions as shown, and two electrons are also derived from the fatty acyl substrate. linoleic acid in eukaryotes. This is the only means by which animals can synthesize fatty acids with double bonds at positions beyond C-9. • Mammals cannot synthesize most polyunsaturated fatty acids – Essential fatty acids – Introduce double bonds between the double bond at the 8- or 9- position and the carboxyl group – form a double bond at 5-position (6) if one already exists at the 8-position (9) Arachidonic acid • mammals can also add double bonds to unsaturated fatty acids • synthesized from linoleic acid in eukaryotes • The precursor for prostaglandins and other biologically active derivatives Figure 24.15 Arachidonic acid is synthesized from linoleic acid in eukaryotes. This is the only means by which animals can synthesize fatty acids with double bonds at positions beyond C-9. Regulation of Fatty Acid Synthesis Allosteric modifiers, phosphorylation and hormones • Allosteric regulation – Malonyl-CoA blocks the carnitine acyltransferase and thus inhibits b-oxidation – Citrate activates acetyl-CoA carboxylase – Fatty acyl-CoAs inhibit acetyl-CoA carboxylase Figure 24.16 Regulation of fatty acid synthesis and fatty acid oxidation are coupled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl-CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. Regulation of FA Synthesis • Phosphorylation and hormones – Citrate activation and acyl-CoA inhibition of ACC are dependent on the phosphorylation state – Phosphorylation causes inhibition of fatty acid biosynthesis • Hormone signals regulate ACC and fatty acid biosynthesis – Glucagon activates lipases/inhibits ACC – Insulin inhibits lipases/activates ACC Figure 24.17 Hormonal signals regulate fatty acid synthesis, primarily through actions on acetyl-CoA carboxylase. Availability of fatty acids also depends upon hormonal activation of triacylglycerol lipase. 24.2 – How Are Complex Lipids Synthesized? Complexed lipids: 1. Glycerolipid – – Triacylglycerols Glycerophospholipids 2. Sphingolipids Phospholipids (membrane components) 1. Glycerophospholipids 2. Sphingolipids Synthetic pathways depend on different organism • Sphingolipids and triacylglycerols only made in eukaryotes • Phosphatidylethanolamine (PE) accounts for 75% of phospholipids in E.coli – No PC, PI, sphingolipids, cholesterol in E.coli – But some bacteria do produce PC Glycerolipid Biosynthesis Glycerolipids are synthesized by phosphorylation & acylation of glycerol • Phosphatidic acid (PA) is the precursor for all other glycerolipids in eukaryotes • Eukaryotic systems can also utilize DHAP as a starting point Unsatuated Fatty Acid Figure 24.18 Synthesis of glycerolipids in eukaryotes begins with the formation of phosphatidic acid, which may be formed from dihydroxyacetone phosphate or glycerol as shown. Satuated Fatty Acid Glycerolipid Biosynthesis • PA is converted either to DAG or CDP-DAG • DAG is a precursor for synthesis of TAG, phosphatidylethanolamine (PE) and phosphatidylcholine (PC) • TAG is synthesized mainly in adipose tissue, liver, and intestines Figure 24.19 Diacylglycerol and CDPdiacylglycerol are the principal precursors of glycerolipids in eukaryotes. Phosphatidylethanolamine and phosphatidylcholine are formed by reaction of diacylglycerol with CDPethanolamine or CDPcholine, respectively. Glycerolipid Biosynthesis • PE synthesis – begins with phosphorylation of ethanolamine to form phosphoethanolamine – Transfer of a cytidylyl group from CTP to from CDP-ethanolamine – Phosphoethanolamine transferase link phosphoethanolamine to the DAG • Synthesis of PC is entirely analogous • PC can also be converted from PE by methylation reactions • Exchange of ethanolamine for serine converts PE to PS (phosphatidylserine) Figure 24.21 The interconversion of phosphatidylethanolamine and phosphatidylserine in mammals. Other PLs from CDP-DAG Figure 24.22 • CDP-diacylglycerol is used in eukaryotes to produce: – Phosphatiylinositol (PI) in one step • 2-8% in animal membrane • Breakdown to form inositol-1,4,5-triphosphate & DAG (second messengers) – Phosphatiylglycerol (PG) in two steps – Cardiolipin in three steps Figure 24.22 CDP-diacylglycerol is a precursor of phosphatidylinositol, phosphatidylglycerol, and cardiolipin in eukaryotes. Plasmalogen Biosynthesis Dihydroxyacetone phosphate (DHAP) is the precursor to the plasmalogens • Acylation of DHAP • Exchange reaction produces the ether linkage by long-chain alcohol (acyl-CoA reductase) • Ketone reduction • Acylation again • CDP-ethanolamine delivers the head group • A desaturase produces the double bond in the alkyl chain Figure 24.23 Biosynthesis of plasmalogens in animals. (1) Acylation at C-1 is followed by (2) exchange of the acyl group for a long-chain alcohol.(3) Reduction of the keto group at C-2 is followed by (4 and 5) transferase reactions, which add an acyl group at C-2 and a polar head-group moiety, and a (6) desaturase reaction that forms a double bond in the alkyl chain. The first two enzymes are of cytoplasmic origin, and the last transferase is located at the endoplasmic reticulum. Acyl-CoA Acyl-CoA reductase Figure 24.24 Platelet-activating factor, formed from 1-alkyl-2lysophosphatidylcholine by acetylation at C-2, is degraded by the action of acetylhydrolase. Sphingolipid Biosynthesis High levels made in neural tissue 1. Initial reaction is a condensation of serine and palmitoyl-CoA (by 3-ketosphinganine synthase) – 2. 3. 4. • 3-ketosphinganine synthase is PLP-dependent Ketone is reduced with help of NADPH Acylation to form N-acyl-sphinganine Desaturated to form ceramide Ceramide is precursor for other sphingolipids Figure 24.25 Biosynthesis of sphingolipids in animals begins with the 3ketosphinganine synthase reaction, a PLP-dependent condensation of palmitoylCoA and serine. Subsequent reduction of the keto group, acylation, and desaturation (via reduction of an electron acceptor, X) form ceramide, the precursor of other sphingolipids. Sphingolipid Biosynthesis Ceramide is precursor for other sphingolipids • Sphingomyelin – – – • Cerebrosides – – • Rich in myelin sheath Insulates nerve axons By transfer of phosphocholine from PC Glycosylation of ceramide Galactosylceramide makes up ~15% of the lipid of myelin sheath Gangliosides – Cerebrosides contain one or more sialic acid Figure 24.26 Glycosylceramides (such as galactosylceramide), gangliosides, and sphingomyelins are synthesized from ceramide in animals. Gangliosides 1. UDP-glucose 2. UDP-galactose 3. UDP-N-acetylgalactosamine 4. CMP-sialic acid (N-acetylneuraminidate) 24.3 – How Are Eicosanoid Synthesized and What Are Their Functions? • • Eicosanoid are all derived from 20-carbon fatty acid (arachidonic acid) Eicosanoids are local hormones 1. Exert their effect at very low concentration 2. Usually act near their sites of synthesis • • PLA2 releases arachidonic acid from phospholipids (PC) Can be released by PLC & DAG lipase Figure 24.27 Arachidonic acid, derived from breakdown of phospholipids (PL), is the precursor of prostaglandins, thromboxanes, and leukotrienes. The letters used to name the prostaglandins are assigned on the basis of similarities in structure and physical properties. The class denoted PGE, for example, consists of bhydroxyketones that are soluble in ether, whereas PGF denotes 1,3-diols that are soluble in phosphate buffer. PGA denotes prostaglandins possessing a,b-unsaturated ketones. The number following the letters refers to the number of carbon - carbon double bonds. Thus, PGE2 contains two double bonds. Specificities of phospholipases A1, A2, C, and D. Eicosanoids are local hormones • Eicosanoids include – – – – Prostaglandins (PG) Thromboxanes (Tx) Leukotrienes Other hydroxyeicosanoic acid • Tissue injury and inflammation triggers arachidonate release and eicosanoid synthesis • All PGs are cyclopentanoic acids • Initiated by PGH synthase associated with the ER • PGH synthase • Prostaglandin endoperoxide synthase • Cyclooxygenase • Catalyzes simultineous oxidation and cyclization of arachidonic acid Two isoforms in animals (a) COX-1: normal, physiological production of PG (b) COX-2: induced by cytokines, mitogens, and endotoxins in inflammatory cells (a) COX-1 (b) COX-2 Aspirin & NSAIDs • Aspirin and other nonsteroid anti-inflammatory drugs (NSAIDs) inhibit the cyclooxygenase – Aspirin covalently – Others noncovalently Specifically inhibition of COX2 24.4 – How Is Cholesterol Synthesized? Occurs primarily in the liver • The most prevalent steroid in animal cells is cholesterol • Serve as cell membranes, precursor of bile acids and steroid hormones, and vitamin D3 • 1. 2. 3. Occurs primarily in the liver Biosynthesis begins in the cytosol with the synthesis of mevalonate from acetyl-CoA First step is a thiolase reaction Second step makes HMG-CoA Third step produces 3R-mevalonate • HMG-CoA reductase • The rate-limiting step in cholesterol biosynthesis • HMG-CoA reductase is site of action of cholesterol-lowering drugs Figure 24.32 A reaction mechanism for HMG-CoA reductase. Two successive NADPHdependent reductions convert the thioester, HMG-CoA, to a primary alcohol. Regulation of HMG-CoA Reductase As rate-limiting step, it is the principal site of regulation in cholesterol synthesis 1. Phosphorylation by cAMP-dependent kinases inactivates the reductase 2. Degradation of HMG-CoA reductase half-life is 3 hrs and depends on cholesterol level: High [cholesterol] means a short half-time 3. Gene expression (mRNA production) is controlled by cholesterol levels: If [cholesterol] is low, more mRNA is made Figure 24.33 HMG-CoA reductase activity is modulated by a cycle of phosphorylation and dephosphorylation. Squalene is synthesized from Mevalonate • Six-carbon mevalonate makes 5-carbon isopentenyl pyrophosphate and dimethylallyl pyrophosphate • Condensation of these two 5-carbon intermediates produces geranyl pyrophosphate (10-carbon) • Addition of another isopentenyl pyrophosphate yields farnesyl pyrophosphate • Two farnesyl pyrophosphates link to form squalene • Bloch and Langdon were first to show that squalene is derived from acetate units and that cholesterol is derived from squalene geranyl pyrophosphate Figure 24.34 The conversion of mevalonate to squalene. Cholesterol from Squalene • • • • At the endoplasmic reticulum membrane Squalene monooxygenase converts squalene to squalene-2,3-epoxide 2,3-oxidosqualene:lanosterol cyclase converts the epoxide to lanosterol Though lanosterol looks like cholesterol, 20 more steps are required to form cholesterol All at/in the endoplasmic reticulum membrane Figure 24.35 Cholesterol is synthesized from squalene via lanosterol. The primary route from lanosterol involves 20 steps, the last of which converts 7-dehydrocholesterol to cholesterol. An alternative route produces desmosterol as the penultimate intermediate. Inhibiting Cholesterol Synthesis • • • • Merck and the Lovastatin story... HMG-CoA reductase is the key - the ratelimiting step in cholesterol biosynthesis Lovastatin (mevinolin) blocks HMG-CoA reductase and prevents synthesis of cholesterol Lovastatin is an (inactive) lactone In the body, the lactone is hydrolyzed to mevinolinic acid, a competitive inhibitor of the reductase, Ki = 0.6 nM HB page 797 The structures of (inactive ) lovastatin, (active) mevinolinic acid, mevalonate, and synvinolin. 24.5 – How Are Lipids Transported Throughout the Body? Lipoproteins are the carriers of most lipids in the body • Lipoprotein - a cluster of lipids, often with a monolayer membrane (phospholipids), together with an apolipoprotein Lipoproteins • HDL & VLDL are assembled primarily in the ER of liver cells (some in intestines) • Chylomicrons form in the intestines • LDL not made directly, but is made from VLDL • LDL appears to be the major circulatory complex for cholesterol & cholesterol esters Lipoproteins • Chylomicrons carry TAG & cholesterol esters from intestine to other tissues • VLDLs carry lipid from liver • Mostly in the capillaries of muscle and adipose cells, lipoprotein lipases hydrolyze triglycerides from lipoproteins, making the lipoproteins smaller and raising their density • Thus chylomicrons and VLDLs are progressively converted to IDL and then LDL, which either return to the liver for reprocessing or are redirected to adipose tissues and adrenal glands Figure 24.38 Lipoprotein components are synthesized predominantly in the ER of liver cells. Following assembly of lipoprotein particles (red dots) in the ER and processing in the Golgi, lipoproteins are packaged in secretory vesicles for export from the cell (via exocytosis) and released into the circulatory system. Lipoproteins • LDLs are main carriers of cholesterol and cholesterol esters • Newly formed HDL contains virtually no cholesterol esters – Cholesterol esters are accumulated through the action lecithin:cholesterol acyltransferase (LCAT) • HDLs function to return cholesterol and cholesterol esters to the liver Figure 24.39 Endocytosis and degradation of lipoprotein particles. (ACAT is acyl-CoA cholesterol acyltransferase.) The LDL Receptor • • • • • A complex plasma membrane protein LDL binding domain on N-terminus N-linked and O-linked oligosaccharide domains A single TMS A cytosolic domain essential to aggregation of receptors in the membrane during endocytosis Dysfunctions in or absence of LDL receptors lead to familial hypercholesterolemia Figure 24.40 The structure of the LDL receptor. The aminoterminal binding domain is responsible for recognition and binding of LDL apoprotein. The O-linked oligosaccharide-rich domain may act as a molecular spacer, raising the binding domain above the glycocalyx. The cytosolic domain is required for aggregation of LDL receptors during endocytosis. 24.6 – How Are Bile Acids Biosynthesized? • • • • Carboxylic acid derivatives of cholesterol Essential for the digestion of food, especially for solubilization of ingested fats Synthesized from cholesterol in the liver, stored in the gallbladder, and secreted as need into the intestine Cholic acid conjugates with taurine and glycine to form taurocholic and glycocholic acids First step is oxidation of cholesterol by a mixedfunction oxidase (7a-hydroxylase) 24.7 – How Are Steroid Hormones Synthesized and Utilized? Desmolase (in mitochondria) converts cholesterol to pregnenolone, precursor to all others • Pregnenolone migrates from mitochondria to ER where progesterone is formed • Progesterone is a branch point - it produces sex steroids (testosterone and estradiol), and corticosteroids (cortisol and aldosterone) Figure 24.43 The steroid hormones are synthesized from cholesterol, with intermediate formation of pregnenolone and progesterone. Testosterone, the principal male sex hormone steroid, is a precursor to b-estradiol. Cortisol, a glucocorticoid, and aldosterone, a mineralocorticoid, are also derived from progesterone. (27C) (19C) aromatase (18C) (21C) • Anabolic steroids are illegal and dangerous Figure 24.44 The structure of stanozolol, an anabolic steriod.