Amino-Acids, Peptides, and Proteins Volume 10

A Review of the Literature Published During 1977

By R. C. Sheppard

The Royal Society of Chemistry

Copyright © 1979 The Chemical Society
All rights reserved.
ISBN: 978-0-85186-094-7

Contents

Chapter 1 Amino-acids By G. C. Barrett,
Chapter 2 Structural Investigation of Peptides and Proteins,
Chapter 3 Peptide Synthesis By E. Atherton and R. C. Sheppard, with Appendices compiled by A. V. Stachulski and A. Hallett,
Chapter 4 Peptides with Structural Features not Typical of Proteins By B. W. Bycroft and A. E. Faruk,
Chapter 5 Chemical Structure and Biological Activity of Hormones and Related Compounds,

CHAPTER 1

Amino-acids

BY G. C. BARRETT

1 Introduction

The usual steady increase in the number of papers eligible for citation in this Chapter continues to press the question whether to be more selective in the material reported or to restrict the description of the work reported. Even more papers are cited this year, and this represents a certain amount of extra selectivity. The main areas of literature expansion, in the biological and metabolic studies of amino-acids, continue to be largely excluded from this Chapter.

Textbooks and Reviews. — An unusually large number of reviews have appeared recently covering the occurrence and biosynthesis of α-amino-acids, the chemistry of β-amino-acids and of cyclic α-imino-acids, free radicals formed in condensation reactions of sugars with amino-acids, αβ-unsaturated and related amino-acids in peptides, and cross-linking residues in proteins. Amino-acids present in potato, unusual amino-acids in fungi, and the biological significance of N-methylated lysine and arginine derivatives, are topics in recent reviews.

Reviews of amino-acid chemistry and of the distribution of non-protein amino-acids provide material which is largely complementary to that in this Report.

Other reviews and textbooks are cited in the various sections of this Chapter.

2 Naturally Occurring Amino-acids

Occurrence of Known Amino-acids. — The variations found in the proportions of amino-acids in fossils of different age are probably due to variable rates of decomposition of the protein amino-acids, but may indicate stages in molecular evo1ution. There are several other papers in the earth sciences literature dealing with the natural occurrence of amino-acids, but excepting those inferring fossil age from racemization (see Section 5), they are mostly of a routine analytical nature.

Further examples of the existence of D-amino-acids in pea seedlings (see Vol. 9, p. 2) are of aspartic and glutamic acids. Other simple amino-acids (leucine, tyrosine, and phenylalanine) exist as their amides, together with 5-hydroxylysine and canavanine, in Ladino clover seeds. Simple derivatives of familiar amino-acids which have been found in new locations are O-acetylserine (in Nicotiana tabacum), 3-N-oxalyl-2,3-diaminopropionic acid in seeds of Crotalaria, Acacia, and Lathyrus sativus, accompanied by the 2-N-oxalyl isomer in Lathyrus, and 2-amino-3-ureidopropionic acid (alias albizzine) in Dialium The organic component which envelopes the silicaceous cell walls of diatoms includes 4-hydroxy- and 3,4-dihydroxy-L-proline.

Less-common amino-acids in plants, reported in the recent literature, include cyclopentenylglycine in seeds of Hydnocarpus anthelminthicaNG-methyl-arginine and the NGNG-dimethyl analogue in seeds of broad bean, octopine, octopinic acid, lysopine, and histopine in Agrobacterium tumefaciens-induced suflower crown gall tumours, and S-methylmethionine (vitamin U). A useful review of unusual amino-acids in edible mushrooms, including cis-3-amino-L-proline in Morchella esculenta, L-2-aminohex-4-ynoic acid and its threo– and erythro-3-hydroxy-analogues with L-3-(3-carboxy-4-furyl)alanine in Tricholomopsis rutilans (see also Vol. 7, p. 3), and γ-propylidene-L-glutamic acid in Mycena pura, has appeared. 2S,3R-2-Amino-3-hydroxypent-4-ynoic acid is a toxic amino-acid present in the fungus Sclerotium rolfsii.

Although no attempt can be made to cover the full literature on microbial production of amino-acids, room is found for representative papers.

Auxotrophic mutants of Pseudomonas aeruginosa accumulate L,L-2,6-diamino-pimelic acid, and α-methylene-γ-aminobutyric acid, the enzymic decarboxylation product of γ-methylene-L-glutamic acid, occurs in Mycena pura (cf. Vol. 8, p. 3). The purer realms of the biosynthesis literature include the conversion of L-lysine into ε-hydroxy-lysine by cell-free extracts of Aerobacter aerogenes, and L-ornithine into L-Δ1-pyrroline-5-carboxylic acid by ornithine aminotrans-ferase. Since rumen ciliate protozoa can convert proline, ornithine, or arginine into δ-aminovaleric acid, the α-amino-acids must be on the biosynthetic pathway to the δ-amino-acid. The controversy (see Vol. 9, p. 2) continues concerning the significance of the existence of saccharopine and 2-amino-adipic acid in higher plants to the lysine biosynthetic pathway. The production of amino-acids by immobilized enzymes has been reviewed.

Higher organisms are represented in papers reporting the presence of more than ten quaternary amines, including δ-valerobetaine, γ-butyrobetaine, and the betaines of glycine, valine, and homoserine, in the ovary of the shellfish Callista brevishiphonata, and a similar mixture in the adductor muscle of the fan mussel Atrina pectinata. The spruce budworm Choristoneura fumiferana contains N-phosphorylarginine.

Methylated amino-acids identified as constituents of proteins provide new material for structure-function hypotheses. Ribosomal proteins of Escherichia coli carry N-terminal N-methylalanine, N-methylmethionine, and N-trimethyl-alanine residues, and include a γ-methylglutamyl residue. Cytochromes from Crithidia oncopelti and Candida krusei contain NN-dimethylproline and Nε-trimethyllysine residues, respectively. NG-Dimethylarginine occurs in sizeable amounts in non-histone nuclear proteins from rat-liver nuclei. Majusculamides A and B contain N-methyl-O-methyl-D-tyrosine and N-methyl-L-valinamide residues.

New Natural Free Amino-acids. — Sunflower plants infected with Agrobacterium tumefaciens develop crown gall tumours from which novel acidic amino-acids histopine [Nα-(1-carboxyethyl)-L-histidine] and [Nα-(1,3-dicarboxypropyl)-L-ornithine have been isolated. Plant sources for other new amino-acids are Gymnocladus dioicus, a legume whose seeds have already proved to contain several uncommon amino-acids and from which L-cis-5-hydroxypipecolic acid has been isolated. Related species Morus alba and Lathyrus japonias also contain this amino-acid. The trans-configuration has been assigned to 4-carboxy-L-proline, isolated from Chondria coerulesceus Lentinic acid, the N-(γ-L-glutamyl) derivative of MeSO2CH2(SOCH2)3CH(NH2)CO2H, has been isolated from Lentinus edodes.

New amino-acids of interest in biosynthetic studies are β-hydroxy-Nε-tri-methyl-lysine, identified as an intermediate in the biosynthesis in Neurospora crassa of carnitine, and ‘pretyrosine’ (1), on the pathway to L-tyrosine in blue-green algae Pseudomonas aeruginosa. Aromatic amino-acids in Cortinarius brunneus and in Pachymatisma johnstoni include 4-hydroxy-3-methoxy-L-phenylalanine and 6-bromohypaphorine (6-bromo-L-tryptophan [Nα-trimethyl betaine), respectively.

Diastereoisomers of 2-amino-4-keto-3-methylpentanoic acid isolated from Bacillus cereus are of particular interest as vitamin B12 antimetabolites. The N-terminus of each of the nucleoside peptide antibiotics, the polyoxins, is 5-O-carbamoyl-2-amino-2-deoxy-L-xylonic acid (2; ‘polyoxamic acid’). Full details are available of the isolation of 3-(2,5-SS-dicysteinyl-3,4-dihydroxyphenyl)-alanine from the tapetum lucidum of alligator eye (see Vol. 8, p. 4).

Higher homologues of the amino-acids are represented in N-β-alanyldopamine, from wings of Papilio xuthus, and 4-acetamido-2-butenoic acid (MeCONH-CH2CH2CH=CHCO2H) from Fusarium graminearum.

New Amino-acids from Hydrolysates. — In a previous section, the occurrence of unusual, but known, amino-acids in peptides and proteins has been surveyed, and this section is exclusively concerned this year with residues at cross-link sites in proteins.

Analogues of the familiar lysine-based cross-links desmosine and allysine have arisen in protein studies, with the identification of hydroxyallysine as an intermediate in the formation of collagen cross-links, ε-(γ-glutamyl)lysine as a cross-link in the keratin fraction of human stratum corneum, and the novel desmosine relatives pyridinoline (3) and anabilysine (4), the fluorescent material from bovine Achilles tendon collagen, and the cross-link residue in glutaralde-hyde-treated ovalbumin, respectively.

3 Chemical Synthesis and Resolution of Amino-acids

Asymmetric Synthesis. — The general possibilities for asymmetric synthesis of α-amino-acids illustrated in recent Volumes of this Report are developed further in studies published in 1977. Routes based on chiral Schiff bases give variable asymmetric yields, but L-γ-carboxyglutamic acid has been obtained as its N-phthaloyl γγ-di-t-butyl ester derivative in 100% optical purity (Scheme 1). The alternative approach, alkylation of the Schiff base formed between a chiral ketone and an α-amino-acid ester, has been studied for the asymmetric synthesis of α-methyl-α-amino-acids from DL-alanine t-butyl ester. A variant of this procedure, alkylation of the cobalt(III) complex of N-salicylideneglycine, has been used for the synthesis of L-glutamic acid from methyl acrylate; electrochemical reduction was used in this case and in an extraordinary example, cathodic reduction of syn– or anti-phenylgly-oxylic acid oximes leading to R(-)-phenylglycine predominantly at cathodic potentials below 1.4 V, and to enantiomeric excesses of the S-isomer at potentials above this value, when strychnine is present.

Prochiral acylaminoacrylates and cinnamates give moderate asymmetric yields of corresponding N-acylamino-acids by hydrogenation in the presence of chiral phosphine-rhodium complex catalysts. This system is now more a test-bed for new homogeneous catalysts and no additional interest in amino-acid synthesis has emerged from the most recent papers.

Higher homologous amino-acids for which asymmetric syntheses have been reported are 3-aminobutanoic acid (Michael addition of a chiral amine to crotononitrile followed by hydrolysis and catalytic reduction), and S-homo-proline and S-homopipecolic acid via the corresponding chiral lactams.

General Methods of Synthesis of α-Amino-acids. — The preceding section has served to preview some standard synthetic methods, but a broad view of synthetic methods, both those of long standing and others undergoing current evaluation, is attempted here.

Direct methods of assembly of α-amino-acids, either by alkylation of glycine derivatives (including α-hydroxy- and -methoxyglycines) and alanine derivatives or by the carboxylation of aliphatic amines are of special interest. Ureidoalkylation of arenes must by now be one of the methods of choice for the synthesis of aryl-substituted phenylglycines and certain aliphatic amino-acids, while carbanion alkylation involving glycine-derived Schiff bases shows signs of conforming to the requirements of reliable high-yield procedures so that these routes, too, may more credibly enter the standard repertoire (but unwanted di-alkylation can be troublesome). The most interesting paper in this area describes γ-radiolytic carboxylation of amines in aqueous formate buffers; EtNH2 gives a mixture of alanine and β-alanine, isomeric aminopropanes give all possible mono-carboxylation products, while proline is formed from either 1,4-diaminobutane or pyrrolidine (accompanied by ornithine or 3-carboxyproline, respectively).

Use of isocyanides is illustrated in a study of the Ugi synthesis, exploring the influence of reactant concentrations on the proportions of the four-component condensation product (5) and of the side-product [6; an interesting puzzle is provided by the fact that (6) is not formed when the aldehyde component is omitted] when used for the synthesis of amino-malonic acid derivatives (Scheme 2). β-Branched amino-acid derivatives result from the Michael addition of carbanions to isocyanoacrylate esters.

Reduction of α-keto-acid oximes, phenylhydrazones, or Schiff bases gives corresponding α-amino-acid derivatives. Other standard general methods which have been used are alkylation of diethyl acetamidomalonate, the hydantoin synthesis, including the synthesis of hydantoins in moderate yields from anodic oxidation of an alcohol with ammonium carbonate and KCN, substitution reactions of α-halogenopropionates and γ-bromobutyrates, and alkylation of glycines, α-isocyano- and -nitro-propionates, and azlactones.

Prebiotic Synthesis; Model Reactions. — A still larger number of papers has appeared on this topic, partly due to studies of the scope for organic synthesis in models of the present environments on other planets, as opposed to primordial Earth (e.g. Mars, Jupiter). Apart from the chemistry of hydrogen cyanide polymers, there are few significant new additions to synthetic methods arising from these studies. The pioneers in this field have reviewed the origin of organic compounds on Earth and in meteorites.

Studies of gas-phase reactions of a familiar type but in a novel context – the ammonia-rich atmosphere of Jupiter – have shown that HCN and higher alkanes can be formed by photolysis of NH3 : H2 : He : CH4, (1 : 15 : 2 : 3) 77 and that electric discharge in a similar mixture containing water can lead to amino-acids when cyanide ions are also present. An unexpected result, the formation of porphyrin-like pigments in such systems, has been reported, and the continuing investigations of another group of workers have demonstrated further the formation of amino-acids and urea from glow-discharge electrolysis of aqueous ammonia in the presence of elemental carbon, or of bicarbonate, or formate ions.

Hydroxylamine-formaldehyde mixtures have been shown to be capable of yielding about 40 amino-acids in aqueous solution at pH 5.5, at 105 °C with 82 or without kaolin. Transition metal molybdates are important in influencing the relative amounts of alanine, aspartic acid, β-alanine, and particularly proline, at the expense of glycine and serine. These studies are relatively unusual in this area in not involving some external energy supply (electromagnetic or acoustic) but the production of glycine and alanine from hydroxylamine-formaldehyde in high-intensity ultrasound was reported a little earlier. If simple monosaccharides are regarded as oligomers of formaldehyde, the reported formation of amino-acids in aqueous solutions of sugars in the presence of nitrates under N2, O2, or CO2, in u.v. light, at first sight a refreshing new approach, becomes more easily related to conventional studies in this area. A more extraordinary detail from this study, however, is that exclusion of nitrate does not bring amino-acid synthesis to a halt, amino-groups in glutamic acid and lysine formed under these conditions originating from atmospheric nitrogen.

Aqueous solutions of HCN exposed to 60Co γ-radiation form polymers from which glycine, alanine, valine, serine, threonine, aspartic and glutamic acids, amongst other compounds, are formed by hydrolysis. 2H-Labelling studies show that poly(aminomalononitriles) formed from HCN-water mixtures under u.v.-irradiation are the major sources of α-amino-acids formed by hydrolysis of the reaction product. The same intermediate may be involved in the pathway from NH3-CH4-H2O electric discharge reaction mixtures to ex-amino acids, and Matthews, Minard, and co-workers argue convincingly that the lower energy of the reaction pathway on which this intermediate lies gives the hypothesis still more support.

Protein and Other Naturally Occurring Amino-acids. — Several examples of the use of standard general methods of synthesis of α-amino-acids, as well as unusual methods, are illustrated in this section. A simple synthesis of DL-proline from pyrrolidine, giving an overall 45% yield, involves successive N-chlorination, dehydrochlorination, and addition of HCN to the resulting 1-pyrroline followed by hydrolysis. A one-pot synthesis of 4-hydroxyproline from glyoxal and oxaloacetic acid with NH4OH under physiological conditions, followed by reduction with sodium borohydride, gives a 40% yield. Dieckmann cyclization of an N-(2-methoxycarbonylethyl)glycine ester represents another approach to the same ring system, and has been used for the synthesis of the stereoisomer of 3-hydroxy-5-methylproline recently shown to be a constituent of Actinomycin Z1 (see Vol. 8, p. 5).

Out-of-the-way methods are mandatory for 1-aminocycloalkanecarboxylic acids, as illustrated in Scheme 3 for the synthesis of coronamic acid. More complex ring systems are present in L-capreomycidine (7 in Scheme 4) and discadenine -[6-(3-methyl-2-butenylamino)purin-3-yl]butyrine (Vol. 9, p. 4), and a new synthesis of the former amino-acid has been reported (Scheme 4), as well as a first synthesis of the latter from the purine and ethyl α-phthalimido-β-bromobutyrate.

(Continues…)Excerpted from Amino-Acids, Peptides, and Proteins Volume 10 by R. C. Sheppard. Copyright © 1979 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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