Download MendeleyStructural origins of the selectivity of the trifunctional oxygenase clavaminic acid synthase.
Zhang, Z., Ren, J., Stammers, D.K., Baldwin, J.E., Harlos, K., Schofield, C.J.(2000) Nat Struct Biol 7: 127-133
- PubMed: 10655615
- DOI: https://doi.org/10.1038/72398
- Primary Citation of Related Structures:
1DRT, 1DRY, 1DS0, 1DS1 - PubMed Abstract:
Clavaminate synthase (CAS), a remarkable Fe(II)/2-oxoglutarate oxygenase, catalyzes three separate oxidative reactions in the biosynthesis of clavulanic acid, a clinically used inhibitor of serine beta-lactamases. The first CAS-catalyzed step (hydroxylation) is separated from the latter two (oxidative cyclization/desaturation) by the action of an amidinohydrolase. Here, we describe crystal structures of CAS in complex with Fe(II), 2-oxoglutarate (2OG) and substrates (N-alpha-acetyl-L-arginine and proclavaminic acid). They reveal how CAS catalyzes formation of the clavam nucleus, via a process unprecedented in synthetic organic chemistry, and suggest how it discriminates between substrates and controls reaction of its highly reactive ferryl intermediate. The presence of an unpredicted jelly roll beta-barrel core in CAS implies divergent evolution within the family of 2OG and related oxygenases. Comparison with other non-heme oxidases/oxygenases reveals flexibility in the position which dioxygen ligates to the iron, in contrast to the analogous heme-using enzymes.
Organizational Affiliation:
The Dyson Perrins Laboratory and the Oxford Centre for Molecular Sciences, South Parks Road, Oxford OX1 3QY, UK.
