Chapter25

Chapter25 - BCH 4054Fall 2000 Chapter 25 Lecture Notes...

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Chapter 25, page 1 BCH 4054—Fall 2000 Chapter 25 Lecture Notes Slide 1 Chapter 25 Lipid Biosynthesis Slide 2 Chapter Topics • Fatty Acid Biosynthesis • Chain elongation and unsaturated FA’s. • Complex Lipid Biosynthesis • Glycerolipids and Sphingolipids • Eicosanoid Biosynthesis • Cholesterol Biosynthesis • Bile Acids and Steroids • Lipoproteins Slide 3 Fatty Acid Biosynthesis • Starting precursor is acetyl-CoA • Occurs in cytoplasm, not in mitochondria • Citrate is the “carrier” of acetyl-CoA formed in the mitochondria to the cytoplasm. • See Fig. 25.1
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Chapter 25, page 2 Slide 4 Fatty Acid Biosynthesis, con’t. • Not simply the reverse of Fatty Acid oxidation, though the chemistry is similar. • Energy difference from two reactions: • “Activation” of acetyl-CoA to make C-C bond formation irreversible. • NADPH as electron donor in double bond reduction (FAD was acceptor in oxidation) The activation of acetyl-CoA requires an ATP for each C-C bond formed, whereas the breaking of C- C bonds by thiolase was a reversible reaction, near equilibrium. NADP has a lower reduction potential (- 0.32 volts) than a flavoprotein (~ 0.0 volts), making the reduction of the double bond favored. Slide 5 Malonyl-CoA an Intermediate • “Activation Step” Acetyl-CoA + ATP + CO 2 acetyl-CoA carboxylase Malonyl-CoA + ADP + P i • A biotin enzyme. • Mechanism similar to: • Pyruvate carboxylase • Propionyl-CoA carboxylase • (See Fig.’s 25.2 and 25.3) Slide 6 Acetyl-CoA Carboxylase • Bacterial enzyme contains three subunits: • Biotin carboxylase • Biotin carboxy carrier protein • Transcarboxylase • Animal enzyme is a single multifunctional protein with three domains on one 230 kD polypeptide chain. • Protomer inactive, polymeric form active.
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Chapter 25, page 3 Slide 7 Regulation of Acetyl-CoA Carboxylase • Good candidate for regulation. • First “committed” step to fatty acids. • Reaction far from equilibrium. • Allosteric regulation: • Citrate activates (promotes polymeric form) • Fatty Acyl-CoA inhibits • Covalent regulation by phosphorylation: • Increases K m for citrate, lowers K i for fatty acyl-CoA • Fig. 25.5 Note that citrate plays two roles: one as the activator of acetyl-CoA carboxylase, the other as the carrier of acetyl units across the mitochondrial membrane. Inhbition by fatty-acyl CoA is an example of end-product inhibition. Hormonally stimulated phosphorylation has the effect of turning off fatty acid synthesis by making the inhibitor more effective and the activator less effective. Slide 8 Fatty Acid Synthase • Overall reaction: CH 3 CO-SCoA + n HOOCCH 2 CO-SCoA + 2n NADPH Fatty Acid Synthase (FAS) CH 3 (CH 2 CH 2 ) n CO-SCoA + n CO 2 + 2n NADP • Chemistry similar to oxidation spiral, But • Intermediates bound to acyl carrier protein ( ACP ), not CoASH (Fig. 25.6) Slide 9 Fatty Acid Synthase • Total of seven enzymatic reactions: (Fig. 25.7) • Acetyl transacylase (
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Chapter25 - BCH 4054Fall 2000 Chapter 25 Lecture Notes...

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