Biosynthesis of Fatty Acids The acetylCo A is

Biosynthesis of Fatty Acids

• The acetyl-Co. A is used as primer • The addition of all the subsequent C 2 units is via malonyl-Co. A • Propionyl- Co. A acts as primer – odd number of carbon fatty acids • Site of fatty acid synthesis

The synthesis of long-chain fatty acids (lipogenesis) • Carried out by two enzyme systems: • acetyl-Co. A carboxylase • fatty acid synthase • The pathway converts acetyl-Co. A to palmitate and requires NADPH, ATP, Mn 2+, biotin, pantothenic acid, and HCO 3− as cofactors.

Fatty acid synthase • a multienzyme complex of one polypeptide chain with seven separate enzymatic activities • Catalyzes the assembly of palmitate from one acetyl-Co. A and seven malonyl-Co. A molecules

• Lipogenesis is regulated at – acetyl-Co. A carboxylase step by • • allosteric modifiers, phosphorylation/dephosphorylation, induction and repression of enzyme synthesis Citrate activates the enzyme, long-chain acyl-Co. A inhibits activity Insulin activates glucagon and epinephrine have opposite actions

• Fatty acid fate – Esterification • Into Acylglycerols • to Cholesteryl ester – Chain elongation – Desaturation

• The equation for the overall synthesis of palmitate from acetyl-Co. A and malonyl-Co. A

Fatty acid synthase multienzyme complex

Biosynthesis of long-chain fatty acids

• Tissues specializing in active lipogenesis – Liver, adipose tissue, and the lactating mammary gland – also possess an active pentose phosphate pathway • Both metabolic pathways are found in the cytosol

• Acetyl-Co. A Is the Principal Building Block of Fatty Acids

The provision of acetyl-Co. A and NADPH for lipogenesis

Elongation of Fatty Acid Chains • in the Endoplasmic Reticulum • fatty acid elongase system • elongates saturated and unsaturated fatty acyl -Co. As (from C 10 upward) by two carbons, using malonyl-Co. A as acetyl donor and NADPH as reductant

Microsomal elongase system

Regulation of Lipogenesis • Excess carbohydrate is stored as fat • Lipogenesis converts surplus glucose and intermediates such as pyruvate, lactate, and acetyl-Co. A to fat • The nutritional state of the organism is the main factor regulating the rate of lipogenesis

• It is depressed under conditions of – Restricted caloric intake – On a fat diet – Deficiency of insulin • an inverse relationship has been demonstrated between hepatic lipogenesis and the concentration of serum-free fatty acids • Sucrose instead of glucose – Increase lipogenesis

Regulation of Lipogenesis • SHORT- & LONG-TERM MECHANISMS • allosteric and covalent modification of enzymes • Long term – Changes in gene expression • Acetyl-Co. A Carboxylase Is the Most Important Enzyme in the Regulation of Lipogenesis

Regulation of acetyl-Co. A carboxylase by phosphorylation/dephosphorylation

• Allosteric effectors – Citrate • Inactive dimer to an active polymeric form • Inactivation – Phosphorylation – Long chain acyl-Co. A • Negative feedback inhibition by product • Increased lipolysis or an influx of free fatty acids into the tissue • Inhibit the mitochondrial tricarboxylate transporter – Citrate effect not occur

• Acetyl-Co. A carboxylase regulated by hormones – glucagon, epinephrine, and insulin via • Changes in its phosphorylation state • Pyruvate Dehydrogenase – Acyl-Co. A causes an inhibition • Inhibiting the ATP-ADP exchange transporter of the inner mitochondrial membrane – Increased intramitochondrial [ATP]/[ADP] ratios • active to inactive pyruvate dehydrogenase – availability of acetyl-Co. A

• Increased levels of free fatty acids – Increase oxidation of acyl-Co. A • Increase the ratios of [acetyl-Co. A]/ [Co. A] and [NADH]/[NAD+] in mitochondria – Inhibiting pyruvate dehydrogenase • Insulin Also Regulates Lipogenesis – acetyl-Co. A carboxylase activity – transport of glucose into the cell • increasing the availability of both pyruvate and glycerol 3 -phosphate for esterification

• Converts the inactive form of pyruvate dehydrogenase to the active form • depress the level of intracellular c. AMP – Inhibits lipolysis • Reduces plasma free fatty acid

• The Fatty Acid Synthase Complex & Acetyl-Co. A Carboxylase Are Adaptive Enzymes – Starvation, feeding of fat, and in diabetes – Induction of enzyme biosynthesis • Insulin • Glucagon (via c. AMP) • Polyunsaturated fatty acids – Inhibition of expression of key enzymes of glycolysis and lipogenesis • longer-term regulation take several days • direct and immediate effect – Free fatty acids and hormones