The Biosynthesis of Membrane Lipids and Steroids StryerChapter 26

1
The Biosynthesis of Membrane Lipids and
Steroids(Stryer-Chapter 26)
BCH/OBI 812 November10, 2003 C. Waechter
Phosphatidate is a key intermediate in the
biosynthesis of triacylglycerols and membrane
phospholipids
Triacylglycerols formed in the liver are packaged
as VLDLs And delivered to muscle and adipocytes
via lipoprotein lipase
2
(No Transcript)
3
-2-
CDP-Diacylglycerol (CDP-DAG) is an activated
phosphatidyl donor for the biosynthesis of
several membrane phospholipids
Formation from phosphatidate and CTP
Reaction is driven by the hydrolysis of PPi
4
Biosynthesis of phosphatidylserine (PS) and
phosphatidylinositol (PI) from CDP-DAG
(or inositol)
(phosphatidylinositol)
5

• Major mechanisms for the biosynthesis of
• phosphatidylcholine (PC)/phosphatidylethanolamine
  (PE)
• Via CDP-choline/CDP-ethanolamine (in ER)

Phosphatidylcholine is formed from free
choline by same mechanism involving different
enzymes
6
2) PS is translocated to inner membrane of
mitochondria and decarboxylated to PE PE is
then returned to ER and converted to PC by three
methylation reactions.
S-adenosylmethionine (SAM) functions as the
activated methyl donor
IM Mitochondria
ER
Platelet Activating Factor (PAF) A potent
bioactive analog of PC
Very low concentrations induce platelet
aggregation and smooth muscle contraction
7
Biosynthesis of sphingolipids from serine and
palmitoyl CoA
8
Glycosphingolipids Cerebrosides/Gangliosides
9
In one class of inherited disorders,
sphingolipids accumulate in lysosomes due to a
genetic defect in a specific sphingolipase In
Tay-Sachs disease ganglioside Gm2 accumulates
because of a deficiency in b-N-acetylhexosaminidas
e.
10
STRUCTURE AND BIOSYNTHESIS OF STEROLS
(CHOLESTEROL)
METABOLIC OVERVIEW
Acetate ? mevalonate ? isopentenyl-P-P ?
squalene ? cholesterol (C2)
(C6) (C5)
(C30) (C27)
11
HMG-COA IS THE PRECURSOR OF MEVALONATE
HMG-COA REDUCTASE, AN INTEGRAL MEMBRANE PROTEIN
IN THE ER, CATALYZES THE RATE-CONTROLLING STEP
IN CHOLESTEROL BIOSYNTHESIS
inhibited by
lovastatin (-) 3-Hydroxyl-3-methylglutaryl CoA
2 NADPH ? Mevalonate NADP CoA

• HMG-CoA activity is controlled by
• Transcriptional control of mRNA formation
• Translational control of polypeptide synthesis
• Regulated proteolysis of enzyme protein
• Phosphorylation of enzyme by AMP-activated
  protein kinase
• (phosphorylation decreases activity)

12
-7-
Complex regulation of HMG-CoA reductase occurs at
several levels and mechanisms
domain senses signals that lead to its
degradation.
13
(No Transcript)
14
CONVERSION OF MEVALONATE TO ISOPENTENYL-P-P
15
SQUALENE (C30) IS FORMED FROM 6 MOLECULES OF
ISOPENTENTYL-P-P (C5)
First two steps are head-to-tail
condensations Squalene is formed
by head-to-head condensation
Squalene synthase is blocked By squalestatin
16
-9-
SQUALENE EPOXIDE CYCLIZES TO LANOSTEROL WHICH IS
CONVERTED TO CHOLESTEROL
17
CHOLESTEROL SERVES AS A PRECURSOR OF BILE SALTS
(AND STEROID HORMONES)
18
(No Transcript)
19
(No Transcript)
20

LDL receptor-mediated endocytosis and regulation
of cholesterol metabolism
(Apo B-100 binds to LDL receptor)
Brown and Goldstein Nobel Prize
(Stryer-p. 341)