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A conformational sampling model for radical catalysis in pyridoxal phosphate- and cobalamin-dependent enzymes

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Menon, Binuraj R. K., Fisher, Karl, Rigby, Stephen E. J., Scrutton, Nigel S. and Leys, David (2014) A conformational sampling model for radical catalysis in pyridoxal phosphate- and cobalamin-dependent enzymes. Journal of Biological Chemistry, 289 (49). pp. 34161-34174. doi:10.1074/jbc.M114.590471

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Official URL: http://dx.doi.org/10.1074/jbc.M114.590471

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Abstract

Cobalamin-dependent enzymes enhance the rate of C–Co bond cleavage by up to ∼1012-fold to generate cob(II)alamin and a transient adenosyl radical. In the case of the pyridoxal 5′-phosphate (PLP) and cobalamin-dependent enzymes lysine 5,6-aminomutase and ornithine 4,5 aminomutase (OAM), it has been proposed that a large scale domain reorientation of the cobalamin-binding domain is linked to radical catalysis. Here, OAM variants were designed to perturb the interface between the cobalamin-binding domain and the PLP-binding TIM barrel domain. Steady-state and single turnover kinetic studies of these variants, combined with pulsed electron-electron double resonance measurements of spin-labeled OAM were used to provide direct evidence for a dynamic interface between the cobalamin and PLP-binding domains. Our data suggest that following ligand binding-induced cleavage of the Lys629-PLP covalent bond, dynamic motion of the cobalamin-binding domain leads to conformational sampling of the available space. This supports radical catalysis through transient formation of a catalytically competent active state. Crucially, it appears that the formation of the state containing both a substrate/product radical and Co(II) does not restrict cobalamin domain motion. A similar conformational sampling mechanism has been proposed to support rapid electron transfer in a number of dynamic redox systems.

Item Type: Journal Article
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Journal or Publication Title: Journal of Biological Chemistry
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Official Date: 2014
Dates:
DateEvent
2014Published
Volume: 289
Number: 49
Page Range: pp. 34161-34174
DOI: 10.1074/jbc.M114.590471
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access

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