Biosynthesis of Fatty Acids - Biochemistry - Lecture Slides, Slides of Biochemistry

Download Biosynthesis of Fatty Acids - Biochemistry - Lecture Slides and more Slides Biochemistry in PDF only on Docsity! Biosynthesis of Fatty Acids Medical Biochemistry Lecture #46 Docsity.com FattyAcids Fatty acids are a class of compounds containing a long hydrocarbon chain and a terminal carboxylate group. Nomenculature: - Systematic name for a fatty acid is derived from the name of its parent hydrocarbon by the substitution of oic for the final e. - For example, the C18 saturated fatty acid is called octadecanoic acid (18:0) because the parent hydrocarbon is octadecane. Docsity.com Fatty acids vary in chain length and degree of unsaturation: • Usually contain an even number of carbon atoms, typically between 14 and 24. The 16- and 18-carbon fatty acids are most common. • May contain one or more double bonds. The double bonds in polyunsaturated fatty acids are separated by at least one methylene group. • The configuration of the double bonds in most unsaturated fatty acids is cis. Docsity.com Properties of fatty acids are markedly dependent on their chain length and on the degree of saturation. • -Melting point of stearic acid is 69.6oC, whereas that of oleic acid (with one double bond) is 13.4oC. • –Melting temperature of palmitic acid (C16) is 6.5 degrees lower than that of stearic acid (C16) Docsity.com FATTY ACID SYNTHESIS (LIPOGENESIS) • Glucose provides the primary substrate for lipogenesis • In humans, adipose tissue may not be an important site, and liver has only low activity • Variations in fatty acid synthesis between individuals may have a bearing on the nature and extent of obesity, and one of the lesions in type I, insulin-dependent diabetes mellitus is inhibition of lipogenesis DE NOVO SYNTHESIS OCCURS IN CYTOSOL • Liver, kidney, brain, lung, mammary gland, and adipose tissue. Docsity.com Hydratase Malonyl transacylase Enoyl reductase Acetyl Ketoacyl transacylase reductase Ketoacyl synthase ACP Thioesterase c 4’-Phospho- yS pantetheine | | ss SH LLL _ Subunit, SH division | 4’-Phospho- pantetheine Ketoacyl synthase Thioesterase ACP Ketoacyl Acetyl reductase transacylase Enoyl reductase transacylase Hydratase Figure 23-2. Fatty acid synthase multienzyme complex. The complex is a dimer of two identical polypeptide monomers, 1 and 2, each consisting of seven enzyme activities and the acyl carrier protein (ACP). (Cys—SH, cysteine thiol.) The —SH of the 4’-phosphopantetheine of one monomer is in close proximity to the —SH of the cysteine residue of the ke- gaeyl.synthase of the other monomer, suggesting a “head-to-tail” arrangement of the two monomers. Though each mare r contains all the partial activities of the reaction sequence, the actual functional unit consists of one-half of one Dane’ interacting with the complementary half of the other. Thus, two acyl chains are produced simultaneously. The “RF e of the enzymes in each monomer is based on Wakil. Docsity.com Step 3: Elongation of fatty acid chains occurs in endoplasmic reticulum • This pathways "microsomal system" converts fatty acyl-CoA to an acyl-CoA derivative having two carbons more, using malonyl-CoA as acetyl donor and NADPH as reductant catalyzed by the microsomal fatty acid elongase system of enzymes. Docsity.com ° ce} MV R—"CH,~"CUS—CoA + *CH-*COUS—CoA Acyl-CoA ‘S-KETOACYL-CoA ‘SYNTHASE oO “COOH Malonyl-CoA CoA— SH +*CO, fe} I I —°CH,—°C CH, "°C -U S— CoA. 3-Ketoat 3-KETOACYL-CoA REDUCTASE OH icyl-CoA NADPH + H* NADP* ° | i ~CH,—CH—*CH, CUS — CoA 3-Hydroxyacyl-CoA 3-HYDROXYACYL-CoA DEHYORASE N H,0 ° tl —°CH,—°CH="CH—C OU S— CoA 2-trans-E 2-trans-ENOYL-CoA REDUCTASE noyl-CoA V N NADP* NADPH + H* oO all R—CH,—°CH,—"CH, CUS — CoA Acyl-CoA Figure 23-6. Microsomal elongase system for fatty acid chain elongation. NADH is also used by the reductases, but NADPH is preferred. aig og Na Hs ~ pan ~~ os — SH [rate] (rie SH Pia eet Hs. so Pan — ®@» @® ny ald aythase multignayme complex = ons. Qn -galleaes 'c00" Acyllacety-malonyl enzyme “G)-on-sh B ° on napen Pan S7UC~ CH, —CH—CHy GENERATORS 0(-}3-Hydroxyacyl enzyme Pentoso phosphate pathway ® leootate oo ‘dehydrogenase ” ic oi Sm fo u Pan S-~E~ CH= CH—CH, cyl enzyme ® / : ° ‘Ator eyeing through é u stops (S)-(@) soven tes GD tere Bite ry Palmitate ie cones ae eee Figure 23-3. Biosynthesis of long-chain fatty acids. Details of how addition of a malonyl residue causes the acyl chain 10 grow by two carbon atoms. (Cys, eysteine residue; Pan, 4'-phosphopantetheine.) Detals of the faty acid synthase dina: ‘ate shown in Figure 23-2. The blocks shown in dark blue contain initially a C, unit derived from acetyl-CoA (as illustrat ‘and subsequently the G, unit formed in reaction @. D it locsity.com Nutritional state regulates lipogenesis: • Lipogenesis converts surplus glucose and intermediates such as pyruvate, lactate, and acetyl- CoA to fat. • Rate is higher in well-fed animals whose diets contains a high proportions of carbohydrates. • It is depressed under conditions of restricted caloric intake, on a high-fate diet, or when there is a deficiency of insulin, as in diabetes mellitus. All these conditions are associated with increased concentrations of plasma free fatty acids. • There is an inverse relationship between hepatic lipogenesis and the concentration of serum-free fatty acids. The greatest inhibition of lipogenesis occurs over the range of free fatty acids (0.3-0.8 µmol/mL pf plasma). Docsity.com • Fat in the diet also causes depression of lipogenesis in the liver, and when there is more than 10% of fat in the diet, there is little conversion of dietary carbohydrates to fat. Docsity.com SHORT AND LONG-TERM MECHANISMS REGULATE LIPOGENESIS • In the short-term, synthesis is controlled by allosteric and covalent modification of enzymes; For long-term, there are changes in gene expression Short-term • Acetyl-CoA carboxylase is most important in regulating synthesis • Activated by citrate, which increases in well-fed state and is an indicator of a plentiful supply of acetyl-CoA • Inhibited by long-chain acyl-CoA. • Pyruvate dehydrogenase regulates availability of free acetyl-CoA for lipogenesis. Acetyl-CoA causes an inhibition of pyruvate dehyrogenase. Docsity.com