Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
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DOI：
10.1073/pnas.0402490101
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发表时间：
2004-05-18
影响因子：
11.1
通讯作者：
Russell, DW
中科院分区：
文献类型：
--
作者：
Cheng, JB;Levine, MA;Russell, DW
生物活性维生素 D 的合成需要分别通过肾脏和肝脏中的细胞色素 P450 酶在 1α 和 25 位进行羟基化。线粒体酶 CYP27B1 催化肾脏中的 1α-羟基化，但肝脏 25-羟化酶的身份在超过 30 年来一直不清楚。我们之前根据酶的生化特性、保守性和表达模式，将微粒体 CYP2R1 蛋白鉴定为肝脏维生素 D 25-羟化酶的潜在候选者。在此，我们报告了一名 25-羟基维生素 D 循环水平低且具有维生素 D 缺乏的典型症状的患者的分子分析。该个体被发现为染色体 11p15.2 上 CYP2R1 基因外显子 2 的过渡突变纯合子。这种遗传突变导致 CYP2R1 蛋白中第 99 位氨基酸被脯氨酸取代为进化上保守的亮氨酸，并消除了维生素 D 25-羟化酶活性。这些数据将 CYP2R1 鉴定为生物学相关的维生素 ID 25-羟化酶，并揭示了人类遗传病（选择性 25-羟基维生素 D 缺乏症）的分子基础。
The synthesis of bioactive vitamin D requires hydroxylation at the 1alpha and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1alpha-hydroxylation in the kidney but the identity of the hepatic 25-hydroxylase has remained unclear for >30 years. We previously identified the microsomal CYP2R1 protein as a potential candidate for the liver vitamin D 25-hydroxylase based on the enzyme's biochemical properties, conservation, and expression pattern. Here, we report a molecular analysis of a patient with low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency. This individual was found to be homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2. The inherited mutation caused the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and eliminated vitamin D 25-hydroxylase enzyme activity. These data identify CYP2R1 as a biologically relevant vitamin ID 25-hydroxylase and reveal the molecular basis of a human genetic disease, selective 25-hydroxyvitamin D deficiency.