Fatty Acid Synthesis from Acetyl-CoA and Malonyl-CoA

Fatty Acid Synthesis

• Palmitate is synthesized from acetyl-CoA and malonyl-CoA, with acetyl-CoA forming carbon atoms 15 and 16 of palmitate.
• The addition of subsequent C2 units is via malonyl-CoA.
• Propionyl-CoA acts as a primer for the synthesis of long-chain fatty acids with an odd number of carbon atoms, found in ruminant fat and milk.

NADPH and Lipogenesis

• NADPH serves as a donor of reducing equivalents in the reduction of 3-ketoacyl and 2,3-unsaturated acyl derivatives.
• The oxidative reactions of the pentose phosphate pathway are the chief source of hydrogen required for the reductive synthesis of fatty acids.
• Tissues specializing in active lipogenesis (liver, adipose tissue, and lactating mammary gland) possess an active pentose phosphate pathway.
• Both metabolic pathways are found in the cytosol of the cell, with no membranes or permeability barriers against the transfer of NADPH.

Fatty Acid Synthesis Reaction

• Fatty acid synthesis from acetyl-CoA and malonyl-CoA occurs by a series of reactions catalyzed by:
  • 6 different enzymes plus a separate acyl carrier protein (ACP) in bacteria.
  • Individual domains of a very large polypeptide that includes an ACP domain in mammals.

Evolution of Mammalian Fatty Acid Synthase

• Evolution of the mammalian fatty acid synthase has involved gene fusion.

Production of Malonyl-CoA

• The initial and controlling step in fatty acid synthesis is the production of malonyl-CoA.
• Bicarbonate as a source of CO2 is required in the initial reaction for the carboxylation of acetyl-CoA to malonyl-CoA in the presence of ATP and acetyl-CoA carboxylase.
• Acetyl-CoA carboxylase has a requirement for the vitamin biotin.

Fatty Acid Synthesis Pathway

• The pathway involves the input of acetyl-CoA, which is carboxylated to malonyl-CoA.
• The reaction takes place in two steps: (1) carboxylation of biotin involving ATP and (2) transfer of the carboxyl to acetyl-CoA to form malonyl-CoA.
• ATP-dependent carboxylation provides energy input, and the CO2 is lost later during condensation with the growing fatty acid.

Dehydrogenation, Hydration, and Dehydrogenation

• Step 1: Dehydrogenation of alkane to alkene is catalyzed by isoforms of acyl-CoA dehydrogenase.
• Step 2: Hydration of alkene is catalyzed by two isoforms of enoyl-CoA hydratase.
• Step 3: Dehydrogenation of alcohol is catalyzed by β-hydroxyacyl-CoA dehydrogenase.
• Step 4: Transfer of fatty acid chain is catalyzed by acyl-CoA acetyltransferase (thiolase) via a covalent mechanism.

Fatty Acid Catabolism for Energy

• Repeating the four-step process six more times results in the complete oxidation of palmitic acid into eight molecules of acetyl-CoA.
• FADH2 and NADH are formed in each cycle, and acetyl-CoA enters the citric acid cycle and is further oxidized into CO2, producing more GTP, NADH, and FADH2.