BluB cannibalizes flavin to form the lower ligand of vitamin B12
BluB cannibalizes flavin to form the lower ligand of vitamin B12
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DOI：
10.1038/nature05611
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发表时间：
2007-03-22
期刊：
影响因子：
64.8
通讯作者：
Walker, Graham C.
中科院分区：
文献类型：
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作者：
Taga, Michiko E.;Larsen, Nicholas A.;Walker, Graham C.
维生素B-12（钴胺素）是已知最大的非聚合天然产物之一，也是唯一一种完全由微生物合成的维生素（1）。维生素B-12的低级配体5，6-二甲基苯并咪唑（DMB）的生物合成知之甚少（1-3）。最近，我们发现苜蓿中华根瘤菌（Sinorhizobium meliloti）基因bluB是DMB生物合成所必需的（4）。在这里，我们表明，BluB触发前所未有的碎片和收缩的结合黄素单胞苷肽辅因子和核糖基尾裂解，形成DMB和D-赤藓糖4-磷酸。我们的结构分析表明，BluB类似于NAD（P）H-黄素氧化还原酶，除了其异常紧密的结合口袋容纳黄素单甘肽，而不是NAD（P）H。我们表征晶体学早期中间体沿着反应坐标，揭示分子氧平衡减少黄素。因此，BluB分离并引导还原的黄素激活分子氧，以进行自身的蚕食。对DMB生物合成的这项研究澄清了维生素B-12的一个方面，这一方面在其他方面是不完整的，并可能有助于更好地了解维生素B-12相关疾病。
Vitamin B-12 (cobalamin) is among the largest known non-polymeric natural products, and the only vitamin synthesized exclusively by microorganisms(1). The biosynthesis of the lower ligand of vitamin B-12, 5,6-dimethylbenzimidazole (DMB), is poorly understood(1-3). Recently, we discovered that a Sinorhizobium meliloti gene, bluB, is necessary for DMB biosynthesis(4). Here we show that BluB triggers the unprecedented fragmentation and contraction of the bound flavin mononucleotide cofactor and cleavage of the ribityl tail to form DMB and D-erythrose 4-phosphate. Our structural analysis shows that BluB resembles an NAD(P)H-flavin oxidoreductase, except that its unusually tight binding pocket accommodates flavin mononucleotide but not NAD( P) H. We characterize crystallographically an early intermediate along the reaction coordinate, revealing molecular oxygen poised over reduced flavin. Thus, BluB isolates and directs reduced flavin to activate molecular oxygen for its own cannibalization. This investigation of the biosynthesis of DMB provides clarification of an aspect of vitamin B-12 that was otherwise incomplete, and may contribute to a better understanding of vitamin B-12-related disease.