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'''ALTERATION OF THE CO-SUBSTRATE SELECTIVITY OF DEACETOXYCEPHALOSPORIN C SYNTHASE: THE ROLE OF ARGININE-258''' | '''ALTERATION OF THE CO-SUBSTRATE SELECTIVITY OF DEACETOXYCEPHALOSPORIN C SYNTHASE: THE ROLE OF ARGININE-258''' | ||
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[[Category: Schofield, C J.]] | [[Category: Schofield, C J.]] | ||
[[Category: 2-oxoglutarate-dependent oxygenase]] | [[Category: 2-oxoglutarate-dependent oxygenase]] | ||
[[Category: | [[Category: Alternative 2-oxoacid]] | ||
[[Category: | [[Category: Cephem antibiotic biosynthesis]] | ||
[[Category: | [[Category: Chemical cosubstrate rescue]] | ||
[[Category: | [[Category: Co-substrate selectivity]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 18:54:22 2008'' | |||
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Revision as of 15:54, 2 May 2008
ALTERATION OF THE CO-SUBSTRATE SELECTIVITY OF DEACETOXYCEPHALOSPORIN C SYNTHASE: THE ROLE OF ARGININE-258
Overview
Deacetoxycephalosporin C synthase is an iron(II) 2-oxoglutaratedependent oxygenase that catalyzes the oxidative ring-expansion of penicillin N to deacetoxycephalosporin C. The wild-type enzyme is only able to efficiently utilize 2-oxoglutarate and 2-oxoadipate as a 2-oxoacid co-substrate. Mutation of arginine 258, the side chain of which forms an electrostatic interaction with the 5-carboxylate of the 2-oxoglutarate co-substrate, to a glutamine residue reduced activity to about 5% of the wild-type enzyme with 2-oxoglutarate. However, other aliphatic 2-oxoacids, which were not co-substrates for the wild-type enzyme, were utilized by the R258Q mutant. These 2-oxoacids "rescued" catalytic activity to the level observed for the wild-type enzyme as judged by penicillin N and G conversion. These co-substrates underwent oxidative decarboxylation as observed for 2-oxoglutarate in the normal reaction with the wild-type enzyme. Crystal structures of the iron(II)- 2-oxo-3-methylbutanoate (1.5 A), and iron(II)-2-oxo-4-methylpentanoate (1.6 A) enzyme complexes were obtained, which reveal the molecular basis for this "chemical co-substrate rescue" and help to rationalize the co-substrate selectivity of 2-oxoglutaratedependent oxygenases.
About this Structure
1HJF is a Single protein structure of sequence from Streptomyces clavuligerus. Full crystallographic information is available from OCA.
Reference
Alteration of the co-substrate selectivity of deacetoxycephalosporin C synthase. The role of arginine 258., Lee HJ, Lloyd MD, Clifton IJ, Harlos K, Dubus A, Baldwin JE, Frere JM, Schofield CJ, J Biol Chem. 2001 May 25;276(21):18290-5. Epub 2001 Feb 21. PMID:11279000 Page seeded by OCA on Fri May 2 18:54:22 2008
