Amino Acid Metabolism E-Book

David A. Bender

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 796

Veröffentlichungsjahr: 2012

Beschreibung

Amino Acid Metabolism, 3rd Edition covers all aspects of the biochemistry and nutritional biochemistry of the amino acids. Starting with an overview of nitrogen fixation and the incorporation of inorganic nitrogen into amino acids, the book then details other major nitrogenous compounds in micro-organisms, plants and animals. Contents include a discussion of the catabolism of amino acids and other nitrogenous compounds in animals, and the microbiological reactions involved in release of nitrogen gas back into the atmosphere. Mammalian (mainly human) protein and amino acid requirements are considered in detail, and the methods that are used to determine them.

Chapters consider individual amino acids, grouped according to their metabolic origin, and discussing their biosynthesis (in plants and micro-organisms for those that are dietary essentials for human beings), major metabolic roles (mainly in human metabolism) and catabolism (again mainly in human metabolism). There is also discussion of regulatory mechanisms for all these metabolic pathways, and of metabolic and genetic diseases affecting the (human) metabolism of amino acids.

Throughout the book the emphasis is on the nutritional importance of amino acids, integration and control of metabolism and metabolic and other disturbances of relevance to human biochemistry and health.

• Completely revised edition of this comprehensive text covering all the latest findings in amino acid metabolism research
• Written by an authority in the field
• Covers new advances in  structural biology
• Clear illustrations of all structures and metabolic pathways
• Full list of recommended further reading for each chapter and bibliography of papers cited in the text

Leseprobe

Table of Contents

Cover

Title page

Copyright page

Figures

Tables

Preface

1 Nitrogen Metabolism

1.1 Nitrogen fixation

1.2 Nitrification and denitrification

1.3 The incorporation of fixed nitrogen into organic compounds

1.4 The synthesis and catabolism of purine and pyrimidine nucleotides

1.5 Deamination of amino acids

1.6 Excretion of nitrogenous waste

1.7 Other nitrogenous compounds in human urine

2 Nitrogen Balance and Protein Turnover – Protein and Amino Acids in Human Nutrition

2.1 Nitrogen balance and protein requirements

2.2 Requirements for individual amino acids

2.3 The fate of amino acid carbon skeletons and the thermic effect of protein

2.4 Inter-organ metabolism of amino acids

2.5 Transport of amino acids across membranes

3 The Role of Vitamin B6 in Amino Acid Metabolism

3.1 Pyridoxal phosphate-dependent reactions

3.2 Amino acid racemases

3.3 Transamination

3.4 Decarboxylation and side-chain elimination and replacement reactions

3.5 Pyruvate-containing enzymes

3.6 Vitamin B6 deficiency and dependency

4 Glycine, Serine and the One-Carbon Pool

4.1 Sources of glycine

4.2 The interconversion of glycine and serine

4.3 Glycine oxidase and glyoxylate metabolism

4.4 One-carbon metabolism

4.5 Serine biosynthesis

4.6 Serine catabolism

4.7 Peptidyl glycine hydroxylase (peptide α-amidase)

4.8 5-Aminolevulinic acid and porphyrin synthesis

4.9 Selenocysteine

5 Amino Acids Synthesized from Glutamate: Glutamine, Proline, Ornithine, Citrulline and Arginine

5.1 Synthesis of 5-aminolevulinic acid from glutamate in plants

5.2 The catabolism of glutamate

5.3 Glutamine

5.4 Glutathione and the γ-glutamyl cycle

5.5 Glutamate decarboxylase and the GABA shunt

5.6 Glutamate carboxylase and vitamin K-dependent post-synthetic modification of proteins

5.7 Proline

5.8 The polyamines

5.9 Arginine, citrulline and ornithine

6 Amino Acids Synthesized from Aspartate: Lysine, Methionine (and Cysteine), Threonine and Isoleucine

6.1 Regulation of the pathway of amino acid synthesis from aspartate

6.2 Lysine

6.3 Methionine and cysteine

7 The Branched-Chain Amino Acids: Leucine, Isoleucine and Valine

7.1 Synthesis of the branched-chain amino acids

7.2 Mammalian catabolism of the branched-chain amino acids

8 Histidine

8.1 Biosynthesis of histidine

8.2 Histidine catabolism

8.3 Histamine

8.4 Methylhistidine

8.5 Carnosine and related histidine-containing peptides

9 The Aromatic Amino Acids: Phenylalanine, Tyrosine and Tryptophan

9.1 Biosynthesis of phenylalanine, tyrosine and tryptophan

9.2 Metabolism of phenylalanine and tyrosine

9.3 Catabolism of phenylalanine and tyrosine

9.4 Metabolism of tryptophan

9.5 Quinone cofactors in amine oxidases

Bibliography

Index

This edition published 2012, © 2012 by John Wiley & Sons, Ltd

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Library of Congress Cataloguing-in-Publication Data

Bender, David A.

 Amino acid metabolism / David A Bender. – 3rd ed.

p. ; cm.

 Includes bibliographical references and index.

 ISBN 978-0-470-66151-2 (cloth)

 I. Title.

 [DNLM: 1. Amino Acids–metabolism. QU 60]

 572'.65–dc23

2012009844

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Figures

1.1 

The nitrogen cycle

1.2 

Incorporation of ammonia into glutamate and glutamine

1.3 

The catabolism of glutamate

1.4 

The synthesis of glutamine and asparagine

1.5 

The role of cyanide in nitrogen incorporation

1.6 

Purine synthesis

1.7 

Synthesis of AMP and GMP from IMP

1.8 

Purine catabolism

1.9 

AMP deaminase as a source of ammonia

1.10 

Purine salvage

1.11 

Pyrimidine synthesis

1.12 

Pyrimidine catabolism

1.13 

Deamination of amino acids

1.14 

Transdeamination – transamination linked to glycine oxidase

1.15 

Transdeamination – transamination linked to glutamate dehydrogenase

1.16 

The urea synthesis cycle

1.17 

The metabolism of canavanine

2.1 

Nitrogen balance – protein flux through the gastro-intestinal tract

2.2 

The entry of amino acid carbon skeletons into the citric acid cycle

2.3 

The inter-organ glucose-alanine cycle

3.1 

Interconversion of the vitamin B

6

vitamers

3.2 

Pyridoxal phosphate-catalyzed reactions of amino acids

3.3 

The transaldimination reaction in pyridoxal phosphate-catalyzed reactions

3.4 

Non-enzymic reactions leading to the formation of

iso

-aspartyl and D-aspartyl residues in proteins

3.5 

The reaction of transamination

3.6 

The mitochondrial malate-aspartate shuttle

3.7 

Reactions of bacterial aspartate β-decarboxylase

4.1 

Metabolic sources of glycine

4.2 

The interconversion of glycine and serine

4.3 

The glycine cleavage system

4.4 

Metabolic fates of glyoxylate

4.5 

One-carbon substituted folate derivatives

4.6 

Overview of one-carbon metabolism

4.7 

Serine synthesis

4.8 

Metabolic fates of serine

4.9 

Synthesis of peptide C-terminal amides

4.10 

Synthesis of porphyrins

4.11 

Synthesis of selenocysteine

5.1 

Amino acids synthesized from glutamate

5.2 

Synthesis of 5-aminolevulinic acid from glutamate in plants

5.3 

Catabolism of glutamate

5.4 

Formation of isopeptide bonds by transglutaminase

5.5 

Glutathione

5.6 

The γ-glutamyl cycle

5.7 

The GABA shunt as an alternative to the citric acid cycle

5.8 

Synthesis of GABA from arginine

5.9 

The reaction of glutamate carboxylase

5.10 

The intrinsic and extrinsic blood clotting cascades

5.11 

Synthesis of proline from glutamate and ornithine

5.12 

Catabolism of hydroxyproline

5.13 

The reaction of peptide prolyl hydroxylase

5.14 

Synthesis of putrescine

5.15 

Synthesis and catabolism of the polyamines

5.16 

Synthesis of hypusine

5.17 

Arginine synthesis from glutamate

5.18 

Arginine catabolism through arginine deiminase

5.19 

Synthesis of nitric oxide

5.20 

Methylarginine

5.21 

The role of creatine as a phosphagen

5.22 

Synthesis and catabolism of creatine

6.1 

Amino acids synthesized from aspartate

6.2 

Pathways of threonine catabolism

6.3 

Lysine biosynthesis in bacteria and plants – the diaminopimelate pathway

6.4 

Lysine biosynthesis in yeasts and fungi – the α-aminoadipate pathway

6.5 

Pathways of lysine catabolism

6.6 

The Maillard reaction

6.7 

Isopeptide links in proteins

6.8 

Lysine-derived cross-links in collagen

6.9 

Three-way lysine-derived cross-links

6.10 

Formation of desmosine and isodesmosine in elastin

6.11 

Pyrrolysine synthesis

6.12 

The role of carnitine and carnitine palmitoyltransferases in the mitochondrial uptake of fatty acids

6.13 

Carnitine biosynthesis

6.14 

Cysteine and methionine biosynthesis

6.15 

Methionine metabolism in mammals – the methionine cycle and the transsulphuration pathway for cysteine biosynthesis

6.16 

Ethylene biosynthesis and the methylthioadenosine cycle

6.17 

Pathways for hydrogen sulphide formation in mammals

6.18 

Taurine biosynthesis

7.1 

The common pathway of branched-chain amino acid synthesis

7.2 

Leucine biosynthesis

7.3 

Alternative pathways for 2-oxobutyrate synthesis

7.4 

The common pathway of branched-chain amino acid catabolism

7.5 

The reaction of branched-chain oxo-acid dehydrogenase

7.6 

Leucine catabolism

7.7 

Isoleucine catabolism

7.8 

Valine catabolism

7.9 

The role of biotin in carboxylation reactions

8.1 

Histidine biosynthesis

8.2 

Histidine catabolism

8.3 

Formation of the methylidene-imidazole cofactor of histidase

8.4 

Non-enzymic products formed from imidazolone propionate

8.5 

The hydantoin propionate pathway of histidine catabolism

8.6 

The transamination pathway of histidine catabolism

8.7 

Histamine metabolism

9.1 

The shikimate (common) pathway of aromatic amino acid biosynthesis

9.2 

Biosynthesis of phenylalanine and tyrosine from chorismate

9.3 

Biosynthesis of tryptophan from chorismate

9.4 

The phenylpropanoid pathway for lignin biosynthesis

9.5 

Polyphenols synthesized from coumaroyl CoA

9.6 

The reaction of phenylalanine hydroxylase

9.7 

Catecholamine synthesis from tyrosine

9.8 

Catabolism of the catecholamines

9.9 

The reaction of monoamine oxidase and aldehyde dehydrogenase

9.10 

Tyrosinase and the synthesis of melanin

9.11 

Biosynthesis of the thyroid hormones

9.12 

Tyrosine catabolism

9.13 

Auxin biosynthesis from tryptophan

9.14 

Indole formation from tryptophan

9.15 

The biosynthesis of serotonin and melatonin

9.16 

The kynurenine pathway of tryptophan catabolism

9.17 

Biosynthesis of NAD

9.18 

Quinone cofactors formed by post-synthetic modification of proteins

Tables

1.1 

Some organisms capable of fixing nitrogen

1.2 

The proteins encoded by the

nif

genes of

Klebsiella pneumoniae

1.3 

Inhibitors of nucleotide metabolism in cancer chemotherapy

1.4 

Mammalian enzymes that utilize phosphoribosyl pyrophosphate

1.5 

Average daily excretion of nitrogenous compounds by human beings

2.1 

Nitrogen losses from the body

2.2 

Proteolytic enzymes

2.3 

The Enzyme Commission (EC) classification of peptidases

2.4 

Half-lives of some tissue proteins

2.5 

Protein synthesis and energy expenditure after feeding

2.6 

Essential and non-essential amino acids

2.7 

The protein amino acids

2.8 

Reference patterns of essential amino acids

2.9 

Metabolic fates of the carbon skeletons of amino acids

2.10 

ATP yield and thermogenesis from the oxidation of amino acid carbon skeletons

3.1 

Pyridoxal phosphate-catalyzed enzymic reactions

3.2 

Transamination products of the amino acids

3.3 

Vitamin B

6

responsive inborn errors of metabolism

5.1 

Glutamine-dependent amidotransferases

6.1 

Adverse effects of hyperhomocysteinaemia

7.1 

Abnormal urinary organic acids in biotin deficiency and multiple carboxylase deficiency due to lack of holocarboxylase synthetase or biotinidase

8.1 

Genes of the

his

operon of

Salmonella typhimurium

Preface

When Antoine Lavoisier discovered nitrogen in 1787, he named it azote, meaning without life, because of its lack of chemical reactivity and its inability to support life when provided as the atmosphere for experimental animals. However, the metabolism of nitrogenous compounds is central to the metabolic processes of all living organisms. On one level, understanding of the pathways of amino acid metabolism and their regulation is fascinating ‘because they are there’, and they present an intellectual challenge to biochemists, molecular biologists and other biological scientists.

We can also justify research to further our knowledge and understanding of the pathways and their regulation for their importance in human nutrition, both in human and animal health and disease, and also commercially. Several hundred tonnes of each amino acid are manufactured each year by bacterial biosynthesis for use in pharmaceuticals, foodstuffs and nutritional supplements. Selective breeding and genetic modification of plants permits the development of food crops with higher yields of essential amino acids (and especially methionine and lysine, which are limiting in most food crops). Enzymes in the pathways in microorganisms for the biosynthesis of amino acids that are dietary essentials for mammals provide targets for antibacterial, antifungal and antiparasite medication. In plants, enzymes in these pathways provide targets for herbicides that will have little or no effect on human beings and other mammals.

It is more than a quarter of a century since the last edition of this book was published. In that time, there have been major advances in the molecular biosciences that have increased our knowledge and understanding of amino acid metabolism considerably. Structural biology has advanced to the extent that, in many cases, we can effectively sit at the catalytic site of an enzyme and watch the stages in the reaction as different amino acid side-chains in the enzyme donate or remove electrons or form free radicals to catalyze the reaction. We can now visualize the conformational and other changes associated with binding of inhibitors and activators of the enzymes, and also the movement of intermediates through intra-molecular tunnels between one catalytic site of an enzyme and another.

Molecular biology has given us complete genome sequences of many organisms, allowing genes that are homologues of known enzymes to be identified in other organisms. Gene cloning and over-expression, as well as genetic knockout techniques, have allowed us to study the function and regulation of enzymes and pathways. Metabolomic techniques have permitted us to investigate the effects of changes in the activity of individual enzymes on a wide range of metabolites – a far cry from the days when we measured only a limited number of compounds by (often laborious) manual analytical techniques.

The pace and excitement of research on amino acid metabolism is reflected in the many specialist conferences and workshops that are now held. Some concentrate on a single amino acid; others have a broader remit. My students have frequently been surprised, and even amused, by my attendance at the meetings of the International Society for Tryptophan Research. They wonder how it is that a hundred or more apparently sane people can talk about just one amino acid for three or four days at a time, every third or fourth year. The answer is that, for all we know, there remain many areas of amino acid metabolism that are not yet clear. Indeed, three apparently simple questions remain unanswered and cause considerable debate: how much protein does a human being need, to what extent is dietary protein digested, and how much of each essential amino acid is required in the diet? An international symposium on Dietary Protein for Human Health, followed by a United Nations expert consultation held in New Zealand in April 2011, failed to answer these fundamental questions.

This book is on a specialized area of biochemistry, and I have assumed that the reader will have an understanding of the principles of enzymology, metabolism and cell, molecular and structural biology equivalent to that achieved at the end of the second year of a UK BSc course in biochemistry, nutrition or medical bioscience. There are many excellent text books on general biochemistry, and a number of excellent dictionaries of biochemistry and molecular biology. A very useful online dictionary is published by the Biochemical Society at http://www.portlandpress.com/pp/books/online/glick/default.htm.

An advance since the last edition of this book was published that is more to the benefit of the author than the reader is the advent of the online library. No longer do I have to delve among the library stacks to find relevant papers and carry round weighty (and often dusty) volumes. They are all available to me electronically, from the comfort of my desk. I have cited more than a thousand references in the bibliography, and I have probably read five times that many papers in preparing this book – and without physically setting foot in the library! In general, I have cited reviews rather than primary research papers, because these are more likely to be useful to students and will, in turn, lead them into the primary research literature. To those colleagues whose papers I have not cited, I apologize for any unintended insult. I may well have read your papers and found them helpful to my thinking, but perhaps less potentially useful to readers than those papers that I have cited.

David A Bender December 2011

1

Nitrogen Metabolism

Some microorganisms are capable of reducing nitrogen gas to ammonium, which can then be incorporated into amino acids, and thence into other organic nitrogenous compounds, including purines, pyrimidines, amino sugars, phospholipid bases and a variety of cofactors and coenzymes that are vitamins for animals. Plants and other microorganisms can incorporate ammonium and inorganic nitrates and nitrites into amino acids and other nitrogenous compounds. Animals cannot utilize inorganic nitrogen compounds to any significant extent, but rather are reliant on plant foods (and also, to some extent, microorganisms) for amino acids for the synthesis of tissue proteins and other nitrogenous compounds, including purines and pyrimidines. Other organic nitrogenous compounds in plant foods can be utilized to a greater or lesser extent.

Ruminants are able to make use of inorganic nitrogen compounds indirectly, because of their large intestinal population of commensal bacteria that can synthesize amino acids from ammonium. This is economically important, since chemically synthesized urea fed to ruminants releases more expensive protein-rich oil-seed cake and protein from bacteria, yeasts and fungi for human consumption, or as feedstuff for monogastric livestock.

The major end products of amino acid catabolism by animals are relatively simple organic compounds such as urea, purines and uric acid, as well as ammonium salts (and in some cases ammonia gas) and nitrate and nitrite salts. Various microorganisms can oxidize ammonia to nitrogen gas, reduce nitrites and nitrates to nitrogen gas or catalyze a reaction between ammonia and nitrite to produce nitrogen gas.

There is, thus, a cycle of nitrogen metabolism:

nitrogen gas is fixed as ammonium;

ammonium is incorporated into amino acids;

other nitrogenous compounds are synthesized from amino acids;

this is followed by catabolism, ultimately yielding ammonium and nitrates, then denitrification reactions releasing nitrogen gas.

This nitrogen cycle is shown in Figure 1.1.

Figure 1.1 The nitrogen cycle.Nitrogenase EC 1.18.6.1 (ferredoxin-linked), 1.19.6.1 (flavodoxin-linked).

As a result of human activity, the nitrogen cycle is no longer in balance. There is an excess of nitrogen fixation overdenitrification, resulting in the accumulation of fixed nitrogen in rivers, lakes and oceans and of nitrogen oxides in the atmosphere. Global production of nitrogen fertilizers was 80 × 106 million tonnes in 1997, and is projected to rise to 134 × 106 million tonnes by 2020; half of all the chemically synthesized nitrogen fertilizer used up until 1990 was used between 1980 and 1990.

The burning of fossil fuels and biomass accounts for release into the atmosphere of some 20 × 106 tonnes of nitrogen oxides each year, and lightning probably produces about half as much. It is estimated that terrestrial ecosystems produced 90–140 × 106 tonnes of fixed nitrogen a year prior to human activity and that widespread cultivation of legume crops has added 32–55 × 106 tonnes of fixed nitrogen per year. Marine ecosystems are estimated to fix 30–300 × 106 tonnes of nitrogen a year. Overall, human activities are estimated to fix 210 × 106 tonnes of nitrogen a year, compared with 140 × 106 tonnes from biological nitrogen fixation and the action of lightning (Galloway et al., 1995; Vitousek et al., 1997).

There are two consequences of this excess of nitrogen fixation overdenitrification. Nitrous oxide (N2O) is a greenhouse gas, and hence it contributes to global warming and climate change. It also catalyzes the destruction of ozone in the stratosphere. Nitrates in drinking water present a health hazard; gastric microorganisms reduce nitrate (NO3−) to nitrite (NO2−), which can react with haemoglobin to yield methaemoglobin, which does not transport oxygen. Although mammals have methaemoglobin reductase and can regenerate active haemoglobin, young infants are especially at risk from excessive nitrate intake, because foetal haemoglobin is considerably more sensitive to nitrite than is adult haemoglobin.

A nitrate concentration greater than 10 mg N/l of water is considered to pose a threat to public health. Nitrites are also able to react with amines under the acidic conditions of the stomach to form carcinogenic nitrosamines, although it is not clear whether the small amounts of nitrosamines formed from dietary amines and nitrites pose a significant health hazard. There is therefore great interest in bacteria that can be used to denitrify drinking water (section 1.2; Martinez-Espinosa et al., 2011).

1.1 Nitrogen Fixation

The N ≡ N triple bond in nitrogen gas is extremely stable, with a bond energy of 0.94 MJ (225 kcal) per mol; this is the bond that has to be broken to fix nitrogen. The Haber-Bosch process for synthesis of ammonia (the basis of the chemical fertilizer industry) uses temperatures of 300–550°C and pressures of 15–25 MPa (150–250 atm), with an iron catalyst, to reduce nitrogen with hydrogen gas to form ammonia:

Nitrogen-fixing microorganisms (diazotrophes) catalyze the same reaction at temperatures as low as 10°C and 100 kPa (1 atm) pressure. This bacterial nitrogen fixation accounts for some 100 × 10 tonnes of nitrogen per year. As shown in , the bacteria and cyanobacteria (formerly known as blue-green algae) that catalyze nitrogen fixation occupy a wide variety of ecological niches. Among heterotrophic bacteria, diazotrophes may be obligate or facultative anaerobes or obligate aerobes, and autotrophic diazotrophes may be aerobic or anaerobic, photosynthetic or non-photosynthetic. Non-photosynthetic autotrophic diazotrophes include those that can reduce sulphate to sulphide (e.g. spp.) and the methanogenic archaea.