Lipid Biosynthesis

 

Functions of lipid

·       Storage of energy

·       Constituents of cellular membranes

·       Anchors for membrane proteins

·       Cofactors for enzymes

·       Signaling molecules

·       Pigments

·       Detergents

·       Transporters

·       Antioxidants

 

Catabolism of fatty acids is occurred at mitochondria. It uses NADH and produces acetyl-CoA. Intermediates are linked to SH groups of CoA.

Biosynthesis of fatty acids is occurred at cytosol. It uses NADPH and requires malonyl CoA and acetyl CoA. Intermediates are linked to SH groups of acyl carrier proteins. Enzymes of synthesis are one polypeptide.

 

Most fatty acids are supplied by diet. Excess carbohydrates and proteins in diet are converted to fatty acids and stored as triacylglycerols. Fatty acid synthesis occurs primarily in cytosol of the liver and lactating mammary glands. Lesser extent, in adipose tissue. Biosynthesis process incorporates carbons from acetyl coenzyme A (CoA) into the growing fatty acid chain. Fatty acids synthesis is an endergonic and reductive process. It uses ATP as a source of energy. NADPH is the source of reductive equivalents. Acetyl CoA is the precursor of fatty acid biosynthesis in cytosol. Acetyl CoA is produced in the mitochondria by the oxidation of pyruvate and catabolism of fatty acids, ketone bodies and certain amino acids. CoA portion of Acetyl CoA cannot cross the inner mitochondrial membrane. The transfer of acetyl group from mitochondria to cytosol is made by the acetyl group shuttle. Only acetyl portion enters cytosol as part of citrate. Intramitochondrial acetyl CoA reacts with Oxaloacetate to form citrate. Reaction is catalyzed by citrate synthetase. Citrate is then carried across mitochondrial membrane by the specific tricarboxylic carrier system. This occurs when the mitochondrial citrate concentration is high. In cytosol, citrate is cleaved by citrate lyase in the presence of ATP and Mg ions to yield acetyl CoA and OAA.

Fatty acid biosynthesis is a stepwise assembly of acetyl CoA units (mostly as malonyl CoA) ending with palmitate. (C 16 saturated).  It involves 2 steps. They are initiation, ATP dependent carboxylation of Acetyl CoA and the elongation of cycle of fatty acid synthesis.

The carboxylation of acetyl CoA to form malonyl CoA is catalyzed by enzyme, Acetyl CoA carboxylase (ACC). It is a two steps reaction. Reaction requires bicarbonate as a source of carbon dioxide, ATP and Biotin. Acetyl CoA carboxylase contains biotin as the prosthetic group. Biotin is covalently bound to a lysis residue of the enzyme, carboxylase. The inactive form of ACC is a dimer and activated by citrate. Malonyl CoA is the first intermediate in fatty acid biosynthesis. Production of Malonyl CoA is the controlling step in fatty acid synthesis. Production of Malonyl CoA is the controlling step in the fatty acid synthesis.

The remaining series of reactions of fatty acid synthesis in eukaryotes is catalyzed by the multifunctional enzyme, fatty acid synthase (FAS). Fatty acid synthase catalyzes the synthesis of long chain saturated fatty acid from acetyl CoA, malonyl CoA and NADPH. Fatty acid synthase is a multienzyme complex in mammals. A dimer containing identical subunits. Each monomer consists of one polypeptide chain containing all the 6 enzymes of fatty acid synthase and an ACP (Acyl carrier protein) with a molecule of 4’- phosphopantetheine. 4’- phosphopantetheine carries intermediates in fatty acid synthesis. These intermediates are bound to SH of a phosphopantheine group of ACP. The aggregation of all the enzymes of a particular pathway into one multienzyme functional unit. Offers great efficiency and freedom from interface by other competing processes. This achieves the effect of compartmentalization of the process within the cell.

In bacteria, plants and lower forms the individual enzymes of the system are separate. In eukaryotes the acetyl group of acetyl CoA is first transferred to the fatty acid synthase complex. This is catalyzed by acetyl trans acylase. The malonyl group is transferred from malonyl CoA to the Fatty acid synthase complex to form acetyl (acyl) malonyl enzyme catalyzed by malonyl trans acylase. Reactions are continued until a saturated 16 carbon acyl radical (palmityl) has been formed. Lengthening process stops at 16 carbons. The 16 carbons saturated fatty acid palmitate is the final product of the fatty acid synthase complex. A total of 7 ATP and 14 NADPH  will be consumed for making one palmitate molecule.