Resolving the Multidecade-Long Mystery in MoaA Radical SAM Enzyme Reveals New Opportunities to Tackle Human Health Problems.
Resolving the Multidecade-Long Mystery in MoaA Radical SAM Enzyme Reveals New Opportunities to Tackle Human Health Problems.
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解决MoaA中长达数十年之久的谜团激进的SAM酶揭示了解决人类健康问题的新机会。
DOI：
10.1021/acsbiomedchemau.1c00046
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发表时间：
2022-04-20
期刊：
影响因子：
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通讯作者：
Pang, Haoran
中科院分区：
文献类型：
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作者：
Yokoyama, Kenichi;Li, Di;Pang, Haoran
MoaA是最保守的自由基S-腺苷-L-甲硫氨酸（SAM）酶之一，并且在所有三个生命王国的大多数生物体中发现。MoaA有助于钼辅因子（Moco）的生物合成，钼辅因子是一种氧化还原酶辅因子，用于各种酶，如人类的嘌呤和硫催化剂以及细菌的厌氧呼吸。与许多其他辅因子不同，在大多数生物体中，Moco不能作为营养素吸收，需要从头生物合成。因此，Moco生物合成与几个人类健康问题有关，如人类Moco缺乏症和细菌感染。尽管具有医学和生物学意义，但二十多年来，莫科特有的吡喃蝶呤结构的生物合成机制仍然难以捉摸。这种转化需要MoaA自由基SAM酶和另一种蛋白MoaC的作用。最近，MoaA和MoaC的功能分别被阐明为自由基SAM GTP 3′，8-环化酶和环吡喃蝶呤一磷酸（cPMP）合酶。这一发现解决了该领域的关键谜团，并揭示了研究MoaA和MoaC的酶学和化学生物学的新机会，以阐明酶催化的新机制或解决Moco相关人类健康问题中未解决的问题。本文综述了MoaA和MoaC的功能和作用机制的研究进展，并对该领域的未来发展方向进行了讨论。
MoaA is one of the most conserved radical S-adenosyl-l-methionine (SAM) enzymes, and is found in most organisms in all three kingdoms of life. MoaA contributes to the biosynthesis of molybdenum cofactor (Moco), a redox enzyme cofactor used in various enzymes such as purine and sulfur catabolism in humans and anaerobic respiration in bacteria. Unlike many other cofactors, in most organisms, Moco cannot be taken up as a nutrient and requires de novo biosynthesis. Consequently, Moco biosynthesis has been linked to several human health problems, such as human Moco deficiency disease and bacterial infections. Despite the medical and biological significance, the biosynthetic mechanism of Moco’s characteristic pyranopterin structure remained elusive for more than two decades. This transformation requires the actions of the MoaA radical SAM enzyme and another protein, MoaC. Recently, MoaA and MoaC functions were elucidated as a radical SAM GTP 3′,8-cyclase and cyclic pyranopterin monophosphate (cPMP) synthase, respectively. This finding resolved the key mystery in the field and revealed new opportunities in studying the enzymology and chemical biology of MoaA and MoaC to elucidate novel mechanisms in enzyme catalysis or to address unsolved questions in Moco-related human health problems. Here, we summarize the recent progress in the functional and mechanistic studies of MoaA and MoaC and discuss the field’s future directions.