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Fosfomycin Biosynthesis via Transient Cytidylylation of 2-Hydroxyethylphosphonate by the Bifunctional Fom1 Enzyme
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-07-20 00:00:00 , DOI: 10.1021/acschembio.7b00419 Su-Hee Cho 1 , Seung-Young Kim 2 , Takeo Tomita 1 , Taro Shiraishi 1 , Jin-Soo Park 1 , Shusuke Sato 3 , Fumitaka Kudo 3 , Tadashi Eguchi 3 , Nobutaka Funa 2 , Makoto Nishiyama 1 , Tomohisa Kuzuyama 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-07-20 00:00:00 , DOI: 10.1021/acschembio.7b00419 Su-Hee Cho 1 , Seung-Young Kim 2 , Takeo Tomita 1 , Taro Shiraishi 1 , Jin-Soo Park 1 , Shusuke Sato 3 , Fumitaka Kudo 3 , Tadashi Eguchi 3 , Nobutaka Funa 2 , Makoto Nishiyama 1 , Tomohisa Kuzuyama 1
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Fosfomycin is a wide-spectrum phosphonate antibiotic that is used clinically to treat cystitis, tympanitis, etc. Its biosynthesis starts with the formation of a carbon–phosphorus bond catalyzed by the phosphoenolpyruvate phosphomutase Fom1. We identified an additional cytidylyltransferase (CyTase) domain at the Fom1 N-terminus in addition to the phosphoenolpyruvate phosphomutase domain at the Fom1 C-terminus. Here, we demonstrate that Fom1 is bifunctional and that the Fom1 CyTase domain catalyzes the cytidylylation of the 2-hydroxyethylphosphonate (HEP) intermediate to produce cytidylyl-HEP. On the basis of this new function of Fom1, we propose a revised fosfomycin biosynthetic pathway that involves the transient CMP-conjugated intermediate. The identification of a biosynthetic mechanism via such transient cytidylylation of a biosynthetic intermediate fundamentally advances the understanding of phosphonate biosynthesis in nature. The crystal structure of the cytidylyl-HEP-bound CyTase domain provides a basis for the substrate specificity and reveals unique catalytic elements not found in other members of the CyTase family.
中文翻译：
通过双功能Fom1酶瞬时胞苷化2-羟乙基膦酸酯合成磷霉素。
磷霉素是临床上用于治疗膀胱炎，中耳炎，广谱抗生素膦等。它的生物合成从磷酸烯醇丙酮酸磷酸突变酶Fom1催化形成碳-磷键开始。我们确定了在Fom1额外胞苷酰转移酶（CyTase）域Ñ除了磷酸phosphomutase域在Fom1 -末端Ç-终点。在这里，我们证明Fom1是双功能的，并且Fom1 CyTase域催化2-羟乙基膦酸酯（HEP）中间体的胞嘧啶化，以产生cydydylyl-HEP。基于Fom1的这一新功能，我们提出了一种修订的磷霉素生物合成途径，该途径涉及瞬时CMP偶联中间体。通过这种生物合成中间体的瞬时胞化作用对生物合成机理的鉴定从根本上促进了对膦酸酯生物合成本质的理解。胞嘧啶-HEP结合的CyTase结构域的晶体结构为底物特异性提供了基础，并揭示了CyTase家族其他成员中未发现的独特催化元素。
更新日期：2017-07-20
中文翻译：
通过双功能Fom1酶瞬时胞苷化2-羟乙基膦酸酯合成磷霉素。
磷霉素是临床上用于治疗膀胱炎，中耳炎，广谱抗生素膦等。它的生物合成从磷酸烯醇丙酮酸磷酸突变酶Fom1催化形成碳-磷键开始。我们确定了在Fom1额外胞苷酰转移酶（CyTase）域Ñ除了磷酸phosphomutase域在Fom1 -末端Ç-终点。在这里，我们证明Fom1是双功能的，并且Fom1 CyTase域催化2-羟乙基膦酸酯（HEP）中间体的胞嘧啶化，以产生cydydylyl-HEP。基于Fom1的这一新功能，我们提出了一种修订的磷霉素生物合成途径，该途径涉及瞬时CMP偶联中间体。通过这种生物合成中间体的瞬时胞化作用对生物合成机理的鉴定从根本上促进了对膦酸酯生物合成本质的理解。胞嘧啶-HEP结合的CyTase结构域的晶体结构为底物特异性提供了基础，并揭示了CyTase家族其他成员中未发现的独特催化元素。
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