Lipid Biosynthesis and Metabolism

Lipid Biosynthesis Learning Objectives

• Lipid biosynthesis is vital for various functions
• Fatty acid biosynthesis involves acetyl-CoA carboxylase and fatty acid synthase, encompassing chemical changes and utilizing ATP
• Fatty acid elongation and desaturation processes are briefly explained
• Conversion of carbohydrates and amino acids to fatty acids is described
• Regulation of lipid metabolism correlates with blood glucose levels
• Triacylglycerols, phospholipids, eicosanoids, and cholesterol biosynthesis are part of the overall process

Subcellular Lipid Metabolism Locations

• Animal cells/yeast cells: Mitochondria are crucial for fatty acid oxidation, acetyl-CoA production, ketone body synthesis, and fatty acid elongation. The endoplasmic reticulum handles phospholipid and sterol synthesis (later stages), as well as fatty acid elongation and desaturation. The cytosol is where NADPH production (via pentose phosphate pathway and malic enzyme) occurs, along with earlier stages of isoprenoid/sterol synthesis and fatty acid synthesis. Malate is converted to pyruvate through a malic enzyme-catalyzed reaction, and NADP is converted to NADPH.
• Plant cells: Chloroplasts are the site of NADPH and ATP production, and fatty acid synthesis. Glyoxysomes are involved in fatty acid oxidation.

Fatty Acid Biosynthesis

• Fatty acids are synthesized in the cytosol, not a simple reversal of fatty acid oxidation
• Palmitic acid (16:0) biosynthesis involves 8 acetyl-CoA, 7 ATP, 14 NADPH and 14 H⁺ molecules. The process ends up giving palmitic acid, 7ADP, 7Pi, 14 NADP⁺, 6H₂O and 8 coenzyme-A
• Two enzymes are involved in this process: Acetyl-CoA Carboxylase and Fatty Acid Synthase

Acetyl-CoA Carboxylase (ACC)

• ACC catalyses the carboxylation of acetyl CoA to yield malonyl CoA
• This reaction is a committed step in fatty acid biosynthesis in animals

Fatty Acid Synthase (FAS) complex

• FAS is a multi-enzyme protein complex with three polypeptides
• Acyl Carrier Protein (ACP), a subunit, contains phosphopantetheine for acyl chain attachment
• Cycles of condensation, reduction, dehydration and reduction reactions occur during acyl chain lengthening
• The fatty acyl chain with 16 carbons is cleaved from ACP at the end of the reaction.

Triclosan

• Triclosan, an antibacterial chemical, inhibits fatty acid synthesis by specifically blocking enoyl-ACP reductase.

Transport of acetyl-CoA

• Acetyl-CoA is carried from the mitochondria into the cytosol for fatty acid synthesis via a tricarboxylate transport system.
• Sources include pyruvate from glucose catabolism. The pyruvate is converted into Acetyl CoA

Elongation and Desaturation of Fatty Acids

• Palmitate is the starting material for elongation and desaturation of longer-chain fatty acids, including stearate and oleate.
• Elongation increases the number of carbons
• Desaturation introduces double bonds

Essential Fatty Acids

• Animals cannot synthesize certain fatty acids like linoleate and α-linolenate; thus, they are essential dietary components
• Plants can produce a variety of polyunsaturated fatty acids from oleate. These can be further desaturated

Biosynthesis of Glycerophospholipids

• Glycerophospholipids have a glycerol backbone
• Two main pathways activate polar head groups (e.g., ethanolamine or choline) using CTP, producing CDP-ethanolamine or CDP-choline, respectively
• The phosphoryl group then attacks CTP, forming CDP-ethanolamine or CDP-choline. The PPi product is further hydrolyzed
• The activated head groups are transferred to diacylglycerol to generate the glycerophospholipids.

Biosynthesis of Sphingolipids

• Sphingolipids have a sphinganine backbone (a C18 amino alcohol)
• Palmitoyl-CoA and serine are the starting materials
• Several reactions (including 3-ketosphinganine synthase, 3-ketodihydrosphingosine reductase) lead to sphinganine
• N-acylsphinganine (dihydroceramide) is then formed from sphinganine through acyl-CoA transferase
• Further reactions produces ceramide, a precursor to other sphingolipids
• Different sphingolipids (like sphingomyelin and gangliosides) are produced by adding different polar head groups to ceramide

Biosynthesis of Eicosanoids

• Eicosanoids are potent signaling molecules derived from arachidonic acid
• Examples include prostaglandins (pain and inflammation regulators) and thromboxanes (involved in blood clotting)

Prostaglandin H₂ synthase (COX)

• COX is involved in eicosanoid synthesis
• It has two catalytic activities: cyclooxygenase and peroxidase
• Two isoforms exist (COX-1 and COX-2), with different functions

Different Pain Killers/Anti-inflammatory Drugs Targeting COX

• Drugs target COX enzymes, inhibiting inflammation
• Aspirin (acetylsalicylic acid) is a common example
• Other drugs include ibuprofen, rofecoxib (Vioxx), and celecoxib (Celebrex)

Salicylic Acid

• Salicylic acid is a natural pain-reliever found in willow bark
• Structurally related to aspirin
• Naturally, plant hormones suppress diseases and wilting

Cholesterol Biosynthesis

• Cholesterol biosynthesis is a complex process with several steps
• The process starts from squalene and involves reactions to form cholesterol
• Multiple enzymes and intermediate molecules are involved in cholesterol biosynthesis

Cholesterol-Lowering Drugs

• Drugs that lower cholesterol (e.g., lovastatin and atorvastatin) are structural analogs of HMG-CoA. They competitively inhibit the enzyme HMG-CoA reductase.

Fates of Newly Synthesized Cholesterol

• Newly synthesized cholesterol can be incorporated into the cell membrane
• It can be used to make steroid hormones like testosterone and estrogen
• Cholesterol is packaged as a cholesteryl ester in lipoproteins.

Summary of Lipid Metabolism

• Triacylglycerol, phospholipid/sphingolipid, eicosanoid, and cholesterol metabolism are outlined in a comprehensive diagram.
• Metabolism of these molecules all link to Carbohydrates via Acetyl CoA and oxidative phosphorylation.

Explore the essential processes of lipid biosynthesis, including fatty acid synthesis and its regulation in relation to glucose levels. This quiz covers the various pathways involved in lipid metabolism across different subcellular locations, such as mitochondria and the endoplasmic reticulum. Test your knowledge on key enzymes and the conversion processes of nutrients into lipids.