CHOLESTEROL BIOSYNTHESIS

 

·        All 27 Cs are derived from acetyl-CoA.  (p. 243; Fig. 9-10)

·        Discovery of isoprene (C5); p. 671) and squalene (C30 ; see Figs. 19-39, 40)

·        Serendipitous discovery of relationship between acetate and mevalonate (C6).

Mevalonate could substitute for acetate for growth of acetate-requiring bacterial mutant.

 

 

FOUR STAGES OF CHOLESTEROL SYNTHESIS

 

1.   Acetate ® Mevalonate  (by three cytosolic enzymes)

 

·        Thiolase

 

 

·       
Hydroxymethylglutaryl-CoA synthase

                                                                                 b-Hydroxymethylglutaryl-CoA (HMG-CoA)

 

·        HMG-CoA reductase  (Fig. 19-38)

·        The first two enzymes in cytosol are involved in cholesterol synthesis, whereas the corresponding mitochondrial enzymes are involved in ketone body (acetoacetate) synthesis.

·        The synthesis of mevalonate is irreversible, and is the rate-determining step in cholesterol synthesis.

·        HMG-CoA reductase can be inhibited by cholesterol.

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2.   a.  Mevalonate ®® Isopentenyl pyrophosphate (IPP)       (Fig. 19-38)

      b.  IPP ⇌ Dimethylallyl pyrophosphate (DMP) by isopentenyl pyrophosphate isomerase (p. 672)

 

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3.   (IPP +  DMP) ®®® Squalene  (Fig. 19-39)

 

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4.   Squalene ®®® Cholesterol

·        squalene ® 2,3-oxidosqualene (Fig. 19-40) catalyzed by squalene epoxidase, requires NADPH.

·        2,3-oxidosqualene ® lanosterol (Fig. 19-41)

·        lanosterol ® cholesterol by 19 steps

(Need to know structures of 2,3-oxidosqualene and lanosterol.)

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COMPLEX LIPIDS

 

 

1. Phosphatidic Acid, Diacylglycerol, Triacylglycerol.  (Fig. 19-30)

·        Phosphatidic acid, diacylglycerol, and triacylglycerol are all synthesized from fatty acyl-CoA and glycerol-3-phosphate or dihydroxyacetone phosphate.

·        The acyltransferases are not completely specific for any particular acyl-CoA with respect to either chain length or degree of unsaturation.  However, in human adipose tissue triacylglycerols, 1-acyl group is mostly saturated (especially the C-16 palmitoyl) and the 2-acyl group is mostly unsaturated (especially the C-18, cis-D9 oleyl).

 

2. Phosphatidylethanolamine, Phosphatidylcholine, and Phosphatidylserine

·        Both ATP and CTP are required to activate ethanolamine and choline.  The activated metabolites subsequently react with 1,2-diacylglycerol to generate phosphatidylethanolamine and phosphatidylcholine.  (Fig. 19-34)

·        Phosphatidylserine can be obtained from phosphatidylethanolamine and serine by an exchange reaction.  (p. 664)

 

3. Phosphatidylinositol and Phosphatidylglycerol

·        Both Phosphatidylinositol and Phosphatidylglycerol are from Phosphatidic Acid (Fig. 19-35).

·        CTP is required to activate phosphatidic acid to form CDP-diacylglycerol.