ArticleBiochemistry2013
Chemical mutagenesis of vaccinia DNA topoisomerase lysine 167 provides insights to the catalysis of DNA transesterification.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I.Molecules (Basel, Switzerland) · 2023Article
- Precise Probing of Residue Roles by Post-Translational β,γ-C,N Aza-Michael Mutagenesis in Enzyme Active Sites.ACS central science · 2017Article
- Protonation states of active-site lysines of penicillin-binding protein 6 from Escherichia coli and the mechanistic implications.Proteins · 2014Article
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2 authors.
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Abstract
Vaccinia DNA topoisomerase IB (TopIB) relaxes supercoils by forming and resealing a covalent DNA-(3'-phosphotyrosyl(274))-enzyme intermediate. Conserved active site side chains promote the attack of Tyr274 on the scissile phosphodiester via transition state stabilization and general acid catalysis. Two essential side chains, Lys167 and Arg130, act in concert to protonate and expel the 5'-O leaving group. Here we gained new insights to catalysis through chemical mutagenesis of Lys167. Changing Lys167 to cysteine crippled the DNA cleavage and religation transesterification steps (k(cl) = 4.3 × 10(-4) s(-1); k(rel) = 9 × 10(-4) s(-1)). The transesterification activities of the K167C enzyme were revived by in vitro alkylation with 2-bromoethylamine (k(cl) = 0.031 s(-1); k(rel) ≥ 0.4 s(-1)) and 3-bromopropylamine (k(cl) = 0.013 s(-1); k(rel) = 0.22 s(-1)), which convert the cysteines to γ-thialysine and γ-thiahomolysine, respectively. These chemically installed lysine analogues were more effective than a genetically programmed arginine 167 substitution characterized previously. The modest differences in the transesterification rates of the 2-bromoethylamine- and 3-bromopropylamine-treated enzymes highlight that TopIB is tolerant of a longer homolysine side chain for assembly of the active site and formation of the transition state.
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