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Amino-Acids, Peptides, and Proteins Volume 5
A Review of the Literature Published During 1972
By R. C. Sheppard The Royal Society of Chemistry
Copyright © 1974 The Chemical Society
All rights reserved.
ISBN: 978-1-84755-729-2
CHAPTER 1
Amino-acids
BY P. M. HARDY
The general format and topics covered in this chapter remain as in previous volumes. The purely biological effects of amino-acids or their simple derivatives have only been reported where there is some definite chemical interest involved, and biosynthetic studies as such are not included. Synthetic and degradative work is only discussed where novel methods or intermediates are involved. Amino-acid derivatives useful for peptide synthesis are dealt with in Chapter 3. Crystal structures are listed but not described. Reactions of protein- or peptide-bound amino-acid residues are only dealt with if they are also of interest in connection with free amino-acids or their simple derivatives.
1 Naturally Occurring Amino-acids
Occurrence of Known Amino-acids. — As is customary in this section, only papers dealing with amino-acids which are rarely encountered or which are of particular current interest are mentioned.
The idea has been put forward that some compounds, such as the non-protein amino-acids, may be synthesized by many more plants, or even by all of them, than has hitherto been recognized. However, they may be formed in amounts that fall below the threshold concentration that can be recognized in plant extracts by routine analytical procedures. An attempt has been made to test this concept by studying the nitrogenous fraction produced by the large-scale processing of sugar beet. Many non-protein amino-acids and derivatives are in fact present in this mixture in very small quantities, too small to have been recognized after a small-scale extraction. These include L-azetidine-2-carboxylic acid, ε-N-acetyl-lysine, γ-L-glutamyl-γ-aminobutyric acid, and γ-N-acetyl-L-α,γ-diaminobutyric acid; two new natural amino-acids from this source are reported below (p. 3). Fowden concludes that the particular genetic complexes necessary for the formation of individual secondary products may be more widely distributed in plants than often thought. Different patterns of product accumulation may reflect differences in the degree to which genes are 'switched on'. ε-N-Acetyl-lysine is a new plant product, but further studies on its appearance in histones are reported.
NGN'G-Dimethylarginine and NGNG-dimethylarginine have been identified in the basic Al protein from bovine myelin. These residues produce methylamine and dimethylamine, respectively, on alkaline hydrolysis of the protein ; these amines were identified by a g.l.c.–mm.s. method as dimethylamine is not detected on amino-acid analysis. Dityro-sine, the fluorescent oo'-biphenol analogue of tyrosine, has now been isolated from bovine ligamentum nuchae; it also occurs in uterine protein. It can be simply synthesized by the action of horseradish peroxidase and hydrogen peroxide on tyrosine. A survey of the protein of medulla cells from hair or quill of a number of mammalian species has been made, and the occurrence of the ε-(γ-glutamyl)lysine cross-link seems to be a general phenomenon. This cross-link contributes to the insolubility of these proteins.
The antibiotic edeine D has been found to contain a residue of β-phenyl -β-alanine. This replaces a residue of β-tyrosine in the close analogue edeine A. Participation of an e-amino-group in a peptide bond in racemo-mycin-C has been confirmed by the isolation of ε-N-(L-β-lysyl)-L-β-lysine from a partial acid hydrolysate. The possibility of transpeptidation occurring during hydrolysis was ruled out by N-derivatization experiments. The fungus Boletus satanas has been shown to contain γ-hydroxy-norvaline. G.l.c. analysis of the N-[(S)-α-methoxypropionyl]-lactones derived from two isomers separated by ion-exchange chromatography showed one lactone to be the pure (2S, 4R)-isomer and the other to be partly racemized, (2S, 4S) : (2R, 4R) = 3 : 2.
New Natural Free Amino-acids. — The antimetabolite rhizobotoxine, first isolated in 1965 from the root nodules produced by Rhizobium japonicumin the soybean Glycine max(L.) Merr., has now been identified as the enol-ether 2-amino-4-(2-amino-3-hydroxypropoxy)-trans -but-3-enoic acid, CH2OH·CH(NH2)CH2·O·CH:CH·CH(NH2)CO2H. Its dihydro-derivative O-(2-amino-3-hydroxypropyl)homoserine is also produced by the same bacterium. This is the first instance of an alkyl-ether derivative of homoserine being found in the absence of added alcohol.
Four new amino-acids have been characterized from members of the Leguminosae; their structures, however, differ widely. A (1S, 3S) isoquinoline derivative (1) occurs in a variety of the velvet bean. It can readily be synthesized from L-dopa and acetaldehyde in a largely stereoselective condensation. 4,5-Dihydroxy-L-pipecolic acid has been isolated from Calliandra haematocephala Hassk. and synthesized by cis -hydroxylation of natural 4,5-dehydropipecolic acid with osmium tetroxide, but its stereo-chemistry is not yet fully known. An amino-acid previously synthesized as an analogue of phenylalanine, p-aminophenylalanine, has now turned up in the form of its L-isomer in Vigna vexillata, and S-(2-hydroxy-2-carboxy-ethanethiomethyl)-L-cysteine, HO2 C·CH(OH)· CH2S·CH2·SCH2CH(NH2) -CO2H, has been reported to occur in Acacia georginae seed. The latter can be prepared from L-L-djenkolic acid by treatment with a limited quantity of sodium nitrite in acetic acid (NH2 [right arrow] OH), but racemization during this substitution is almost complete.
As far as other plants are concerned, Fowden and his colleagues have added a new cyclopropane amino-acid (2) and a new unsaturated amino-acid (3) to their series of such compounds isolated from the Sapidaceae and Hippocastanaceae, and the seeds of the Kentucky coffee tree have yielded two stereoisomers of β-hydroxy-γ-methylglutamic acid and other non-protein amino-acids as yet unidentified. The sugar beet, ITLβITL vulgaris, has been found to contain two new amino-acid derivatives, ε -N-acetyl-allo-δ-hydroxy-L-lysine and γ-N-lactyl -L-αγ-diaminobutyric acid. Details of the isolation of 4-methylene-DL-proline from Eriobotrya japonica have now been published.
Four unsaturated amino-acids from fungi have been reported. The fruit bodies of Tricholomopsis rutilans contain L-2-amino-4-methyl-5 -hexenoic acid, and a New Guinea fungus, as yet only tentatively identified, yields L-2-aminohex-4-ynoic acid. More exotic is the occurrence of trans -2-amino-5-chlorohexenoic acid (4) in Amanita solitaria, a mushroom with a chlorine-like odour. Although this compound is readily obtainable from the allenic amino-acid (5) known to occur in this fungus, it is probably a true metabolite and not an artefact as addition to (5) requires treatment with hot 1M-HCl. A strain of thermophilic fungi has been shown to produce the rather complex amino-acid thermozymocidin (6), an anti-fungal material. Methanolic hydrogen chloride converts thermozymocidin into the α -amino-γ-lactone hydrochloride (7). Although the stereochemistry has not been fully elucidated, it seems that the adjacent hydroxymethyl and secondary hydroxygroups in the lactone have the trans configuration as ketal or acetal derivatives cannot be prepared.
A new guanidino-compound, L-thalassemine, has been isolated from the body-wall muscle of the echuiroid worm Thalassema neptuni. This amino-acid, guanidoethylphospho-O-(α-NN -dimethyl)serine, occurs together with its N1-phosphoryl-derivative (8); the occurrence of NN- dimethylserine either free or combined has not been previously noted.
New Amino-acids from Hydrolysates. — Acid fission of the antibacterial compound ristocetin A yields a number of unusual amino-acids. One of these contains a diphenyl ether grouping with hydroxyl and — CH(NH2) -CO2H units on one ring and methyl and — CH(NH2)CO2H units on the other. The n.m.r. coupling pattern and nuclear Overhauser experiments favour the substitution patterns (9) and (10) for the two ring systems.
One of the co-occurring amino-acids seems to be identical except that it lacks the methyl group. The structure of the depsipeptide detoxin-D has been elucidated. It contains the novel pyrrolidine amino-acid (11); the o.r.d. spectrum of the N-valyl lactone derivative of (11) formed upon alkaline hydrolysis of detoxin-D shows the ring substituents to be cis. A hitherto unidentified amino-acid produced by acid hydrolysis of chlorosis-inducing toxins from the plant pathogen Pseudomonas has now been characterized as 3-aminomethyl -6-carboxy-3-hydroxy-2-piperidone (12).
Hydrolysis of the antitubercular peptides tuberactinomycins A and N gives threo-γ-hydroxy-β-lysine if hydrochloric acid is used, but the erythro- isomer if sulphuric acid is used. It is therefore not clear which stereoisomer exists in the original peptide.
Although chlorination of the aromatic ring of tyrosine is known to occur under some conditions during acid hydrolysis with hydrochloric acid, 3 -chlorotyrosine has not previously been reported to occur naturally. Three reports have appeared in 1972 of its isolation, from the sclero-protein of the whelk Buccinum undatum, from locust cuticular protein, and in the cuticle of Limulus polyphemus. In the latter 3,5-dichlorotyrosine was also present. The conditions of isolation in all three cases were thought to be such as to make chlorination during protein degradation unlikely. Two papers concerning new collagen cross-links have been published. Isolation of 2, 10-diamino-5-hydroxymethyl-6-(Nτ-histidyl)-undecandioic acid (13), termed aldol-histidine, from borohydride-reduced cow-skin insoluble collagen provides the first evidence for a histidine-containing cross -link. Its biosynthesis probably involves a Michael addition of the histidine imidazole to the known collagen component 2,10-diamino-5- formyl-5 -undecendioic acid ; the product on reduction would yield (13). After reduction of calf insoluble collagen with NaB3H4, a labelled degradation product has been identified as N-(δ-hydroxynorleucino) -2,3,4,5,6-pentahydroxyhexylamine. This no doubt arises by the reduction of the Schiff base formed by interaction of the carbonyl group of a hexose sugar and the ε-amino-group of δ-hydroxylysine. The structure of the amino-acid was established by mass spectral comparison with Nε-galactosyl -hydroxylysine, but the specific hexose configuration remains to be determined.
2 The Chemical Synthesis and Resolution of Amino-acids
General Methods of Synthesis. — The preparation of α-amino-acids from α-keto-acids continues to be explored. A detailed study of the temperature dependence of the hydrogenolytic asymmetric transamination of ethyl pyruvate by several optically active amines has now appeared. Amines of the R configuration produce (R)-alanine (D-alanine) at lower temperatures, but as the reaction temperature increases (S)-alanine is formed. Using (R)-α:-methylbenzylamine, for example, configurational inversion occurs between 10 and 20 °C. The highest optical purity recorded for the alanine was 68%. Reduction of α-keto-acids by (R)-(+)-α -phenethylamineborane or its enantiomer gives better yields of α -amino-acids than does the use of sodium cyanoborohydride, but the optical purity of the products is low. This is ascribed to the relatively large distance between the asymmetric carbon of the reducing agent and the developing tetrahedral carbon of the product in the transition state. The imine obtained from R- or S-α-methylbenzylamine and ethyl glyoxylate reacts with enneacarbonyldi-iron to form two diastereoisomeric complexes of the structure Fe(CO)4- (PhCHMeN:CH·CO2Et) which can be readily separated. Treatment of these with halogeno-compounds such as benzyl bromide or ethyl bromo-acetate followed by catalytic hydrogenation leads to phenylalanine and aspartic acid, respectively. Optical purities of 77 and 78% were obtained. Treatment of the iron complex with acetyl chloride gives some alanine as well as threonine; the intermediate acyl complex apparently undergoes partial decarbonylation.
Di-isopinocamphenylborane has been used as the chiral reagent in the asymmetric synthesis of α-amino-acids from nitriles. The imino-borane intermediate [i.r. shows it to be a mixture of the monomer and dimer (14)] is treated with acetone cyanohydrin as a source of HCN, and subsequent cleavage from the boron with methanol liberates the α-aminonitrile ready for hydrolysis. Convenience is claimed as an advantage of this method. Valine prepared from 2-methylpropionitrile in this way had an optical purity of 12.4%.
Two papers concerning the use of dehydroamino-acid derivatives as α -amino-acid precursors have appeared. Reduction of α-acylamino-acrylic acids using catalysts prepared from Rh(hexa-1,5-diene)Cl2 and o -anisylmethylcyclohexylphosphine (i.e. a phosphine in which the chirality is on the phosphorus itself) gave products of up to 90% optical purity. Reductive hydrolysis of unsaturated azlactones with Raney nickel in alcoholic ammonia under 2–3 atmospheres of hydrogen gives acylamino-acid amides and hence α-amino-acids in yields often better than those obtained from such azlactones by other methods.
An admirably brief communication reports a new general method of α -amino-acid synthesis through amination of α-lithiated carboxylic acid salts. Phenylacetic acid, for example, on successive treatment with lithium isopropylamine and O-methylhydroxylamine gave, after work-up, a 55.5% yield of α-phenylglycine. This is the first report of the conversion of carboxylic acids into α-amino-acids by a one-stage procedure. A way in which the optical purity of intermediates in the asymmetric synthesis of α-amino-acids can be established has been put forward,43 and the preparation of ex-amino-acids by the C-alkylation of glycine as its bis-(N-salicylidene glycinato)cobaltate(III) complex by acrylonitrile, methyl acrylate, and acetaldehyde has been described.
Synthesis under Simulated Prebiotic Conditions. — It has been pointed out that reliance on Rf values or column chromatographic elution positions alone for the identification of amino-acids produced under simulated prebiotic conditions is insufficient for unambiguous identification. Examination of products from the action of an electric discharge on a mixture of methane, nitrogen, water, and traces of ammonia by g.l.c.–m.s. has shown that a peak at the isoleucine position on the amino-acid analyser is in fact α-hydroxy-γ-aminobutyric acid. The spectrum of products also indicates that no selective synthesis of the branched-chain amino-acids present in proteins occurs. All the non-protein amino-acids found in the Murchison meteorite are produce d in this electric discharge reaction, and the pattern of relative abundances is on the whole quite similar.
The hitherto neglected prebiotic synthesis of the sulphur amino-acids has now received attention. Addition of hydrogen sulphide to the gas mixture detailed in the preceding paragraph leads to the formation of methionine; a synthetic scheme has been proposed Scheme 1). The presence of acrolein in the products was established, and this is thought to be a key intermediate in the formation of glutamic acid, homocysteine, α,γ-diamino-butyric acid, and α-hydroxy -γ-aminobutyric acid as well as methionine.
The prebiotic synthesis of amino-acids by the attack of cyanide ion on nitriles (Scheme 2) does not appear to be feasible under the dilute conditions considered reasonable except in the cases of aspartic and glutamic acids. Only in these instances does the inductive effect of the side-chain group R result in a rapid enough addition. Morphological and compositional resemblances between material occurring in precambrian rock from South Africa and the products of simulated prebiotic syntheses have been noted.
Two papers concerning the study of prehistoric amino-acids have appeared. The racemization of amino-acids near neutral pH has been considered and related to organic geochemistry, and the dating of fossil bones using the extent of racemization of isoleucine has been proposed.
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Excerpted from Amino-Acids, Peptides, and Proteins Volume 5 by R. C. Sheppard. Copyright © 1974 The Chemical Society. Excerpted by permission of The Royal Society of Chemistry.
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