Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
Proc Natl Acad Sci U S A. 2021 Jun 8;118(23). doi: 10.1073/pnas.2019863118.
The epoxide-containing phosphonate natural product fosfomycin is a broad-spectrum antibiotic used in the treatment of cystitis. Fosfomycin is produced by both the plant pathogen and soil-dwelling streptomycetes. While the streptomycete pathway has recently been fully elucidated, the pseudomonad pathway is still mostly elusive. Through a systematic evaluation of heterologous expression of putative biosynthetic enzymes, we identified the central enzyme responsible for completing the biosynthetic pathway in pseudomonads. The missing transformation involves the oxidative decarboxylation of the intermediate 2-phosphonomethylmalate to a new intermediate, 3-oxo-4-phosphonobutanoate, by PsfC. Crystallographic studies reveal that PsfC unexpectedly belongs to a new class of diiron metalloenzymes that are part of the polymerase and histidinol phosphatase superfamily.
含环氧化物的膦酸酯天然产物磷霉素是一种广谱抗生素，用于治疗膀胱炎。磷霉素由植物病原体和土壤居住的链霉菌产生。虽然链霉菌途径最近已被完全阐明，但假单胞菌途径仍然大多难以捉摸。通过对假定生物合成酶的异源表达进行系统评估，我们确定了负责在假单胞菌中完成生物合成途径的中心酶。缺失的转化涉及中间产物 2-膦酰甲基丙二酸通过 PsfC 的氧化脱羧转化为新的中间产物 3-氧代-4-膦丁酸盐。晶体学研究表明，PsfC 出人意料地属于一种新的二铁金属酶类，属于聚合酶和组氨酸醇磷酸酶超家族的一部分。
