生物谷報道：女王大學科學家發(fā)現(xiàn)了維生素D是如何在我們身體中被破壞的,，維生素D最近越來越多的被用于治療和預防癌癥及其它疾病,。
這一發(fā)現(xiàn)最早在生物化學教授Glenville Jones的實驗室中被觀測到，它顯示改變羥化酶中一個氨基酸就會導致完全不同的結果,。盡管科學家在25年前就已經(jīng)知道這種酶有兩種完全不同的路徑,，但在這之前他們無法解釋為什么會產(chǎn)生這樣的情況。
研究結果發(fā)表在網(wǎng)絡版Proceedings of the National Academy of Sciences上,。
針對這種酶的早期研究證明在不同物種體內,，它們的作用有著區(qū)別。例如在人類和老鼠中,，這些酶傾向于其中一種路徑,，而在另外一些物種中，它則傾向另一種路徑,。利用液相質譜技術,，科學家分析了多個種類的動物體細胞。小組改變了人體內酶的某些關鍵位置,，以觀察是否會影響路徑,。
結果非常令人驚訝,，只需改變一個氨基酸就能使酶從一個路徑完全變?yōu)榱硪宦窂健６疫@種變化可以反復,。Jones博士表示：“這非常重要,，在生物化學領域很難找到分子和酶的這樣預言性的工作。”
科學家相信,，羥化酶在人體細胞功能中起著重要作用,。當維生素D類藥物用于治療某些癌癥時，癌細胞通過這些酶進行對抗,。Jones博士說：“如果我們可以抑制這種反應,，就可以用維生素D復合物治療某些癌癥。”
維生素D缺乏還會導致其它疾病,，如多發(fā)性硬化,、肌無力和骨骼疾病等。 （教育部科技發(fā)展中心）
原文鏈接：http://www.physorg.com/news104511326.html
原始出處:
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 1,25-(OH)2D3-26,23-lactone
( 1,25-(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 1,25-(OH)2D3, leading to the excretory form, calcitroic acid, and 23-hydroxylation, culminating in 1,25-(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.
