Fatty Acid Metabolism and Its Regulation

223 Pages·1984·2.66 MB·English

by  Unknown

FATTY ACID METABOLISM AND ITS REGULATION
New Comprehensive Biochemistry
Volume 7
General Editors
A. NEUBERGER
London
L.L.M. van DEENEN
Utrecht
ELSEVIER
AMSTERDAM-NEWY ORK.OXFORD
Fattv Acid Metabolism and Its
J
Regulation
Editor
Shosaku NUMA
Department of Medicul Chernistrv, Kvoto Unroerriry Facuity of Medicine, Kvoto 606
(Jupun)
1984
ELSEVIER
AMSTERDAM .NEW YORK-OXFORD
0 Elsevier Science Publishers B.V., 1984
All rights reserved. No part of this publication may be reproduced, stored
in a retrieval system, or transmitted, in any form or by any means, elec-
tronic, mechanical, photocopying, recording or otherwise without the prior
permission of the copyright owner.
ISBN for the series: 0444 80303 3
ISBN for the volume: 0444 80528 1
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Elsevier Science Publishers B.V.
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Sole distributors for the U.S.A. and Canada
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Library of Congress Cataloging in Publication Data
Main entry under title:
Fatty acid metabolism and its regulation.
(New comprehensive biochemistry ; v. 7)
Includes bibliographical references and index.
1. Acids, Fatty--Metabolism--Regulation. I. Numa,
.
Shcsaku, 1929- 11. Series. [DNIX: 1. Fatty acids
--Metabolism. 2. Fatty acids--Enzymology. W1 NE372F
v.7 / QU 90 F25191
GIh15.Nh8 vol. 7 [gF'752.F35] 574.19'2s 83-25471
ISBN 0-444-80528-1( U.S.) [ 57 4.1 ' 33I
Printed in The Netherlands
Preface
Since the topic of fatty acid metabolism was last treated in a previous volume of
this series, the main emphasis of research in this field has shifted towards the
molecular characterization of the enzymes involved and their regulation. Biochemi-
cal, molecular-biological and genetic studies carried out during the last decade or so
have provided considerable information as to the molecular and catalytic properties
and the control of the fatty acid-synthesizing and -degrading enzymes.
This volume is devoted to the recent progress in the field of fatty acid metabolism
and its regulation. The first three chapters cover the structural, functional, regulatory
and genetic aspects of acetyl-coenzyme A carboxylase and fatty acid synthetase from
animal, yeast and bacterial sources, which are responsible for fatty acid synthesis de
novo. Chapter 4 concerns the enzymology and control of desaturation and elonga-
tion of preformed fatty acids in mammals. In Chapter 5, the animal enzymes
involved in fatty acid oxidation and the regulation of this enzyme system are
extensively treated. The two final chapters deal with fatty acid synthesis and
degradation and the control of these processes in higher plants. It is hoped that all
the chapters, contributed by leading scientists in the specific areas, will serve those
who teach as well as those engaged in research.
Although the recent studies described have improved the understanding of fatty
acid metabolism and its regulation, many questions remain to be answered. In the
near future, some of the genes encoding the enzymes responsible for fatty acid
metabolism will be isolated and characterized by recombinant DNA techniques.
This approach will be useful for elucidating the structure, catalytic and regulatory
functions and evolution of the enzymes as well as the control of expression of the
genes.
Shosaku Numa
Kyoto, December 1983
This Page Intentionally Left Blank
Con tents
Preface .................................................. V
Chapter I
A cetyl-coenzyme A carboxylase and its regulation
Shosaku Numa and Tadashi Tanabe (Kyoto and Suita) . . . . . . . 1
1. Introduction ........................................... 1
2. Purification . . . . . . . . . . . . . . . . . . . . . . . .......... 2
3. Structure ............................................................. 3
a. Subunit structure . . . . . . . . . . . . . . . . .......... 3
b. Molecularforms ...................................................... 5
4. Reaction mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5. Regulation of acetyl-CoA carboxylase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
a. Activation and inhibition ............... 11
b. Phosphorylation and deph 16
c. Synthesis and degradation 17
6. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
References ............................................................ 23
Chapter 2
Animal and bacterial fatty acid synthetase: structure, function and regulation
Alfred W. Alberts and Michael D. Greenspan (Rahway) . . . . . . . . . . . 29
1. Introduction .......................................... 29
2. Reaction sequence . . . . . . . . . . . . . . . . . . . . . . . . . . ... 30
3. Substrate specificity and cofactor requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4. Chain termination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5. Purification. physical properties and reaction mechanism . . . . . . . . . . . . 39
6. Bacterial fatty acid synthase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
7. Regulation ......................................... .................. 48
Acknowledgements . . . . . . . . . . .... ..... .... 54
References ............................................................ 54
Chapter 3
Genetics of futt,v acid biosynthesis in yeast
Eckhart Schweizer (Erlangen) . . . . . . . . . . . . . . . . . . . . . . . . 59
,
1. Introduction .......................................................... 59
2. Acetyl-CoA carboxylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
a. Biotin apocarboxylase ligase mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
b. Acetyl-CoA carboxylase mutations . . . . . , . , , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
c. Acetyl-CoA carboxylase structure ......................................... 62
3. Saturated fatty acid biosynthesis .......... ............ 65
a. Reaction mechanism and FAS enzyme structure ............................... 65
b . Biochemical properties of fatty acid synthetase mutants (fas) ............. 67
c. Interallelic complementation between fas mutants ..... 69
d . In vitro complementation between fas mutant synthetases 75
e. Incorporation of 4'-phosphopantetheine into apo-FAS ........................... 76
4 . Unsaturated fatty acid biosynthesis 76
5 . Regulation of fatty acid biosynthesis in yeast .................................... 77
a . Feedback inhibition of ACC and FAS ............................... 77
b . Regulation of enzyme synthesis 78
c. Control of FAS co 78
d . Control of yeast fa 79
6 . Concluding remarks 79
References ............................................................ 81
Chapter 4
The regulation of desaturation and elongation of fatty acids in mammals
by R . Jeffcoat and A.T. James (Bedford) ........................ 85
1. Introduction .......................................................... 85
2 . The biochemistry of desaturation 88
a. Characterisation of the enzyme ........................................... 88
b . Characterisation of the substrate .......................................... 88
3. The enzymology of desaturation ............................... 89
a . Mechanism of enzyme activity ............................................ 89
b . Fractionation of the A'-desaturase complex ...... 90
4 . The physiological role of A6- and A5-desaturases ........................... 93
a . The enzymology of A6- and A5-desaturases ............................. 93
b . The biochemistry of A6- and A5-desaturases ................................... 94
5 . Evidence for other desaturases ........ 96
a. As-Desaturase ....................................................... 96
b.A4-Desaturase ....................................................... 96
6 . General properties of desaturases ............................................ 97
a . Specificity .......................................................... 97
b . Role of cytoplasmic proteins 98
c. Metalions .......................................................... 99
7 . Elongation of fatty acids .................................................. 99
8 . The control of lipogenesis by desaturation and elongation 102
a . Dietary control ...................................................... 102
b . Hormonal control . ......... 107
9 . Conclusions ........................................................... 109
...................... 110
Chapter 5
Fatty acid oxidation and its regulation
Jon Bremer and Harald Osmundsen (Oslo) ....................... 113
1. Introduction .......................................................... 113
2 . Compartmentation of fatty acid metabolism ................................... 113
a. Long-chain fatty acids ................................................. 114
1x
b. Short-chain fatty acids . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
3. Fatty acid activation . . . . . . . . . . . . . , . , . . . . . . 115
a. Short- and medium-chain acyl-CoA synthases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
(i) Acetyl-CoA synthase, 115 - (ii) Propionyl-CoA synthase, 116 - (iii) Butyryl-CoA
synthase, 116 - (iv) Medium-chain acyl-CoA synthase, 116 -
b. Long-chain acyl-CoA synthase(s) . . . . . . . . , . . . , . . . . . . . . . , . . . . . . . . . , . . . . . . . . 117
(i) Cellular localization, 117 - (ii) Properties, 117 -
c. Reaction mechanism of acyl-CoA synthases . . , . . . . . . . . . . , . . . . . . . . . . . . . . , . . . . . 117
d. Acyl-CoA synthase (GDP-forming) . . . . . , . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
4. Mitochondria1o xidation of fatty acids . . . . . . , 118
a. The function of carnitine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
(i) Carnitine acetyltransferase, 120 - (ii) Carnitine palmitoyltransferase, 120 - (iii) Carni-
tine translocase, 121 -
b. P-Oxidation enzymes of the mitochondria . . . , . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . 121
(i) Acyl-CoA dehydrogenases, 121 - (ii) Enoyl-CoA hydratases (crotonases), 122 - (iii)
L-( + )-P-Hydroxyacyl-CoA dehydrogenases, 123 - (iv) Acetyl-CoA acyltransferases (thio-
lases), 124 -
c. Oxidation of unsaturated fatty acids . . .. .................. 124
(i) A3-cis-A2-trans-EnoyI-CisooAm erase -Dienoyl-CoA 4-reductase, 125 - (iii)
3-Hydroxyacyl-CoA epimerase, 125 -
d. Functional characteristics of mitochondria1 P-oxidation 125
e. Ketogenesis and ketone body utilization . . . . . . . . . . . 126
(i) 3-Hydroxy-3-methylglutaryl-CosAy nthase, (HMG-CoA synthase), 127 - (ii) 3-Hydroxy-
3-methylglutaryl-CoA lyase, 128 - (iii) Hydroxybutyrate dehydrogenase, 128 - (iv) Acetyl-
CoA hydrolase, 128 - (v) Succinyl-CoA: acetoacetate-CoA transferase, 129 -
5. Peroxisomal fatty acid oxidation . . . . . ............... 129
a. P-Oxidation enzymes of peroxisomes . . . . , . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
(i) Acyl-CoA oxidase, 129 - (ii) 2-Enoyl-CoA hydratase and P-hydroxyacyl-CoA dehydro-
genase, 130 - (iii) Acetyl-CoA acyltransferase (thiolase), 130 -
b. Functional characteristics of peroxisomal P-oxid ..................... 130
'
c. Hepatic capacities for peroxisomal P-oxidation ..................... 132
6. a-Oxidation of fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
7. o-Oxidation of fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
8. Regulation of fatty acid oxidation . . ...................... 134
a. Effect of competing substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
b. Effect of metabolites and cofactors ............................. 135
(i) Malonyl-CoA. 135 - (ii) Glycerophosphate, 136 - (iii) Carnitine, 137 - (iv) Coenzyme
A, 137 -
c. Inducible changes in peroxisomal and mitochondria18 -oxidation . . . . . . . . . . . . . . . . . . . 138
d. Effect of hormones . . . . . . . . . . . . . . . . . . . . . . . . ........... 138
(i) Insulin and glucagon, 138 - (ii) Vasopressin, 139 - ormones, 139 - (iv)
Adrenal cortex hormones, 140 - (v) Sex hormones, 140 -
9. Fatty acid P-oxidation in various tissues . . . . . . . . . . . ............ 140
a. Heart and skeletal muscle . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
b. Kidney . . . . . . ........................................... 142
c. Gastrointestinal ._____..........1.4.2
___...............1 42
e. Brown adipose tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
f. Brain.. . . . . . . . . . . . ........................................ 143
__.................. 143
143
145