Glyceraldehyde-3-phosphate dehydrogenase catalyzed hydration of the 5-6 double bond of reduced β-nicotinamide adenine dinucleotide (βNADH). Formation of β-6-hydroxy-1,4,5,6-tetrahydronicotinamide adenine dinucleotide

Oppenheimer, Norman J.; Kaplan, Nathan O.

doi:10.1021/bi00720a002

Cited by 49 publications

(38 citation statements)

References 30 publications

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“…73,74 Glyceraldehyde-3-phosphate dehydrogenase can also catalyze formation of this adduct with NADH, apparently assisted by bound anions. 75 The oxidized nicotinamide ring of NAD + can be attacked under basic conditions by various nucleophiles at the C2N, C4N, and C6N atoms, 74 but the source of NAD + in the ADH structures is not clear. It may be difficult to assign waters in specific structures because of the presence of alternative positions and occupancies.…”

Section: Discussionmentioning

confidence: 99%

Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis

et al. 2017

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During catalysis by liver alcohol dehydrogenase (ADH), a water bound to the catalytic zinc is replaced by the oxygen of the substrates. The mechanism might involve a pentacoordinated zinc or a double-displacement reaction with participation by a nearby glutamate residue, as suggested by studies of human ADH3, yeast ADH1, and some other tetrameric ADHs. Zinc coordination and participation of water in the enzyme mechanism were investigated by X-ray crystallography. The apoenzyme and its complex with adenosine 5′-diphosphoribose have an open protein conformation with the catalytic zinc in one position, tetracoordinated by Cys-46, His-67, Cys-174, and a water molecule. The bidentate chelators 2,2′-bipyridine and 1,10-phenanthroline displace the water and form a pentacoordinated zinc. The enzyme–NADH complex has a closed conformation similar to that of ternary complexes with coenzyme and substrate analogues; the coordination of the catalytic zinc is similar to that found in the apoenzyme, except that a minor, alternative position for the catalytic zinc is ∼1.3 Å from the major position and closer to Glu-68, which could form the alternative coordination to the catalytic zinc. Complexes with NADH and N-1-methylhexylformamide or N-benzylformamide (or with NAD+ and fluoro alcohols) have the classical tetracoordinated zinc, and no water is bound to the zinc or the nicotinamide rings. The major forms of the enzyme in the mechanism have a tetracoordinated zinc, where the carboxylate group of Glu-68 could participate in the exchange of water and substrates on the zinc. Hydride transfer in the Michaelis complexes does not involve a nearby water.

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Section: Discussionmentioning

confidence: 99%

Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis

et al. 2017

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“…Hydrated forms can also be produced by incubating NADH and NADPH in acid at room temperature or at neutral pH and elevated temperatures (Yoshida and Dave 1975;Marbaix et al 2011). The water molecule is added to the C5-C6 double bond of the nicotinamide ring, leading to hydroxylation of C6 (Oppenheimer and Kaplan 1974). NADHX and NADPHX exist as mixtures of epimers differing in the orientation of the hydroxyl group.…”

Section: Nad(p)hx Dehydratasementioning

confidence: 99%

Metabolite proofreading, a neglected aspect of intermediary metabolism

Schaftingen

Rim

Marbaix

et al. 2013

J of Inher Metab Disea

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Enzymes of intermediary metabolism are less specific than what is usually assumed: they often act on metabolites that are not their 'true' substrate, making abnormal metabolites that may be deleterious if they accumulate. Some of these abnormal metabolites are reconverted to normal metabolites by repair enzymes, which play therefore a role akin to the proofreading activities of DNA polymerases and aminoacyl-tRNA synthetases. An illustrative example of such repair enzymes is L-2-hydroxyglutarate dehydrogenase, which eliminates a metabolite abnormally made by a Krebs cycle enzyme. Mutations in L-2-hydroxyglutarate dehydrogenase lead to L-2-hydroxyglutaric aciduria, a leukoencephalopathy. Other examples are the epimerase and the ATP-dependent dehydratase that repair hydrated forms of NADH and NADPH; ethylmalonyl-CoA decarboxylase, which eliminates an abnormal metabolite formed by acetyl-CoA carboxylase, an enzyme of fatty acid synthesis; L-pipecolate oxidase, which repairs a metabolite formed by a side activity of an enzyme of L-proline biosynthesis. Metabolite proofreading enzymes are likely quite common, but most of them are still unidentified. A defect in these enzymes may account for new metabolic disorders.

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“…Fortunately, the glyoxalase system converts methylglyoxal to the non-toxic compound D-lactate, which can then be utilized by mitochondrial D-lactate dehydrogenase. Glyceraldehyde 3-phosphate dehydrogenase slowly catalyses the hydration of NADH to FNADH-X_ (Oppenheimer and Kaplan 1974), which is not utilized by dehydrogenases and may even inhibit them. Fortunately again, an ATP-dependent enzyme, whose sequence is presently unknown, reconverts NADH-X to NADH (Acheson et al 1988).…”

Section: The Formation Of L-2-hydroxyglutaratementioning

confidence: 99%

l‐2‐Hydroxyglutaric aciduria, a disorder of metabolite repair

Schaftingen

Rim

Veiga‐da‐Cunha

2008

J of Inher Metab Disea

123

105

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The neurometabolic disorder L: -2-hydroxyglutaric aciduria is caused by mutations in a gene present on chromosome 14q22.1 and encoding L: -2-hydroxyglutarate dehydrogenase. This FAD-linked mitochondrial enzyme catalyses the irreversible conversion of L: -2-hydroxyglutarate to alpha-ketoglutarate. The formation of L: -2-hydroxyglutarate results from a side-activity of mitochondrial L: -malate dehydrogenase, the enzyme that interconverts oxaloacetate and L: -malate, but which also catalyses, very slowly, the NADH-dependent conversion of alpha-ketoglutarate to L: -2-hydroxyglutarate. L: -2-Hydroxyglutarate has no known physiological function in eukaryotes and most prokaryotes. Its accumulation is toxic to the mammalian brain, causing a leukoencephalopathy and increasing the susceptibility to develop tumours. L: -2-Hydroxyglutaric aciduria appears to be the first disease of 'metabolite repair'.

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Glyceraldehyde-3-phosphate dehydrogenase catalyzed hydration of the 5-6 double bond of reduced β-nicotinamide adenine dinucleotide (βNADH). Formation of β-6-hydroxy-1,4,5,6-tetrahydronicotinamide adenine dinucleotide

Cited by 49 publications

References 30 publications

Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis

Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis

Metabolite proofreading, a neglected aspect of intermediary metabolism

l‐2‐Hydroxyglutaric aciduria, a disorder of metabolite repair

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