Metabolic: lecture 27

Fatty Acid Synthesis

• Fatty acids are built in multiple steps, adding one acetate unit at a time. Synthesis is of 2 carbons at a time.
• Acetate units are derived from activated malonate, in the form of malonyl-CoA. This is the active form.
• The overall mechanism includes attaching a two-carbon unit (derived from malonyl-CoA) to a growing fatty acid chain, via an Acyl Carrier Protein (ACP). Then, reduction occurs.
• Acetyl CoA is converted to malonyl CoA for fatty acid chain elongation.

Stage 1: Malonyl-CoA Formation

• Acetyl-CoA carboxylase (ACC) is the enzyme that catalyzes the formation of malonyl-CoA from acetyl-CoA and HCO3⁻.
• ACC is a multi-subunit enzyme.
• It has three subunits, each containing a biotin molecule.
• Biotin is a cofactor that plays a crucial role in carboxylation reactions.
• The enzyme uses ATP and bicarbonate to form malonyl-CoA.

Stage 2: Fatty Acid Synthase (FAS)

• Acyl Carrier Protein (ACP) acts as a shuttle.
• ACP carries the substrate and product without leaving the protein.
• ACP has a prosthetic group (4'-phosphopantetheine).
• This group acts as a flexible arm that tethers the acyl chain.
• FAS delivers acetate in the first step, or malonate in the subsequent steps to the fatty acid synthase.
• It shuttles between active sites, during four-step reactions.
• Fatty acids are synthesized in units of 2 carbons at a time.

Fatty Acid Synthesis Regulation

• Acetyl-CoA carboxylase (ACC) is regulated by both feedback inhibition and allosteric activation.
• It is inactivated by palmitoyl-CoA.
• It is activated by citrate.
• Citrate from mitochondria enters the cytosol and activates ACC; citrate signals excess energy to convert to fat.
• ACC is a key enzyme in fatty acid synthesis.

Fatty Acid Cycle

• Fatty acids are synthesized by a repeating four-step reaction sequence.

• The stages involve: condensation, reduction from carbonyl to hydroxyl, dehydration to trans alkene, and reduction from alkene to alkane.

Overall Palmitate Synthesis

• 8 repeat to synthesize 16-carbon palmitate.
• Each cycle adds 2 carbons.

Palmitate Elongation

• Elongation systems (part of the endoplasmic reticulum and mitochondria) can be used to create longer fatty acids.
• Each elongation step adds 2 carbons.
• Stearate (18:0) is the most common product of elongation.

Fatty Acid Desaturation

• Double bonds are introduced to fatty acids through an enzyme-catalyzed reaction known as desaturation.
• Through desaturation reactions in the endoplasmic reticulum, unsaturated fatty acids are produced.
• Fatty acyl-CoA desaturase (a mixed function oxidase) is the enzyme responsible.
• NADPH provides the electrons required for the reaction.
• Oxygen acts as the final electron acceptor for the reaction.

Fatty Acid Metabolism Regulation

• High blood glucose: insulin activates ACC, which converts acetyl-CoA to malonyl-CoA; this inhibits fatty acid oxidation; FA synthesis increases.
• Low blood glucose: glucagon release leads to PKA and AMPK activation; this inactivates ACC, which reduces malonyl-CoA levels allowing fatty acid oxidation to proceed.

Synthesis of storage lipids

• Triglycerides are synthesized from glycerol-3-phosphate and fatty acids.
• Cholesterol is another type of storage lipid.

Synthesis of Phospholipids

• Phosphatidic acid is the precursor to phospholipids and triglycerides.
• Phosphatidic acid phosphatase removes the phosphate group, producing 1,2-diacylglycerol.
• The 3rd carbon of 1,2-diacylglycerol can then be acylated, yielding the triacylglycerol.