Large-Scale Domain Conformational Change Is Coupled to the Activation of the Co鈥揅 Bond in the B12-Dependent Enzyme Ornithine 4,5-Aminomutase: A Computational Study
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- 作者：Jiayun Pang ; Xin Li ; Keiji Morokuma ; Nigel S. Scrutton ; Michael J. Sutcliffe
- 刊名：The Journal of the American Chemical Society
- 出版年：2012
- 出版时间：February 1, 2012
- 年：2012
- 卷：134
- 期：4
- 页码：2367-2377
- 全文大小：656K
- 年卷期：v.134,no.4(February 1, 2012)
- ISSN：1520-5126
文摘
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鈥揅 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掳 rotation and a 14 脜 translation to bring AdoCbl鈥攊nitially positioned 25 脜 away鈥攊nto 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鈥揅 bond homolytic rupture, rendering it unusually stable, and thus catalytically inactive. Upon formation of the closed form, the Co鈥揅 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鈥揅 bond (by 0.03 脜), puckering of the ribose and increased 鈥渟train鈥?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.