W9 Metabolism of Glycolipids, Isoprenoids and Steroids Flashcards
what are the possible starting points for synthesis of phosphatidic acid (first step of glycerolipid synthesis)
glycerol
diacylglycerol
dihydroxyaceton phosphate
how is glycerol converted to phosphatidic acid
phosphorylation of glycerol using ATP via glycerokinase into glycerol-3-P
1st transfer of acyl group to C1 using glycerol-3-P acyltransferase into 1-acylglycerol-3-P
2nd transfer of acyl group to C2 using same enzyme to form phosphatidic acid
how is diacylglycerol converted into phosphatidic acid
phoshorylation using ATP via diacylglycerol kinase into phosphatidic acid
1st way dihydroxyacetone-P can be converted into phosphatidic acid
transfer of acyl group to C1 using dihydroxyacetone-P acyltransferase to form 1-acyldihydroxyaceton-P
reduction of C=O using NADPH via acyldihydroxyacetone-P reductase into 1-acylglycerol-3-P
transfer of acyl group using 1-acylglycerol-3-P acyltransferase into phosphatidic acid
2nd way dihydroxyacetone-P can be converted into phosphatidic acid
reduction into glycerol-3-P using NADH via glycerol-3-P dehydrogenase
transfer of acyl group via glycerol-3-P acyltransferase into 1-acylglycerol-3-P
2nd transfer of acyl group using 1-acylglycerol-3-P acyltransferase into phosphatidic acid
what happens to phosphatidic acid in eukaryotes
converted directly either to diacylglycerol or cytidine disphophodiacylglycerol (CDP-diacylglycerol)
diacylglycerol is a precursor for synthesis of triacylglycerol, phosphatidylethanolamine and phosphatidylcholine
how is biosynthesis of triacylglycerols in intestines different
triacylglycerols from diet broken down into 2-monoglycerols by specific lipases
acyltransferases then acylate 2-monoglycerol to produce new triacylglycerols
describe the interconversion of phosphatidylethanolamine and phosphatidylserine
phosphatidylserine synthesised from phoshatidylethanolamine in ER using phosphatidylserine synthase 2
reverse reaction using phospatidylserine decarboxylase in mitochondria
how is phosphatidic acid activated to CDP-diacylglycerol
reaction of CTP with phosphatidic acid catalysed by CDP-diacylglycerol synthase
reaction is driven forward by enzymatic hydrolysis of pyrophosphate catalysed by the ubiquitous pyrophosphate
how is CDP-diacylglycerol used as precursor for synthesis of other phospholipids
can be converted to phosphatidylinositol, phosphatidylglycerol and cardiolipin
how does ceramide act as precursor of shingolipids
transfer of phoshocholine from phosphatidylcholine produces sphingomyelin
glycosylation of ceramide by sugar nucleotides yields cerebrosides like galactosylceramide which makes up 15% of the lipids of myelin sheath structures
what are globosides
sphingolipids with more than one sugar residues
how is cerebroside further converted to gangliosides
using CMP-sialic acid and sialytransferase
cerebrosides containing one or more sialic acid moieties are called gangliosides
what are eicosanoids
derived from 20C fatty acids
are the breakdown products of phospholipids
biologically active eicosanoids are short-lived, locally acting hormones
what are the 3 main forms cholesterol is exported as
biliary cholesterol
bile acids
cholesteryl esters
what is arachinodic acid a precursor of
prostaglandins, thromboxane and leukotriene
how is biosynthesis of prostaglandins initiated
initiated by enzyme prostaglandin endoperoxide H synthase (PGHS)/ cyclooxygenase (COX)
enzyme first introduces 2 molecules of O2 to arachidonic acid > form PGG2 > POX activity converts PGG2 into PGH2 using glutathione
how does aspirin inhibits prostaglandin biosynthesis
inhibits COX enzymes by irreversibly acetylating serine at active site > blocks active site > prevent binding of arachidonic acid
what are the 3 distinct processes in cholesterol biosynthesis
- conversion of C2 fragments (acetate) to a C6 isoprenoid precursor (mevalonate)
- conversion of six C6 mevalonates via activated C5 intermediates to the C30 squalene
- cyclisation of squalene and its transformation to the C27 cholesterol
explain the process of synthesis of mevalonate
cholesterol biosynthesis begins in cytosol with synthesis of mevalonate from acetyl-CoA
rate limiting step catalysed by HMG-CoA reductase > responsible for formation of 3R-mevalonate via 2 NADPH-dependent reductions to produce 3R-mevalonate
how is squalene synthesised from mavalonate
mevalonate converted to 5-pyrophosphomevalonate > isopentenyl pyrophosphate (5C)
isomerisation of double bond in isopentenyl pyrophosphate yields dimethylallyl pyrophosphate (5C)
condensation of the two 5C intermediates reduces geranyl pyrophosphate > addition of another 5C isopentenyl group > farnesyl pyrophosphate (occurs in cytosol)
farnesyl pyrohosphate converted to squalene using NADPH (occurs in the ER)
how is cholesterol synthesised from squalene
ER enzyme bound, squalene monooxygenase converts squalene to squalene-2,3-epoxide; reaction employs FAD and NADPH as coenzymes and requires O2
a second ER membrane enzyme, 2,3-oxidosqualene lanosterol cyclase catalyses the succession of 1,2 shifts of hydride ions and methyl groups to form lanosterol
another 20 steps required to convert lanosterol to cholesterol with enzymes all associated with the ER
how are bile salts synthesised from cholesterol
conversion of cholesterol to 7 alpha-hydroxycholesterol using 7alpha-hydroxylase (limiting step) > alpha-hydroxyl group formed at position 7 of cholesterol
reduction, hydroxylation and conversion of hydroxyls to alpha > oxidation of side chain > chenodeoxycholic acid and colic acid formed
what is the fate of HDL
nascent HDL is synthesised in the liver and intestinal cells > exchanges proteins with chylomicrons and VLDL
HDL picks up free cholesterol from cell membranes > converted into cholesterol ester (CE) by lecithin-cholesterol acyltransferase (LCAT) dependent reaction
HCL transfers CE to VLDL in exchange for triacylglycerols via cholesterol transfer protein (CETP)
how are steroid hormones synthesised from cholesterol
begins with desmolase (found in mitochondria of tissues that synthesise steroids) reaction > converting cholesterol to pregnenolone > transported to ER > hydroxyl oxidation and migration of double bond produces progesterone
progesterone becomes precursor of other sex hormone steroids and corticosteroids
how is cholesterol synthesis regulated
rate limiting step: conversion of HMG CoA to mevalonate
HMG-CoA reductase regulated covalently by PP2A, PKA, and AMPK
glucagon promotes phosphorylation > inactivation of HMG CoA > reduce cholesterol synthesis
insulin promotes dephospho rylation > activation of HMG CoA > increase cholesterol synthesis
intracellular cholesterol concentrations
what is oxysterol
derivative of cholesterol with dual functions:
- promote degradation of HMG-CoA > reduce synthesis of mevalonate
- prevent receptor-mediated endocytosis > reduce cholesterol concentration
