Decyanation of vitamin B12 by a trafficking chaperone
Decyanation of vitamin B12 by a trafficking chaperone
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DOI：
10.1073/pnas.0805989105
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发表时间：
2008-09-23
影响因子：
11.1
通讯作者：
Banerjee, Ruma
中科院分区：
文献类型：
--
作者：
Kim, Jihoe;Gherasim, Carmen;Banerjee, Ruma
60年前发现的维生素B-12或氰钴胺素中的氰化物基团是如何被去除的谜团，已经通过证明贩运伴侣MMACHC催化还原性脱氰反应而得到解决。通过胞质黄蛋白氧化还原酶从NADPH转移的电子被用来切割钴碳键，并还原消除氰化物配体。该产物cob(II)alamin是一种已知的底物，可被同化为活性辅助因子形式甲基钴胺素和5'-脱氧腺苷钴胺素，并以两种依赖b -12的靶酶（蛋氨酸合成酶和甲基丙二酰辅酶a变化酶）所需要的“碱基关闭”状态结合。MMACHC缺陷是先天性B12代谢错误的最常见原因，我们的研究结果解释了这些患者的成纤维细胞对维生素B12反应较差，但对水钴胺素（一种缺乏氰化物配体的辅因子形式）表现出一些代谢纠正，这反映了患者对氰胺与水钴胺素表现出较差的临床反应。
The mystery of how the cyanide group in vitamin B-12 or cyanocobalamin, discovered 60 years ago, is removed, has been solved by the demonstration that the trafficking chaperone, MMACHC, catalyzes a reductive decyanation reaction. Electrons transferred from NADPH via cytosolic flavoprotein oxidoreductases are used to cleave the cobalt-carbon bond with reductive elimination of the cyanide ligand. The product, cob(II)alamin, is a known substrate for assimilation into the active cofactor forms, methylcobalamin and 5'-deoxyadenosylcobalamin, and is bound in the "base-off" state that is needed by the two B-12-dependent target enzymes, methionine synthase and methylmalonyl-CoA mutase. Defects in MMACHC represent the most common cause of inborn errors of B12 metabolism, and our results explain the observation that fibroblasts from these patients are poorly responsive to vitamin B12 but show some metabolic correction with aquocobalamin, a cofactor form lacking the cyanide ligand, which is mirrored by patients showing poorer clinical responsiveness to cyano- versus aquocobalamin.