1. Biosynthesis of Fatty Acids Medical Biochemistry Lecture #46

2. 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.

3. F.A. Nomenclature (cont.) - C18 with one double bond is called octadecenoic acid (18:1); with two double bonds is called octadecadienoic acid (18:2); with three double bonds, octadecatrienoic acid (18:3).

5. 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.

6. Properties of fatty acids are markedly dependent on their chain length and on the degree of saturation. -Melting point of stearic acid is 69.6 o C, whereas that of oleic acid (with one double bond) is 13.4 o C. –Melting temperature of palmitic acid (C16) is 6.5 degrees lower than that of stearic acid (C16)

7. 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.

8. Reaction is catalyzed by acetyl-CoA carboxylase. It is a multienzyme protein. The enzyme contains a variable number of identical subunits, each containing biotin, biotin carboxylase, biotin carboxyl carrier protein, and transcarboxylase, as well as a regulatory allosteric site. Step 1: Formation of Malonylcoenzyme A is the committed step in fatty acid synthesis: It takes place in two steps: carboxylation of biotin (involving ATP) and transfer of the carboxyl to acetyl-CoA to form malonyl- CoA.

9. Step 2: Fatty acid synthase catalyzes the remaining steps. It is a multienzyme polypeptide complex that contains acyl carrier protein (ACP). ACP contains the vitamin pantothenic acid in the form of 4'- phosphopantetheine. ACP takes over the role of CoA. It offers great efficiency and freedom from interference by competing reactions Synthesis of all enzymes in the complex is coordinated, since it is encoded by a single gene It is a dimer, and each monomer is identical, consisting of one chain containing all seven enzyme activities of fatty acid synthase and an ACP with a 4'-phosphopantetheine-SH group. Dimer is arranged in a "head to tail" configuration. Monomer is not active.

11. 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.

15. 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).

16. 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.

17. 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.

18. Hormones (short term) Insulin stimulates lipogenesis by several mechanisms: a. increases transport of glucose into the cell (e.g., adipose tissues) and thereby increases the availability of both pyruvate for fatty acid synthesis and glycerol-3-phosphate for esterification of the newly formed fatty acids. b. Converts inactive form of pyruvate dehydrogenase to the active form in adipose tissues c. Activates acetyl-CoA carboxylase d. Insulin depress intracellular cAMP levels, inhibits lipolysis e. Insulin antagonizes the actions of glucagon and epinephrine

19. Long-term Expression is increased in response to fed state and is decreased in fasting, feeding of fat, and in diabetes (adaptive mechanism).