Coupling between
            <scp>d</scp>
            -3-phosphoglycerate dehydrogenase and
            <scp>d</scp>
            -2-hydroxyglutarate dehydrogenase drives bacterial
            <scp>l</scp>
            -serine synthesis

Zhang, Wen; Zhang, Manman; Gao, Chao; Zhang, Yipeng; Ge, Yubin; Guo, Shiting; Guo, Xiaoting; Zhou, Zengtong; Liu, Qiuyuan; Zhang, Yingxin; Ma, Cuiqing; Tao, Fei; Xu, Ping

doi:10.1073/pnas.1619034114

Cited by 44 publications

(72 citation statements)

References 54 publications

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“…However, given our previous observation that Ser3 and Ser33 reduce αKG to the D enantiomer of this dicarboxylic acid [38], this is most likely also the product of the 3PGA-αKG transhydrogenase activity. While this work was ongoing, other investigators independently showed that the Pseudomonas and E. coli phosphoglycerate dehydrogenases (SerA) also actually act as 3PGA-αKG transhydrogenases that produce D-2HG [52,53], perfectly corroborating our results with the yeast enzymes. Only relatively few examples of transhydrogenases are known so far.…”

Section: Nad(p)hx Repair Deficiency Leads To Discrete Changes In Genesupporting

confidence: 84%

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

Becker-Kettern

Paczia

Conrotte

et al. 2018

Preprint

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reading frame; PSAT1, phosphoserine transaminase 1. Keywords-metabolite repair, NAD(P)HX dehydratase, NAD(P)HX epimerase, Saccharomyces cerevisiae, inborn errors of metabolism.Conflict of interest-The authors declare that they have no conflicts of interest with the contents of this article.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/302257 doi: bioRxiv preprint first posted online Apr. 16, 2018; 2 ABSTRACT NADHX and NADPHX are hydrated and redox inactive forms of the NADH and NADPH cofactors, known to inhibit several dehydrogenases in vitro. A metabolite repair system that is conserved in all domains of life and that comprises the two enzymes NAD(P)HX dehydratase and NAD(P)HX epimerase, allows reconversion of both the S-and R-epimers of NADHX and NADPHX to the normal cofactors. An inherited deficiency in this system has recently been shown to cause severe neurometabolic disease in children. Although evidence for the presence of NAD(P)HX has been obtained in plant and human cells, little is known about the mechanism of formation of these derivatives in vivo and their potential effects on cell metabolism. Here, we show that NAD(P)HX dehydratase deficiency in yeast leads to an important, temperature-dependent NADHX accumulation in quiescent cells with a concomitant depletion of intracellular NAD + and serine pools. We demonstrate that NADHX potently inhibits the first step of the serine synthesis pathway in yeast. Human cells deficient in the NAD(P)HX dehydratase also accumulated NADHX and showed decreased viability. In addition, those cells consumed more glucose and produced more lactate, potentially indicating impaired mitochondrial function. Our results provide first insights into how NADHX accumulation affects cellular functions and pave the way for a better understanding of the mechanism(s) underlying the rapid and severe neurodegeneration leading to early death in NADHX repair deficient children.

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Section: Nad(p)hx Repair Deficiency Leads To Discrete Changes In Genesupporting

confidence: 84%

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

Becker-Kettern

Paczia

Conrotte

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…However, given our previous observation that Ser3 and Ser33 reduce αKG to the D enantiomer of this dicarboxylic acid , this is most likely also the product of the 3PGA‐αKG transhydrogenase activity. While this work was ongoing, other investigators independently showed that the Pseudomonas and E. coli phosphoglycerate dehydrogenases (SerA) also actually act as 3PGA‐αKG transhydrogenases that produce D‐2HG , perfectly corroborating our results with the yeast enzymes. Only relatively few examples of transhydrogenases are known so far.…”

Section: Discussionsupporting

confidence: 85%

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

et al. 2018

View full text Add to dashboard Cite

NADHX and NADPHX are hydrated and redox inactive forms of the NADH and NADPH cofactors, known to inhibit several dehydrogenases in vitro. A metabolite repair system that is conserved in all domains of life and that comprises the two enzymes NAD(P)HX dehydratase and NAD(P)HX epimerase, allows reconversion of both the S- and R-epimers of NADHX and NADPHX to the normal cofactors. An inherited deficiency in this system has recently been shown to cause severe neurometabolic disease in children. Although evidence for the presence of NAD(P)HX has been obtained in plant and human cells, little is known about the mechanism of formation of these derivatives in vivo and their potential effects on cell metabolism. Here, we show that NAD(P)HX dehydratase deficiency in yeast leads to an important, temperature-dependent NADHX accumulation in quiescent cells with a concomitant depletion of intracellular NAD and serine pools. We demonstrate that NADHX potently inhibits the first step of the serine synthesis pathway in yeast. Human cells deficient in the NAD(P)HX dehydratase also accumulated NADHX and showed decreased viability. In addition, those cells consumed more glucose and produced more lactate, potentially indicating impaired mitochondrial function. Our results provide first insights into how NADHX accumulation affects cellular functions and pave the way for a better understanding of the mechanism(s) underlying the rapid and severe neurodegeneration leading to early death in NADHX repair-deficient children.

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“…This indicated that EtfAB-I was first reduced to form the red anionic semiquinone with pseudooxynicotine by Pno, and the subsequent decrease of absorption at 370 nm was caused by the formation of fully reduced hydroquinone (33). In order to quantify the activity of EtfAB-I, we added DCPIP to investigate the effects of EtfAB-I on the reduction of DCPIP with pseudooxynicotine by Pno (where PMS was omitted), as described previously (34). Increased DCPIP-reducing activity was observed when purified EtfAB-I was added (Fig.…”

Section: Resultsmentioning

confidence: 99%

6-Hydroxypseudooxynicotine Dehydrogenase Delivers Electrons to Electron Transfer Flavoprotein during Nicotine Degradation by Agrobacterium tumefaciens S33

Wang

Shang

et al. 2019

Appl Environ Microbiol

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Agrobacterium tumefaciens S33 degrades nicotine via a novel hybrid of the pyridine and the pyrrolidine pathways. The hybrid pathway consists of at least six steps involved in oxidoreductive reactions before the N-heterocycle can be broken down. Collectively, the six steps allow electron transfer from nicotine and its intermediates to the final acceptor O 2 via the electron transport chain (ETC). 6-Hydroxypseudooxynicotine oxidase, renamed 6-hydroxypseudooxynicotine dehydrogenase in this study, has been characterized as catalyzing the fourth step using the artificial electron acceptor 2,6-dichlorophenolindophenol. Here, we used biochemical, genetic, and liquid chromatography-mass spectrometry (LC-MS) analyses to determine that 6-hydroxypseudooxynicotine dehydrogenase utilizes the electron transfer flavoprotein (EtfAB) as the physiological electron acceptor to catalyze the dehydrogenation of pseudooxynicotine, an analogue of the true substrate 6-hydroxypseudooxynicotine, in vivo, into 3-succinoyl-semialdehyde-pyridine. NAD(P) ϩ , O 2 , and ferredoxin could not function as electron acceptors. The oxygen atom in the aldehyde group of the product 3-succinoylsemialdehyde-pyridine was verified to be derived from H 2 O. Disruption of the etfAB genes in the nicotine-degrading gene cluster decreased the growth rate of A. tumefaciens S33 on nicotine but not on 6-hydroxy-3-succinoylpyridine, an intermediate downstream of the hybrid pathway, indicating the requirement of EtfAB for efficient nicotine degradation. The electrons were found to be further transferred from the reduced EtfAB to coenzyme Q by the catalysis of electron transfer flavoprotein:ubiquinone oxidoreductase. These results aid in an in-depth understanding of the electron transfer process and energy metabolism involved in the nicotine oxidation and provide novel insights into nicotine catabolism in bacteria. IMPORTANCE Nicotine has been studied as a model for toxic N-heterocyclic aromatic compounds. Microorganisms can catabolize nicotine via various pathways and conserve energy from its oxidation. Although several oxidoreductases have been characterized to participate in nicotine degradation, the electron transfer involved in these processes is poorly understood. In this study, we found that 6-hydroxypseudooxynicotine dehydrogenase, a key enzyme in the hybrid pyridine and pyrrolidine pathway for nicotine degradation in Agrobacterium tumefaciens S33, utilizes EtfAB as a physiological electron acceptor. Catalyzed by the membrane-associated electron transfer flavoprotein:ubiquinone oxidoreductase, the electrons are transferred from the reduced EtfAB to coenzyme Q, which then could enter into the classic ETC. Thus, the route for electron transport from the substrate to O 2 could be constructed, by which ATP can be further sythesized via chemiosmosis to support the baterial growth. These findings provide new knowledge regarding the catabolism of N-heterocyclic aromatic compounds in microorganisms.

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

Cited by 44 publications

References 54 publications

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

6-Hydroxypseudooxynicotine Dehydrogenase Delivers Electrons to Electron Transfer Flavoprotein during Nicotine Degradation by Agrobacterium tumefaciens S33

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