A directed-overflow and damage-control N-glycosidase in riboflavin biosynthesis.
A directed-overflow and damage-control N-glycosidase in riboflavin biosynthesis.
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DOI：
10.1042/bj20141237
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发表时间：
2015-02-15
期刊：
影响因子：
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通讯作者：
Hanson AD
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作者：
Frelin O;Huang L;Hasnain G;Jeffryes JG;Ziemak MJ;Rocca JR;Wang B;Rice J;Roje S;Yurgel SN;Gregory JF 3rd;Edison AS;Henry CS;de Crécy-Lagard V;Hanson AD
植物和细菌通过相同的多步骤途径合成人体必需的微量营养素核黄素（维生素B2）。该途径的早期中间体是众所周知的反应性的，并且可能在体内过度产生，因为核黄素生物合成酶缺乏反馈控制。在这里，我们证明处置核黄素中间体的COG 3236（DUF 1768），以前未知的功能，融合到两个不同的核黄素途径酶在植物和细菌（RIBR和RibA，分别）的蛋白质。我们提出了化学信息学、生物化学、遗传学和基因组学证据，表明：（i）植物和细菌COG 3236蛋白切割核黄素生物合成前两个中间体的N-糖苷键，产生相对无害的产物;（ii）某些COG 3236蛋白在多酶核黄素生物合成复合物中，使它们优先获得核黄素中间体;和（iii）COG 3236在拟南芥和大肠杆菌中的作用有助于维持黄素水平。因此，COG 3236蛋白说明了化学生物学中的两个新兴原理：定向溢流代谢，其中过量的通量被转移出途径，以及从反应性代谢物中预先占据损伤。
Plants and bacteria synthesize the essential human micronutrient riboflavin (vitamin B2) via the same multistep pathway. The early intermediates of this pathway are notoriously reactive, and may be overproduced in vivo because riboflavin biosynthesis enzymes lack feedback controls. Here we demonstrate disposal of riboflavin intermediates by COG3236 (DUF1768), a protein of previously unknown function that is fused to two different riboflavin pathway enzymes in plants and bacteria (RIBR and RibA, respectively). We present cheminformatic, biochemical, genetic, and genomic evidence to show that: (i) plant and bacterial COG3236 proteins cleave the N-glycosidic bond of the first two intermediates of riboflavin biosynthesis, yielding relatively innocuous products; (ii) certain COG3236 proteins are in a multienzyme riboflavin biosynthesis complex that gives them privileged access to riboflavin intermediates; and (iii) COG3236 action in Arabidopsis thaliana and Escherichia coli helps maintain flavin levels. COG3236 proteins thus illustrate two emerging principles in chemical biology: directed overflow metabolism, in which excess flux is diverted out of a pathway, and the pre-emption of damage from reactive metabolites.