Chapter 21
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### 1. Overview
- Main topics covered:
- Fatty Acid Biosynthesis
- Desaturases, Oxidases, Eicosanoids
- Triacylglycerol (TAG) Synthesis
- Phospholipids Synthesis
- Cholesterol Biosynthesis
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### 2. Fatty Acid Biosynthesis
- Basics of Fatty Acid Synthesis:
- Fatty acids are synthesized by adding two-carbon units from malonyl-CoA.
- Malonyl-CoA is formed from acetyl-CoA and bicarbonate by the enzyme Acetyl-CoA Carboxylase (ACC).
- Key Reaction Steps:
- Four main steps in fatty acid synthesis:
1. Condensation: The growing chain is combined with an activated acetate.
2. Reduction: A carbonyl group is reduced to a hydroxyl group.
3. Dehydration: The hydroxyl group is removed, forming a trans-alkene.
4. Reduction: The alkene is reduced to an alkane.
- Fatty Acid Synthase (FAS):
- A multi-enzyme complex that catalyzes these reactions.
- FAS I: Found in vertebrates and fungi, produces mainly palmitate (16:0).
- FAS II: Found in plants and bacteria, produces diverse fatty acids (saturated, unsaturated, and branched).
- Uses NADPH as an electron donor.
- Growing chain is carried by Acyl Carrier Protein (ACP).
- Energy and Location:
- Fatty acid biosynthesis occurs in the cytosol of adipocytes, hepatocytes, and mammary glands.
- Citrate transports acetyl-CoA from mitochondria to the cytosol.
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### 3. Regulation of Fatty Acid Synthesis
- Key Regulatory Enzyme: Acetyl-CoA Carboxylase (ACC)
- Inhibited by palmitoyl-CoA (product of fatty acid synthesis).
- Activated by citrate and ATP (signaling excess energy).
- Hormonal regulation:
- Insulin activates ACC (through dephosphorylation).
- Glucagon and epinephrine inhibit ACC (by phosphorylation).
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### 4. Desaturation and Elongation of Fatty Acids
- Elongation:
- Occurs in the endoplasmic reticulum (ER) and mitochondria, adding two carbon units to existing fatty acids.
- Desaturation:
- Mammals can introduce double bonds up to the Δ9 position (e.g., palmitate to palmitoleate, stearate to oleate).
- Plants can desaturate beyond Δ9, producing essential fatty acids like linoleate (18:2) and α-linolenate (18:3).
- Desaturation catalyzed by fatty acyl-CoA desaturase, a mixed-function oxidase.
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### 5. Oxidases vs. Oxygenases
- Oxidases:
- Don’t incorporate oxygen into the product (e.g., fatty acyl-CoA desaturase).
- Oxygenases:
- Incorporate oxygen into the product, classified as monooxygenases or dioxygenases.
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### 6. Eicosanoids and Prostaglandins
- Eicosanoids:
- Potent hormones derived from arachidonic acid (20:4).
- Produced by cyclooxygenase (COX) enzymes in response to stimuli (e.g., inflammation).
- COX-1 and COX-2:
- COX enzymes convert arachidonate to prostaglandins, thromboxanes, and leukotrienes.
- NSAIDs (aspirin, ibuprofen) inhibit COX, reducing inflammation and pain.
- COX-2 inhibitors like Vioxx were developed to avoid gastrointestinal side effects but had cardiovascular risks.
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### 7. Triacylglycerol (TAG) and Phospholipids Synthesis
- Triacylglycerol (TAG) Synthesis:
- Stored as fat in adipocytes and liver, providing energy reserves.
- Glycerol-3-phosphate (from glycolysis) acts as a precursor.
- Acyl transferases add fatty acids to glycerol-3-phosphate, forming phosphatidic acid, which can lead to TAG or phospholipid synthesis.
- Even during starvation, TAG synthesis occurs via glyceroneogenesis.
- Regulation:
- Insulin stimulates TAG synthesis.
- Glucagon and epinephrine stimulate TAG breakdown.
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### 8. Cholesterol Biosynthesis
- Pathway Overview:
- Cholesterol is synthesized from acetyl-CoA in the liver through a multi-step process:
1. Formation of Mevalonate (from acetyl-CoA via HMG-CoA reductase).
2. Conversion to activated isoprenes.
3. Formation of Squalene from six isoprenes.
4. Cyclization of Squalene to form cholesterol.
- Regulation:
- HMG-CoA reductase is the rate-limiting enzyme, regulated by feedback inhibition, phosphorylation, and proteolytic degradation.
- Statins inhibit HMG-CoA reductase to lower cholesterol levels.
- Fates of Cholesterol:
- Cholesterol is used in membranes, bile acids, and steroid hormones, and is transported via lipoproteins.
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### 9. Lipoproteins and Cholesterol Transport
- Classes of Lipoproteins:
- Chylomicrons: Transport dietary fats from the intestines to tissues.
- VLDL (Very Low-Density Lipoproteins): Deliver triacylglycerols to tissues, become LDL after losing TAGs.
- LDL (Low-Density Lipoproteins): Deliver cholesterol to tissues (high levels linked to atherosclerosis).
- HDL (High-Density Lipoproteins): Return excess cholesterol to the liver for disposal (protective role).
- Cholesterol and Cardiovascular Disease:
- High LDL levels are associated with atherosclerosis and heart disease.
- HDL helps remove cholesterol, preventing plaque buildup.
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