W9 Metabolism of Glycolipids, Isoprenoids and Steroids

Question 1

what are the possible starting points for synthesis of phosphatidic acid (first step of glycerolipid synthesis)

Answer 1

glycerol

diacylglycerol

dihydroxyaceton phosphate

Question 2

how is glycerol converted to phosphatidic acid

Answer 2

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

Question 3

how is diacylglycerol converted into phosphatidic acid

Answer 3

phoshorylation using ATP via diacylglycerol kinase into phosphatidic acid

Question 4

1st way dihydroxyacetone-P can be converted into phosphatidic acid

Answer 4

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

Question 5

2nd way dihydroxyacetone-P can be converted into phosphatidic acid

Answer 5

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

Question 6

what happens to phosphatidic acid in eukaryotes

Answer 6

converted directly either to diacylglycerol or cytidine disphophodiacylglycerol (CDP-diacylglycerol)

diacylglycerol is a precursor for synthesis of triacylglycerol, phosphatidylethanolamine and phosphatidylcholine

Question 7

how is biosynthesis of triacylglycerols in intestines different

Answer 7

triacylglycerols from diet broken down into 2-monoglycerols by specific lipases

acyltransferases then acylate 2-monoglycerol to produce new triacylglycerols

Question 8

describe the interconversion of phosphatidylethanolamine and phosphatidylserine

Answer 8

phosphatidylserine synthesised from phoshatidylethanolamine in ER using phosphatidylserine synthase 2

reverse reaction using phospatidylserine decarboxylase in mitochondria

Question 9

how is phosphatidic acid activated to CDP-diacylglycerol

Answer 9

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

Question 10

how is CDP-diacylglycerol used as precursor for synthesis of other phospholipids

Answer 10

can be converted to phosphatidylinositol, phosphatidylglycerol and cardiolipin

Question 11

how does ceramide act as precursor of shingolipids

Answer 11

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

Question 12

what are globosides

Answer 12

sphingolipids with more than one sugar residues

Question 13

how is cerebroside further converted to gangliosides

Answer 13

using CMP-sialic acid and sialytransferase

cerebrosides containing one or more sialic acid moieties are called gangliosides

Question 14

what are eicosanoids

Answer 14

derived from 20C fatty acids

are the breakdown products of phospholipids

biologically active eicosanoids are short-lived, locally acting hormones

Question 15

what are the 3 main forms cholesterol is exported as

Answer 15

biliary cholesterol

bile acids

cholesteryl esters

Question 16

what is arachinodic acid a precursor of

Answer 16

prostaglandins, thromboxane and leukotriene

Question 17

how is biosynthesis of prostaglandins initiated

Answer 17

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

Question 18

how does aspirin inhibits prostaglandin biosynthesis

Answer 18

inhibits COX enzymes by irreversibly acetylating serine at active site > blocks active site > prevent binding of arachidonic acid

Question 19

what are the 3 distinct processes in cholesterol biosynthesis

Answer 19

1. conversion of C2 fragments (acetate) to a C6 isoprenoid precursor (mevalonate)
2. conversion of six C6 mevalonates via activated C5 intermediates to the C30 squalene
3. cyclisation of squalene and its transformation to the C27 cholesterol

Question 20

explain the process of synthesis of mevalonate

Answer 20

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

Question 21

how is squalene synthesised from mavalonate

Answer 21

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)

Question 22

how is cholesterol synthesised from squalene

Answer 22

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

Question 23

how are bile salts synthesised from cholesterol

Answer 23

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

Question 24

what is the fate of HDL

Answer 24

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)

Question 25

how are steroid hormones synthesised from cholesterol

Answer 25

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

Question 26

how is cholesterol synthesis regulated

Answer 26

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

Question 27

what is oxysterol

Answer 27

derivative of cholesterol with dual functions:

1. promote degradation of HMG-CoA > reduce synthesis of mevalonate
2. prevent receptor-mediated endocytosis > reduce cholesterol concentration