δ-(l-α-aminoadipyl)-l-cysteinyl-d-valine synthetase (ACVS): discovery and perspectives
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The δ-(l-α-aminoadipyl)-l-cysteinyl-d-valine (ACV) tripeptide is the first dedicated intermediate in the biosynthetic pathway leading to the penicillin and cephalosporin classes of β-lactam natural products in bacteria and fungi. It is synthesized nonribosomally by the ACV synthetase (ACVS) enzyme, which has been purified and partially characterized from many sources. Due to its large size and instability, many details regarding the reaction mechanism of ACVS are still not fully understood. In this review we discuss the chronology and associated methodology that led to the discovery of ACVS, some of the main findings regarding its activities, and some recent/current studies being conducted on the enzyme. In addition, we conclude with perspectives on what can be done to increase our understating of this very important protein in the future.
Keywordsβ-lactams Penicillin Cephalosporin ACVS Streptomyces Protein purification
This paper is dedicated to Professor A. L. Demain to mark the occasion of his 90th birthday. Throughout his career, Arnie has started many young scientists on their way, supported many established scientists in their research efforts, and made outstanding contributions to many areas of industrial microbiology through his own studies. He is an inspiration to us all. Work on β-lactams in KT’s laboratory at Memorial University of Newfoundland (MUN) is supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada (NSERC). MAM was the recipient of a student fellowship from NSERC and also received support from MUN for completing his program. We would also like to thank Dr. T. Martin Schmeing (Department of Biochemistry, McGill University, Canada) for advice on designing affinity tags for purifying large proteins.
- 6.Baldwin JE, Bird JW, Field RA, O’Callaghan NM, Schofield CJ, Willis AC (1991) Isolation and partial characterisation of ACV synthetase from Cephalosporium acremonium and Streptomyces clavuligerus. Evidence for the presence of phosphopantothenate in ACV synthetase. J Antibiot (Tokyo) 44:241–248CrossRefGoogle Scholar
- 8.Baldwin JE, Shiau CY, Byford MF, Schofield CJ (1994) Substrate specificity of l-delta-(alpha-aminoadipoyl)-l-cysteinyl-d-valine synthetase from Cephalosporium acremonium: demonstration of the structure of several unnatural tripeptide products. Biochem J 301(Pt 2):367–372CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Coque JJ, de la Fuente JL, Liras P, Martin JF (1996) Overexpression of the Nocardia lactamdurans alpha-aminoadipyl-cysteinyl-valine synthetase in Streptomyces lividans. The purified multienzyme uses cystathionine and 6-oxopiperidine 2-carboxylate as substrates for synthesis of the tripeptide. Eur J Biochem 242:264–270CrossRefPubMedGoogle Scholar
- 15.Coque JJ, Martin JF, Calzada JG, Liras P (1991) The cephamycin biosynthetic genes pcbAB, encoding a large multidomain peptide synthetase, and pcbC of Nocardia lactamdurans are clustered together in an organization different from the same genes in Acremonium chrysogenum and Penicillium chrysogenum. Mol Microbiol 5:1125–1133CrossRefPubMedGoogle Scholar
- 21.Jensen SE, Westlake DWS, Wolfe S (1988) Production of the penicillin precursor δ-(l-α-aminoadipyl)-l-cysteinyl-d-valine (ACV) by cell-free extracts from Streptomyces clavuligerus. FEMS Microbiol Lett 49:213–218Google Scholar
- 40.Moore MA (2015) Manipulation of Streptomyces clavuligerus for the purification of δ-(l-α-aminoadipyl)-l-cysteinyl-d-valine synthetase and the mobilization of plasmid DNA. Memorial University of Newfoundland, St. John’sGoogle Scholar
- 54.van der Lende TR, van de Kamp M, Berg M, Sjollema K, Bovenberg RA, Veenhuis M, Konings WN, Driessen AJ (2002) delta-(l-alpha-aminoadipyl)-l-cysteinyl-d-valine synthetase, that mediates the first committed step in penicillin biosynthesis, is a cytosolic enzyme. Fungal Genet Biol 37:49–55CrossRefPubMedGoogle Scholar