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Large-scale domain conformational change is coupled to the activation of the Co–C bond in the B₁₂-dependent enzyme ornithine 4,5-aminomutase: a computational study

Large-scale domain conformational change is coupled to the activation of the Co–C bond in the B₁₂-dependent enzyme ornithine 4,5-aminomutase: a computational study

Pang, Jiayun, Li, Xin, Morokuma, Keiji, Scrutton, Nigel S. and Sutcliffe, Michael J. (2011) Large-scale domain conformational change is coupled to the activation of the Co–C bond in the B₁₂-dependent enzyme ornithine 4,5-aminomutase: a computational study. Journal of the American Chemical Society, 134 (4). pp. 2367-2377. ISSN 0002-7863 (Print), 1520-5126 (Online) (doi:10.1021/ja210417k)

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Abstract

We present here an energetic and atomistic description of how d-ornithine 4,5-aminomutase (OAM), an adenosylcobalamin (AdoCbl; coenzyme B₁₂)-dependent isomerase, employs a large-scale protein domain conformational change to orchestrate the homolytic rupture of the Co–C bond. Our results suggest that in going from the open form (catalytically inactive) to the closed form (catalytically active), the Rossmann domain of OAM effectively approaches the active site as a rigid body. It undergoes a combination of a 52° rotation and a 14 Å translation to bring AdoCbl—initially positioned 25 Å away—into the active-site cavity. This process is coupled to repositioning of the Ado moiety of AdoCbl from the eastern conformation to the northern conformation. Combined quantum mechanics and molecular mechanics calculations further indicate that in the open form, the protein environment does not impact significantly on the Co–C bond homolytic rupture, rendering it unusually stable, and thus catalytically inactive. Upon formation of the closed form, the Co–C bond is activated through the synergy of steric and electrostatic effects arising from tighter interactions with the surrounding enzyme. The more pronounced effect of the protein in the closed form gives rise to an elongated Co–C bond (by 0.03 Å), puckering of the ribose and increased “strain” energy on the Ado group and to a lesser extent the corrin ring. Our computational studies reveal novel strategies employed by AdoCbl-dependent enzymes in the control of radical catalysis.

Item Type: Article
Additional Information: [1] Publication Date (Web): December 22, 2011. [2] Publication Date (Print): February 1, 2012. [3] Published in the Journal of the Americal Chemical Society, (2012) 134 (4), pp 2367–2377.
Uncontrolled Keywords: d-ornithine 4,5-aminomutase (OAM), adenosylcobalamin (AdoCbl; coenzyme B12)-dependent isomerase, homolytic rupture, Rossmann domain
Subjects: Q Science > QA Mathematics > QA75 Electronic computers. Computer science
T Technology > T Technology (General)
T Technology > TA Engineering (General). Civil engineering (General)
Faculty / Department / Research Group: Faculty of Engineering & Science > Department of Pharmaceutical, Chemical & Environmental Sciences
Related URLs:
Last Modified: 07 Dec 2016 14:19
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
URI: http://gala.gre.ac.uk/id/eprint/7646

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