Catalytic Reaction Mechanism of Homogentisate Dioxygenase: A Hybrid DFT Study.
Human homogentisate dioxygenase is an Fe-dependent enzyme responsible for aromatic ring cleavage. The mechanism of its catalytic reaction has been investigated with the hybrid density functional method B3LYP. A relatively big model of the active site was first used to determine the substrate binding...
| Publicado en: | Journal of the American Chemical Society Vol. 127; no. 49; pp. 17303 - 17315 |
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| Autores principales: | , , |
| Formato: | Artículo |
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American Chemical Society
12/14/2005
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=19332513&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 19332513 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 12/14/2005 vid: 127 iid: 49 pid: 997 pub: American Chemical Society artinfo: ui: 19332513 10.1021/ja054433j ppf: 17303 ppct: 12 formats: tig: atl: Catalytic Reaction Mechanism of Homogentisate Dioxygenase: A Hybrid DFT Study. aug: au: Borowski, Tomasz Georgiev, Valentin Siegbahn, Per E. M. affil: Department of Physics, Stockholm center for Physics, Astronomny and Biotechnology, Stockholm University, S-106 91 Stockholm, Sweden. su: Enzymes Density functionals Catalysis Chemical bonds Oxides Functional analysis sug: subj: Enzymes Density functionals Catalysis Chemical bonds Oxides Functional analysis ab: Human homogentisate dioxygenase is an Fe-dependent enzyme responsible for aromatic ring cleavage. The mechanism of its catalytic reaction has been investigated with the hybrid density functional method B3LYP. A relatively big model of the active site was first used to determine the substrate binding mode. It was found that binding of the substrate dianion with a vacant position trans to G1u341 is most favorable. The model was then truncated to include only the most relevant parts of the active-site residues involved in iron coordination and substrate binding. Thus, methylimidazole was used to model His292, His335, His365, and His371, while propionate modeled G1u341. The computational results suggest that the catalytic reaction of homogentisate dioxygenases involves three major chemical steps: formation of the peroxo intermediate, homolytic cleavage of the 0-0 bond leading to an arene oxide radical, and finally, cleavage of the six-membered ring. Calculated barriers for alternative reaction paths are markedly higher than for the proposed mechanism, and thus the computational results successfully explain the product specificity of the enzyme. Interestingly, the results indicate that the type of ring scission, intra or extra with respect to the substituents coordinating to iron, is controlled by the barrier heights for the decay of the arene oxide radical intermediate. pubtype: Academic Journal doctype: Article src: R language: Slovak refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2005 holdings: @attributes: islocal: N |
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