1mb9 Citations

The catalytic cycle of beta -lactam synthetase observed by x-ray crystallographic snapshots.

Proc Natl Acad Sci U S A 99 14752-7 (2002)
Related entries: 1m1z, 1mbz, 1mc1

Cited: 32 times
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Abstract

The catalytic cycle of the ATP/Mg(2+)-dependent enzyme beta-lactam synthetase (beta-LS) from Streptomyces clavuligerus has been observed through a series of x-ray crystallographic snapshots. Chemistry is initiated by the ordered binding of ATP/Mg(2+) and N(2)-(carboxyethyl)-l-arginine (CEA) to the apoenzyme. The apo and ATP/Mg(2+) structures described here, along with the previously described CEA.alpha,beta-methyleneadenosine 5'-triphosphate (CEA.AMP-CPP)/Mg(2+) structure, illuminate changes in active site geometry that favor adenylation. In addition, an acyladenylate intermediate has been trapped. The substrate analog N(2)-(carboxymethyl)-l-arginine (CMA) was adenylated by ATP in the crystal and represents a close structural analog of the previously proposed CEA-adenylate intermediate. Finally, the structure of the ternary product complex deoxyguanidinoproclavaminic acid (DGPC).AMP/PP(i)/Mg(2+) has been determined. The CMA-AMP/PP(i)/Mg(2+) and DGPC.AMP/PP(i)/Mg(2+) structures reveal interactions in the active site that facilitate beta-lactam formation. All of the ATP-bound structures differ from the previously described CEA.AMP-CPP/Mg(2+) structure in that two Mg(2+) ions are found in the active sites. These Mg(2+) ions play critical roles in both the adenylation and beta-lactamization reactions.

Articles - 1mb9 mentioned but not cited (2)

  1. Distinct Conformation of ATP Molecule in Solution and on Protein. Kobayashi E, Yura K, Nagai Y. Biophysics (Nagoya-shi) 9 1-12 (2013)
  2. Engineering the synthetic potential of β-lactam synthetase and the importance of catalytic loop dynamics. Labonte JW, Kudo F, Freeman MF, Raber ML, Townsend CA. Medchemcomm 3 960-966 (2012)


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  4. iso-Migrastatin, migrastatin, and dorrigocin production in Streptomyces platensis NRRL 18993 is governed by a single biosynthetic machinery featuring an acyltransferase-less type I polyketide synthase. Lim SK, Ju J, Zazopoulos E, Jiang H, Seo JW, Chen Y, Feng Z, Rajski SR, Farnet CM, Shen B. J Biol Chem 284 29746-29756 (2009)
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  8. Two oligopeptide-permease-encoding genes in the clavulanic acid cluster of Streptomyces clavuligerus are essential for production of the beta-lactamase inhibitor. Lorenzana LM, Pérez-Redondo R, Santamarta I, Martín JF, Liras P. J Bacteriol 186 3431-3438 (2004)
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  11. Dissection of the stepwise mechanism to beta-lactam formation and elucidation of a rate-determining conformational change in beta-lactam synthetase. Raber ML, Freeman MF, Townsend CA. J Biol Chem 284 207-217 (2009)
  12. Structure of anthrax edema factor-calmodulin-adenosine 5'-(alpha,beta-methylene)-triphosphate complex reveals an alternative mode of ATP binding to the catalytic site. Shen Y, Guo Q, Zhukovskaya NL, Drum CL, Bohm A, Tang WJ. Biochem Biophys Res Commun 317 309-314 (2004)
  13. A "diels-alderase" at last. Townsend CA. Chembiochem 12 2267-2269 (2011)
  14. A conserved tyrosyl-glutamyl catalytic dyad in evolutionarily linked enzymes: carbapenam synthetase and beta-lactam synthetase. Raber ML, Arnett SO, Townsend CA. Biochemistry 48 4959-4971 (2009)
  15. Rate-limiting steps and role of active site Lys443 in the mechanism of carbapenam synthetase. Arnett SO, Gerratana B, Townsend CA. Biochemistry 46 9337-9345 (2007)
  16. Substrate activation and conformational dynamics of guanosine 5'-monophosphate synthetase. Oliver JC, Linger RS, Chittur SV, Davisson VJ. Biochemistry 52 5225-5235 (2013)
  17. A conserved lysine in beta-lactam synthetase assists ring cyclization: Implications for clavam and carbapenem biosynthesis. Raber ML, Castillo A, Greer A, Townsend CA. Chembiochem 10 2904-2912 (2009)
  18. A conserved glutamate controls the commitment to acyl-adenylate formation in asparagine synthetase. Meyer ME, Gutierrez JA, Raushel FM, Richards NG. Biochemistry 49 9391-9401 (2010)
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  20. Exploring the role of conformational heterogeneity in cis-autoproteolytic activation of ThnT. Buller AR, Freeman MF, Schildbach JF, Townsend CA. Biochemistry 53 4273-4281 (2014)