Coupling between d-3-phosphoglycerate dehydrogenase and d-2-hydroxyglutarate dehydrogenase drives bacterial l-serine synthesis
Coupling between d-3-phosphoglycerate dehydrogenase and d-2-hydroxyglutarate dehydrogenase drives bacterial l-serine synthesis
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D-3-磷酸甘油酸脱氢酶和 D-2-羟基戊二酸脱氢酶之间的偶联驱动细菌 L-丝氨酸合成
DOI：
10.1073/pnas.1619034114
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发表时间：
2017-08
影响因子：
11.1
通讯作者：
Xu Ping
中科院分区：
文献类型：
--
作者：
Zhang Wen;Zhang Manman;Gao Chao;Zhang Yipeng;Ge Yongsheng;Guo Shiting;Guo Xiaoting;Zhou Zikang;Liu Qiuyuan;Zhang Yingxin;Ma Cuiqing;Tao Fei;Xu Ping
d-3-磷酸甘油酸脱氢酶（SerA）是L-丝氨酸生物合成的关键酶。它将d-3-磷酸甘油酸脱氢为3-磷酸羟基丙酮酸和2-酮戊二酸还原为d-2-羟基戊二酸（d-2-HG）偶联。这提供了一个例子，说明非能量上有利的反应和能量上有利的反应是如何联系在一起的，从而使代谢过程得以进行。d-2-HG通常被认为是由几种具有“混杂”活性的酶产生的异常代谢产物。我们的研究结果提供了关于酶反应如何在代谢中发挥关键作用的见解，这些酶反应被认为是混杂或偶然的。我们已经鉴定了细菌d-2-羟基戊二酸脱氢酶（D2 HGDH），其将L-丝氨酸生物合成期间产生的d-2-HG转化回2-酮戊二酸。d-2-HG是一种正常代谢产物，在细菌代谢过程中同时产生和分解代谢，而不积累。l-丝氨酸的生物合成是生命中重要的代谢过程，由d-3-磷酸甘油酸脱氢酶（d-3-PG dehydrogenase，SerA）催化的d-3-PG脱氢反应启动。d-2-羟基戊二酸（d-2-HG）是一种与肿瘤和神经代谢紊乱相关的代谢产物。在这里，我们揭示了细菌的拮抗剂和催化剂的d-2-HG参与L-丝氨酸的生物合成在施氏假单胞菌A1501和铜绿假单胞菌PAO 1。SerA催化2-酮戊二酸（2-KG）立体特异性还原为d-2-HG，负责体内d-2-HG的主要产生。SerA结合了d-2-HG生产的能量有利反应，以克服d-3-PG脱氢的热力学障碍。我们鉴定了一种细菌d-2-HG脱氢酶（D2 HGDH），一种黄素腺嘌呤二核苷酸（FAD）依赖性酶，可将d-2-HG转化为2-KG。电子转移黄素蛋白（ETF）和ETF-泛醌氧化还原酶（ETH 2 O）通过其从D2 HGDH转移电子的能力在d-2-HG代谢中也是必不可少的。此外，虽然D2 HGDH缺失的突变体显示生长下降，但通过添加l-丝氨酸来挽救缺陷，表明D2 HGDH在功能上与l-丝氨酸合成相关。大量的流量流经d-2-HG，由SerA产生并由D2 HGDH、ETF和ETH 2 O去除，维持d-2-HG体内平衡。总的来说，我们的研究结果揭示了d-2-HG介导的SerA和D2 HGDH之间的偶联驱动细菌L-丝氨酸合成。
Significance d-3-Phosphoglycerate dehydrogenase (SerA) is a key enzyme in l-serine biosynthesis. It couples the dehydrogenation of d-3-phosphoglycerate to 3-phosphohydroxypyruvate and the reduction of 2-ketoglutarate to d-2-hydroxyglutarate (d-2-HG). This provides an example of how nonenergetically favorable and energetically favorable reactions are linked together to allow metabolic processes to proceed. d-2-HG is often considered as an abnormal metabolite produced by several enzymes with “promiscuous” activities. Our findings offer insights into how an enzymatic reaction that was considered promiscuous or accidental plays a key role in metabolism. We have identified a bacterial d-2-hydroxyglutarate dehydrogenase (D2HGDH), which converts d-2-HG produced during l-serine biosynthesis back to 2-ketoglutarate. d-2-HG is a normal metabolite that is simultaneously produced and catabolized without accumulation in bacterial metabolism. 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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影响因子：
14.8
作者：
Pacold ME;Brimacombe KR;Chan SH;Rohde JM;Lewis CA;Swier LJ;Possemato R;Chen WW;Sullivan LB;Fiske BP;Cho S;Freinkman E;Birsoy K;Abu-Remaileh M;Shaul YD;Liu CM;Zhou M;Koh MJ;Chung H;Davidson SM;Luengo A;Wang AQ;Xu X;Yasgar A;Liu L;Rai G;Westover KD;Vander Heiden MG;Shen M;Gray NS;Boxer MB;Sabatini DM
通讯作者：
Sabatini DM
DOI：
10.1073/pnas.1614102114
发表时间：
2017-02-07
影响因子：
11.1
作者：
Li, Hongde;Chawla, Geetanjali;Tennessen, Jason M.
通讯作者：
Tennessen, Jason M.
影响因子：
5.1
作者：
Lyon, Robert C.;Johnston, Stuart M.;Ellis, Elizabeth M.
通讯作者：
Ellis, Elizabeth M.
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
50.3
作者：
Xu W;Yang H;Liu Y;Yang Y;Wang P;Kim SH;Ito S;Yang C;Wang P;Xiao MT;Liu LX;Jiang WQ;Liu J;Zhang JY;Wang B;Frye S;Zhang Y;Xu YH;Lei QY;Guan KL;Zhao SM;Xiong Y
通讯作者：
Xiong Y