54. Biochemistry -- Lipid Metabolism I Synthesis of Palmitate & Related Molecules

All Lipids are Derived from Acetyl-CoA

• Acetyl-CoA is an activated form of acetic acid
• It is a high-energy intermediate due to the thioester bond
• Acetyl-CoA plays a central role in lipid metabolism just like G6P in carbohydrate metabolism

Fatty Acid (FA) Structure and Nomenclature

• Fatty acids are monocarboxylic hydrocarbons with varying carbon chain lengths (5-26 carbons)
• Physiologically important FAs typically have chain lengths of 16-18 carbons
• Palmitate (16:0) is the primary product of de novo FA synthesis

Key Points about Fat Synthesis

• Palmitate synthesis requires Acetyl-CoA, ATP, NADPH, and two enzymes: Acetyl-CoA Carboxylase and Fatty Acid Synthase
• All palmitate carbons originate from Acetyl-CoA, added two carbons at a time
• Fatty acid synthesis takes place in the cytoplasm

Transfer of Acetyl-CoA from Mitochondrial Matrix to Cytosol

• Acetyl-CoA is produced in the mitochondrial matrix
• There is no membrane carrier for acetyl-CoA, but there is a carrier for citrate
• The Citrate Shuttle allows the continuous production of citrate in mitochondria and its cleavage in the cytoplasm

Acetyl-CoA Carboxylase: Activating the Acetyl Methyl Carbon

• Acetyl-CoA carboxylase catalyzes the carboxylation of acetyl-CoA to malonyl-CoA
• This activation step is required for the elongation of fatty acid chains

Palmitate (C16:0 FA) Synthesis by the Multifunctional Fatty Acid Synthase (FAS)

• Phosphopantetheine acts as an acyl group carrier during fatty acid synthesis
• FAS is a multifunctional enzyme with distinct domains responsible for specific reactions
• The FAS reaction cycle involves 7 repeated rounds of elongation and reduction
• The cycle is initiated by priming with acetyl-CoA
• The cycle involves recursive rounds of elongation and reduction
• The process concludes with hydrolytic release of palmitate

Alternate FA Products of the FAS

• FAS can also produce alternate FA products like myristate (C14:0) and stearate (C18:0)

Fatty Acid Neutralization and Activation for Group Transfer Reactions

• Newly synthesized fatty acids need to be activated for further metabolism
• Activation involves the attachment of CoA to form fatty acyl-CoA

Fatty Acid Elongation and Desaturation

• After palmitate synthesis, fatty acids can be elongated and desaturated
• Elongation adds two carbons to the fatty acid chain
• Desaturation introduces double bonds into the fatty acid chain

Essential Fatty Acids: Linoleate and α-linolenate

• Linoleate (ω-6 FA) and α-linolenate (ω-3 FA) are essential fatty acids
• They contain double bonds beyond carbon-9, which cannot be introduced by human enzymes

Fatty Acid-Derived Signaling Molecules: Eicosanoids

• Eicosanoids are a family of short-lived signaling molecules
• They act as local hormones, exerting effects on nearby cells
• Eicosanoid classes include prostaglandins, leukotrienes, thromboxanes, prostacyclins, and epoxyeicosatrienoic acids

Prostaglandin H2 Synthases (COX-1 and COX-2)

• COX-1 is constitutively expressed in most cell types
• COX-2 expression is regulated and increases during inflammation
• COX-1 is important for thromboxane formation in platelets and GI integrity
• COX-2 is involved in inflammation, and its inhibition is a target for anti-inflammatory therapy

COX Inhibitors

• Non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin inhibit COX activity
• Most NSAIDs inhibit both COX-1 and COX -2
• Selective COX-2 inhibitors, like Celebrex and Vioxx, have been developed

Mobilization of Arachidonate

• Arachidonate is a 20-carbon, polyunsaturated ω-6 FA derived from linoleate
• It is frequently found in phosphoglycerol membrane lipids
• Phospholipase A2 releases arachidonate from membrane phospholipids
• Corticosteroids inhibit PLA2 activity, reducing arachidonate release

Products of Linear and Cyclic Pathways

• Lipoxygenases catalyze the synthesis of leukotrienes from arachidonate (linear pathway)
• PGH2 Synthase catalyzes the synthesis of prostaglandin H2 from arachidonate (cyclic pathway)
• PGH2 is then converted into other prostaglandins, prostacyclins, and thromboxanes
• PGH2 Synthase is also known as cyclooxygenase (COX) due to its cyclization activity
• COX is a heme-containing dioxygenase, bound to ER membranes.

Two Isoforms of COX

• COX-1 is constitutively expressed and is essential for thromboxane formation and GI integrity
• COX-2 is inducible and is involved in inflammation
• Aspirin irreversibly inhibits both COX-1 and COX -2, reducing prostaglandin and thromboxane synthesis
• Selective COX-2 inhibitors are used to treat inflammatory diseases while minimizing GI side effects