期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：36
页码：E7574-E7582
DOI：10.1073/pnas.1619034114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：l -Serine biosynthesis, a crucial metabolic process in most domains of life, is initiated by d -3-phosphoglycerate ( d -3-PG) dehydrogenation, a thermodynamically unfavorable reaction catalyzed by d -3-PG dehydrogenase (SerA). d -2-Hydroxyglutarate ( d -2-HG) is traditionally viewed as an abnormal metabolite associated with cancer and neurometabolic disorders. Here, we reveal that bacterial anabolism and catabolism of d -2-HG are involved in l -serine biosynthesis in Pseudomonas stutzeri A1501 and Pseudomonas aeruginosa PAO1. SerA catalyzes the stereospecific reduction of 2-ketoglutarate (2-KG) to d -2-HG, responsible for the major production of d -2-HG in vivo. SerA combines the energetically favorable reaction of d -2-HG production to overcome the thermodynamic barrier of d -3-PG dehydrogenation. We identified a bacterial d -2-HG dehydrogenase (D2HGDH), a flavin adenine dinucleotide (FAD)-dependent enzyme, that converts d -2-HG back to 2-KG. Electron transfer flavoprotein (ETF) and ETF-ubiquinone oxidoreductase (ETFQO) are also essential in d -2-HG metabolism through their capacity to transfer electrons from D2HGDH. Furthermore, while the mutant with D2HGDH deletion displayed decreased growth, the defect was rescued by adding l -serine, suggesting that the D2HGDH is functionally tied to l -serine synthesis. Substantial flux flows through d -2-HG, being produced by SerA and removed by D2HGDH, ETF, and ETFQO, maintaining d -2-HG homeostasis. Overall, our results uncover that d -2-HG–mediated coupling between SerA and D2HGDH drives bacterial l -serine synthesis.
关键词：d -2-Hydroxyglutarate ; 2-ketoglutarate ; d -3-phosphoglycerate ; l -serine biosynthesis ; bacterial metabolism
