D-a-Aminoadipic acid

AH cephalosporins found in nature (Tables 1 and 2) have the D-a-aminoadipic acid 7-acyl side chain (21). AH of these compounds can be classified as having rather low specific activity. A substantial amount of the early work in the cephalosporin area was unsuccessfiiHy directed toward replacing the aminoadipic acid side chain or modifying it appropriately by fermentation or enzymatic processes (6,22). A milestone ia the development of cephalosporins occurred in 1960 with the discovery of a practical chemical process to remove the side chain to afford 7-ACA (1) (1). Several related processes were subsequendy developed (22,23). The ready avaHabHity of 7-ACA opened the way to thousands of new semisynthetic cephalosporins. The cephalosporin stmcture offers more opportunities for chemical modification than does that of penicillins There are two side chains that especiaHy lend themselves to chemical manipulation the 7-acylamino and 3-acetoxymethyl substituents. 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

The direct cleavage of Ceph C to 7-ACA and D-a-aminoadipic acid by a cephalosporin acylase would be the preferred route. A large number of enzymes were isolated from different microorganisms, e.g., Pseudomonas diminuta, BaciUus megateri-um, but substrate specificity for Ceph C is low. The conversion obtained was on a low level, eg., 8% in 4 hours [8-10], Therefore, today, the direct one-step cleavage is not feasible on an industrial scale and a two-step process had to be developed. 

L-a-amino-/3-phenylbutyric acid, a, /3-diaminobutyric acid L-a, jJ-diaminopropionic acid, / -aminopropionic acid d-aminovaleric acid, 2-aminohexenoic acid, 6-diazo-5-oxo-amino-hexanoic acid D-a-aminoadipic acid... 

Biosynthesis Tlie biosynthesis proceeds by a non-ri-bosomal process via a dipeptide of D-a-aminoadipic acid (D-a-A AA) and Lside chain which is exchanged in the further course of the synthesis of P., in contrast to that of the cephalosporins. The numerous natural and synthetic P. differ in the substituents on the side chain and the carboxy group for nomenclature, see the table. 

A penicillin produced by a species of Cephalosporium that had been isolated by Brotzu in Sardinia was shown by Newton and Abraham to have a side-chain derived from a residue of D-a-aminoadipic acid. 

Cephalosporin C contains a /3-lactam-dihydrothiazine ring system in place of the /3-lactam-thiazolidine ring system in the penicillins. Its structure can be dissected into residues of D-a-aminoadipic acid, L-cysteine, and an oxi-... 

The penicillin structure can be formally dissected into residues of a mono-substituted acetic acid, L-cysteine and D-valine respectively, as shown by the broken lines in I. Cephalosporin C can be dissected similarly into residues of D-a-aminoadipic acid, L-cysteine, ajS-dehydrovaline and acetic acid as shown in III. If the question how the D-centres arise is ignored, these dissections reveal the biogenetic units from which the antibiotics are formed. The expectation that this would be so has been confirmed by work with isotopically labelled compounds. 

Treatment of labelled a-aminoadipic acid sjmthesized by the Cephalosporium sp. in the presence of acetate-l- C with L-amino acid oxidase from Crotalus adamanteus indicated that more than 98% of this amino acid was the L-isomer (Warren et al., 1967). Hence, the apparent concentration of endogenous D-a-aminoadipic acid in the intracellular pool appeared to be too low to cause substantial dilution of the radioactivity of D-a-aminoadipic acid- C which entered the pool from the extracellular fluid and which remained largely unchanged in the cell. The relatively high dilution of radioactivity which accompanied the incorporation of from the labelled D-a-aminoadipic acid into penicillin N and cephalosporin C suggested that either free D-a-aminoadipic acid was not involved... 

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