Clavulanic acid, biosynthesis

Scheme 10.30 Part of clavulanic acid biosynthesis. Bonds installed byclavaminic acid synthase (CAS) are circled. CAS clavaminic acid synthase. PAH proclavaminic acid amidino hydrolase.

Bushell, M.E., Kirk, S., Zhao, H.-J. and Avignone-Rossa, C.A. (2006) Manipulation of the physiology of clavulanic acid biosynthesis with the aid of metabolic flux analysis. Enzyme and Microbial Technology, 39, 149-157. 

Aidoo, K.A., Wong, A., Alexander, D.C. et al. (1994) Cloning, sequencing and disruption of a gene from Streptomyces clavuligerus involved in clavulanic acid biosynthesis. Gene, 147, 41—46. 

Jensen, S.E., Elder, K.J., Aidoo, K.A. and Paradkar, A.S., (2000) Enzymes catalyzing the early steps of clavulanic acid biosynthesis are encoded by two sets of paralogous genes in Streptomyces clavuligerus. Antimicrobial Agents and Chemotherapy, 44, 720-726. 

Figure 4.24 Biosynthetic pathway for clavulanic acid biosynthesis.

Biochemical experiments have demonstrated that the pathway for clavulanic acid biosynthesis begins with the condensation of the amino acid arginine with a three-carbon glycolytic intermediate (133,134) (Figure 8). Because one of the components in this reaction is not an amino acid, an ACVS-like peptide synthetase may not he present, and the condensation may involve a different reaction mechanism. The early steps of the pathway, which at present are not fully understood, lead to the formation of the interme-... 

Townsend CA, Krol Wj. The role of molecular oxygen in clavulanic acid biosynthesis Evi-dence for a bacterial oxidative deamination, j Chem Soc Chem Commun 1988 1234—1236. 

Paradkar AS, Jensen 5E. Functional analysis of the gene encoding the clavaminate synthase 2 isoenzyme involved in clavulanic acid biosynthesis in Streptomyces davtdjgerus. J Bactennl... 

Hodgson JE, Fosberry AP, Rawlinson NS, Ross HNM, Neal RJ, Amell JC, Earl AJ, Lawlor EJ. Clavulanic acid biosynthesis in Streptomyces clavuligerus Gene cloning and characterization. Gene 1995 166 49-55. 

In the first studies on clavulanic acid biosynthesis Elson and Oliver (279) fed [l- C]-acetate, [2- C]-acetate or [l,2- C]-acetate to cultures of Streptomyces clavuligerus during the clavulanic acid production phase. The resulting samples of C-labelled clavulanic acid were isolated as the benzyl ester (287) and examined by C-n.m.r. spectroscopy. The labelling patterns... 

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