Dataset Information

Coupling between d-3-phosphoglycerate dehydrogenase and d-2-hydroxyglutarate dehydrogenase drives bacterial l-serine synthesis.

ABSTRACT: 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.

SUBMITTER: Zhang W

PROVIDER: S-EPMC5594638 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Coupling between d-3-phosphoglycerate dehydrogenase and d-2-hydroxyglutarate dehydrogenase drives bacterial l-serine synthesis.

Zhang Wen W Zhang Manman M Gao Chao C Zhang Yipeng Y Ge Yongsheng Y Guo Shiting S Guo Xiaoting X Zhou Zikang Z Liu Qiuyuan Q Zhang Yingxin Y Ma Cuiqing C Tao Fei F Xu Ping P

Proceedings of the National Academy of Sciences of the United States of America 20170821 36

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 <i>Pseudomonas stutzeri</i> A1501 and ...[more]

PMID: 28827360

Similar Datasets

Project description:l-Serine is the immediate precursor of d-serine, a major agonist of the N-methyl-d-aspartate (NMDA) receptor. l-Serine is a pivotal amino acid since it serves as a precursor to a large number of essential metabolites besides d-serine. In all non-photosynthetic organisms, including mammals, a major source of l-serine is the phosphorylated pathway of l-serine biosynthesis. The pathway consists of three enzymes, d-3-phosphoglycerate dehydrogenase (PGDH), phosphoserine amino transferase (PSAT), and l-phosphoserine phosphatase (PSP). PGDH catalyzes the first step in the pathway by converting d-3-phosphoglycerate (PGA), an intermediate in glycolysis, to phosphohydroxypyruvate (PHP) concomitant with the reduction of NAD+. In some, but not all organisms, the catalytic activity of PGDH can be regulated by feedback inhibition by l-serine. Three types of PGDH can be distinguished based on their domain structure. Type III PGDHs contain only a nucleotide binding and substrate binding domain. Type II PGDHs contain an additional regulatory domain (ACT domain), and Type I PGDHs contain a fourth domain, termed the ASB domain. There is no consistent pattern of domain content that correlates with organism type, and even when additional domains are present, they are not always functional. PGDH deficiency results in metabolic defects of the nervous system whose systems range from microcephaly at birth, seizures, and psychomotor retardation. Although deficiency of any of the pathway enzymes have similar outcomes, PGDH deficiency is predominant. Dietary or intravenous supplementation with l-serine is effective in controlling seizures but has little effect on psychomotor development. An increase in PGDH levels, due to overexpression, is also associated with a wide array of cancers. In culture, PGDH is required for tumor cell proliferation, but extracellular l-serine is not able to support cell proliferation. This has led to the hypothesis that the pathway is performing some function related to tumor growth other than supplying l-serine. The most well-studied PGDHs are bacterial, primarily from Escherichia coli and Mycobacterium tuberculosis, perhaps because they have been of most interest mechanistically. However, the relatively recent association of PGDH with neuronal defects and human cancers has provoked renewed interest in human PGDH.

Dataset Information

Coupling between d-3-phosphoglycerate dehydrogenase and d-2-hydroxyglutarate dehydrogenase drives bacterial l-serine synthesis.

Publications

Coupling between d-3-phosphoglycerate dehydrogenase and d-2-hydroxyglutarate dehydrogenase drives bacterial l-serine synthesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets