PNAS：科学家发现人体内破坏维生素D的酶

生物谷

    生物谷报道：女王大学科学家发现了维生素D是如何在我们身体中被破坏的，维生素D最近越来越多的被用于治疗和预防癌症及其它疾病。

    这一发现最早在生物化学教授Glenville  Jones的实验室中被观测到，它显示改变羟化酶中一个氨基酸就会导致完全不同的结果。尽管科学家在25年前就已经知道这种酶有两种完全不同的路径，但在这之前他们无法解释为什么会产生这样的情况。

    研究结果发表在网络版Proceedings  of  the  National  Academy  of  Sciences上。

    针对这种酶的早期研究证明在不同物种体内，它们的作用有着区别。例如在人类和老鼠中，这些酶倾向于其中一种路径，而在另外一些物种中，它则倾向另一种路径。利用液相质谱技术，科学家分析了多个种类的动物体细胞。小组改变了人体内酶的某些关键位置，以观察是否会影响路径。

    结果非常令人惊讶，只需改变一个氨基酸就能使酶从一个路径完全变为另一路径。而且这种变化可以反复。Jones博士表示：“这非常重要，在生物化学领域很难找到分子和酶的这样预言性的工作。”

    科学家相信，羟化酶在人体细胞功能中起着重要作用。当维生素D类药物用于治疗某些癌症时，癌细胞通过这些酶进行对抗。Jones博士说：“如果我们可以抑制这种反应，就可以用维生素D复合物治疗某些癌症。”

    维生素D缺乏还会导致其它疾病，如多发性硬化、肌无力和骨骼疾病等。（教育部科技发展中心）

    原文链接：http://www.physorg.com/news104511326.html

原始出处:

Published online before print July 23, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0702093104
Biochemistry

Single A326G mutation converts human CYP24A1 from 25-OH-D3-24-hydroxylase into -23-hydroxylase, generating 1 ${alpha}$ ,25-(OH)2D3-26,23-lactone

( 1 ${alpha}$ ,25-(OH)2D3 | cytochrome P450 | dual metabolic pathways | substrate docking )

David E. Prosser, Martin Kaufmann, Brendan O'Leary, Valarie Byford, and Glenville Jones *

Department of Biochemistry, Queen's University, Kingston, ON, Canada K7L 3N6

Edited by Hector F. DeLuca, University of Wisconsin, Madison, WI, and approved June 18, 2007 (received for review March 8, 2007)

Studies of 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) have demonstrated that it is a bifunctional enzyme capable of the 24-hydroxylation of 1 ${alpha}$ ,25-(OH)2D3, leading to the excretory form, calcitroic acid, and 23-hydroxylation, culminating in 1 ${alpha}$ ,25-(OH)2D3-26,23-lactone. The degree to which CYP24A1 performs either 23- or 24-hydroxylation is species-dependent. In this paper, we show that the human enzyme that predominantly 24-hydroxylates its substrate differs from the opossum enzyme that 23-hydroxylates it at only a limited number of amino acid residues. Mutagenesis of the human form at a single substrate-binding residue (A326G) dramatically changes the regioselectivity of the enzyme from a 24-hydroxylase to a 23-hydroxylase, whereas other modifications have no effect. Ala-326 is located in the I-helix, close to the terminus of the docked 25-hydroxylated side chain in a CYP24A1 homology model, a result that we interpret indicates that substitution of a glycine at 326 provides extra space for the side chain of the substrate to move deeper into the pocket and place it in a optimal stereochemical position for 23-hydroxylation. We discuss the physiological ramifications of these results for species possessing the A326G substitution, as well as implications for optimal vitamin D analog design.

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