Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 36, Pages E7574-E7582Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1619034114
Keywords
D-2-Hydroxyglutarate; 2-ketoglutarate; D-3-phosphoglycerate; L-serine biosynthesis; bacterial metabolism
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Funding
- National Natural Science Foundation of China [31470199, 31470164, 31270090]
- Shandong University [2015WLJH25]
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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.
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