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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Single A326G mutation converts human CYP24A1 from 25-OH-D_3-24-hydroxylase into -23-hydroxylase, generating 1 α, 25-(OH)_2D_3-26,23-lactone
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Single A326G mutation converts human CYP24A1 from 25-OH-D_3-24-hydroxylase into -23-hydroxylase, generating 1 α, 25-(OH)_2D_3-26,23-lactone

机译：单个A326G突变将人CYP24A1从25-OH-D_3-24-羟化酶转化为-23-羟化酶，生成1α，25-（OH）_2D_3-26,23-内酯

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摘要

Studies of 25-hydroxyvitamin D_3-24-hydroxylase (CYP24A1) have demonstrated that it is a bifunctional enzyme capable of the 24-hydroxylation of 1α,25-(OH)_2D_3, leading to the excretory form, calcitroicacid, and 23-hydroxylation, culminating in 1α,25-(OH)_2D_3-26,23-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.
机译：对25-羟基维生素D_3-24-羟化酶（CYP24A1）的研究表明，它是一种双功能酶，能够将1α，25-（OH）_2D_3进行24-羟化，从而导致排泄形式，钙柠檬酸和23-羟化，最终形成1α，25-（OH）_2D_3-26,23-内酯。 CYP24A1进行23或24羟基化的程度取决于物种。在本文中，我们显示了主要以24-羟基化其底物的人类酶与仅以有限数量的氨基酸残基将23-羟基化其的负鼠酶有所不同。在单个底物结合残基（A326G）处进行人型诱变会极大地改变酶的区域选择性，从24-羟化酶变为23-羟化酶，而其他修饰则无效。 Ala-326位于I螺旋中，靠近CYP24A1同源性模型中对接的25-羟基化侧链的末端，我们解释的结果表明，326位甘氨酸的取代为Ala-326的侧链提供了额外的空间。将底物移至更深的口袋中，并将其置于23-羟基化的最佳立体化学位置。我们讨论了这些结果对具有A326G取代的物种的生理影响，以及对最佳维生素D类似物设计的启示。

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