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Unformatted text preview: Lecture 21
Overview: • synthesis of phospholipids and triacylglycerol - role of phosphatidate • cholesterol biosynthesis from acetyl CoA (three stages) • regulation of cholesterol biosynthesis • important derivatives of cholesterol: bile salts and hormones HW: 26.3, 26.10, 26.13 Synthesis of phosphatidate Chapter 26 The Biosynthesis of Membrane Lipids and Steroids glycerol phosphate acyltransferase phosphatidate is synthesized in the ER and outer mitochondrial membrane; G3P is from glycolysis and glycerol; attachment of two fatty acids One role of phosphatidate hydrolyzed (remove phosphate) by speciﬁc phosphatase to a diacylglycerol; then acylated with a third fatty acid to generate a triacylglycerol by diglyceride acyltransferase; both enzymes are part of a complex called triacylglycerol synthetase Another role of phosphatidate Use of activated diacylglcerol generation of an activated intermediate: CDP-diacylglycerol (CDP = cytidine diphospho); what drives this reaction?? Synthesis of cardiolipin If the alcohol is phosphatidylglycerol, cardiolipin is formed, an important component of membranes used in oxidative phosphorylation. Role of an activated alcohol: phosphorylated ethanolamine The methyl donor is S-adenosylmethionine (SAM). p. 690 Phosphatidylcholine is used to generate phospholipids (Ch. 12). Phosphatidylserine makes up about 10% of phospholipids in mammals. It is synthesized by a base-exchange reaction. phosphatidylcholine + serine -> choline + phosphatidylserine phosphatidylethanolamine + serine -> ethanolamine + phosphatidylserine Sphingolipids are synthesized from ceramide Cholesterol biosynthesis: role of acetyl CoA biological roles of cholesterol: 1) modulate ﬂuidity of cell membranes, 2) precursor of steroid hormones note use of two-carbon units Synthesis of sphingolipids various biochemical roles 27-carbon unit assembled in three stages Three stages of cholesterol biosynthesis 1) synthesis of isopentenyl pyrophosphate (activated isoprene unit) 2) condensation of six molecules of isopentyl pyrophosphate to form squalene 3) cyclization of squalene and ﬁnal conversion to cholesterol Stage one, step one: Three stages of cholesterol biosynthesis Stage one, step two: Stage one, step three: recall synthesis of ketone bodies (Ch. 22) Three stages of cholesterol biosynthesis C5 -> C10 -> C15 -> C30 Stage two: synthesis of squalene from isoprene Three stages of cholesterol biosynthesis Stage two, step two: Stage two, step one: isomerization condensation (isoprenyl to geranyl unit): C5 -> C10 Three stages of cholesterol biosynthesis Three stages of cholesterol biosynthesis Stage two, step four: condensation (farnesyl to squalene unit): C15 -> C30 (tailto-tail coupling) Can you still identify the isoprene units? Stage two, step three: condensation (geranyl to farnesyl unit): C10 -> C15 Can you identify the isoprene units? 2 farnesyl pyrophosphate (C15) + NADPH -> squalene (C30) + 2 PPi + NADP+ + H+ Three stages of cholesterol biosynthesis Three stages of cholesterol biosynthesis Stage three, step two: conversion of lanosterol to cholesterol in a complex process (19 steps!) Stage three, step one: cyclization of squalene by oxidosqualene cyclase Regulation of cholesterol biosynthesis SREBP pathway Lipoprotein transport of cholesterol and triacylglycerol Overview of lipoprotein particle metabolism Do you know the target(s) of anti-cholesterol drugs? Synthesis of bile salts Synthesis of hormones Nomenclature and structures Steroid are hydroxylated by cytochrome P450 monooxygenases Coenzyme = NADPH Synthesis of hormones Synthesis of hormones Synthesis of hormones Synthesis of vitamins ...
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