L-a-Aminoadipic acid

The first biosynthetic steps are two reactions that generate ACV from its constituent amino acids L-a-aminoadipic add, L-cysteine and L-valine. L-a-aminoadipic acid and L-cysteine are condensed by the enzyme AC synthetase and, in the next step, the resultant 8-(L-a-aminoadipyl)-L-cysteine is coupled with L-valine. In this step the configuration of L-valine is inverted to D-valine. 

Figure 6.9 Formation of isopenicillin N from its constituent amino acids. After condensation of L-a-aminoadipic acid with L-cysteine, L-valine is coupled. During this transformation, the configuration of the latter amino acid inverts to give D-valine.

A simple example is the tripeptide precursor of the penicillin antibiotics, called ACV, an abbreviation for S-(L-a-aminoadipyl)-L-cysteinyl-D-valine. The amino acid precursors for ACV are L-a-aminoadipic acid (an unusual amino acid derived by modification of L-lysine), L-cysteine, and L-valine (not o-valine). 

Following Scheme 4, L-a-aminosuberic acid can be obtained from iV-tosyI -L-gl utamic acid (5, n=2), upon protection of the a-carboxy and tosylamino groups as an oxazolidone 6, by extension of the side chain with the Amdt-Eistert method via the diazo ketone 7 by one methylene moiety in each cycle to produce in subsequent steps the L-a-aminoadipic acid [(5)-2-aminohexanedioic acid, 8, n = 2], L-a-aminopimelic acid [(5)-2-aminoheptanedioic acid, 8, n = 3] and finally L-a-aminosuberic acid [(5)-2-aminooctanedioic acid, 8, n = 4]J22 Treatment with HBr in AcOH was the method of choice for the acidolytic hydrolysis of the tosyl group. 23 ... 

The synthetase that catalyzes the synthesis of the named peptide from L-a-aminoadipic acid, L-cysteine, and L-valine uses ATP as the energy source. The enzyme activity is found in the actinomycete Streptomyces clavuligerus. 

Equation 9.8 shows a simplified scheme of the biosynthesis of penicillin. It starts with the amino acids L-a-aminoadipic acid and L-cysteine from penicillin N in a complex reaction sequence. When phenyl acetic acid is added to the fermentation medium, the side chain of the molecule is modified and the resulting product is called penicillin G. Today, several hundred antibiotics are on the market, most of them have at least one fermentation step in the production process. The production of antibiotics is in the order of 50,000 t/year. 

I. 1-1) starts with the polymerization of L-a-aminoadipic acid, L-cysteine, and L-valine to the linear tripeptide L-a-aminoadipyl-L-cysteinyl-D-valine(ACV-peptide). This reaction is catalyzed by the ACV-synthase (MW about 420 kD) through the following steps (1) the ATP-dependent activation of these amino acids to bind them as thiolesters, (2) the epimerization of L-valine, and hnally (3) the condensation by a thiotemplate mechanism [99]. 

Penicillin Formation by Penicillium Chrysogenum. The first reactions of the penicillin biosynthetic pathway are identical to the ones in A. chrysogenum (Figure 1.1-1). IPN, however, is not epimerized to penicillin N instead it is converted to 6-aminopenicillanic acid (6-APA) by removal of the L-a-aminoadipic acid side chain, which is substituted by a hydrophobic acyl group. Both steps are catalyzed by the same enzyme, the acyl coenzyme A IPN acyltransferase (IAT). The enzymatic activity of lAT is believed to be the result of the processing of a 40-kD monomeric precursor into a dimeric form consisting of two subunits with MWs of 11 and 29 kD. Due to the broad substrate specifity of lAT, various penicillin derivatives are synthesized naturally by attachment of different acyl-CoA derivatives to the 6-APA-core. For industrial purposes, to facilitate extraction by organic solvents, synthesis usually is directed to the less hydrophilic penicillin V or penicillin G. This is by addition of phenoxyacetic acid or phenylacetic acid, respectively, as precursors to the culture broth. 

L-a-Aminoadipic acid plays an essential role in bio nthesis, although in the assembled end-product it appears in the D form. Incorporation studies employing a-[6- C]aminoadipic acid show that the incorporation of the L isomer is considerably faster than that of the D isomer [279]. According to studies carried out on mutant strains of Cephalosporium acremonium, if the common lysine—L-a-aminoadipic acid metabolism is inhibited before the latter, then besides lysine the internal addition of a-aminoadipic acid is necessary to make the microorganisms capable of synthesizing -lactam antibiotics [271]. 

Penicillins and cephalosporins are built from L-a-aminoadipic acid, L-cysteine and L-valine (Fig. 336). An important intermediate is (5-(L- x-aminoadipyl)-L-cysteinyl-D -valine. The S-lactam ring of the 6-aminopenicillanic acid nucleus is formed by dehydrogenation. Synthesis of the thiazolidine ring proceeds with retention of the a -H-atom of the D-valine unit. The dihydrothiazine ring of the cephalosporins... 

As reported for cephamycin C production (Inamine and Bimbaum, 1975), the yields of cephamycins A and B can be increased by addition to the fermentation medium of lysine, L-a-aminoadipic acid, or OL-a-aminoadipic acid, according to Hallada et al. (1975). These workers reported that S. griseus NRRL 3912 produced 427, 546, and 562 units/ ml of cephamycins A and B in the presence of 0, 0.05, and 0.1% l-lysine-HCl, respectively, in the following medium ... 

Full details have been given for the preparation of various iV-(carboxymethyl)-a-amino-acids (220), together with an apparently simple procedure for converting L-lysine into L-a-aminoadipic acid (221) in 35% overall yield. Two... 

A -(t-Butyloxycarbonyl)-L-a-aminoadipic acid 1-t-butyl 6-ethyl ester has been prepared from L-aspartic acid. Hypusine (274), a new amino-acid from bovine brain tissue, has been synthesized by a fairly standard sequence. N -Protected L-2,3-diaminopropanoic acids are prepared from N-protected l-aspartic acid by using a Curtius rearrangement. ... 

In order to establish whether intermediates such as (285) or (286) are involved in the cyclisation of LLD-tripeptide Adlington etal. (268) synthesised the tripeptide containing L-a-aminoadipic acid labelled in all oxygens with This compound was cyclised in the C. acremonium... 

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