The Action of Glyceraldehyde-3-Phosphate Dehydrogenase on Reduced Diphosphopyridine Nucleotide

Rafter, Gale W.; Chaykin, Sterling; Krebs, Edwin G.

doi:10.1016/s0021-9258(18)65605-4

Cited by 97 publications

(20 citation statements)

References 19 publications

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“…NADH and NADPH can be damaged by hydration of one of the double bonds of the nicotinamide ring under specific stress conditions, such as increased temperature or acidic pH, leading to the formation of the aberrant forms NADHX and NADPHX (Fig 4). NADHX can also be formed by the activity of glyceraldehyde 3-phosphate dehydrogenase (Rafter et al, 1954). NAD(P)HX can spontaneously react to cyclic NAD(P) HX in an irreversible way (Fig 4).…”

Section: Primary Deficiencies Of Nad + Synthesismentioning

confidence: 99%

NAD ⁺ homeostasis in human health and disease

et al. 2021

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Depletion of nicotinamide adenine dinucleotide (NAD + ), a central redox cofactor and the substrate of key metabolic enzymes, is the causative factor of a number of inherited and acquired diseases in humans. Primary deficiencies of NAD + homeostasis are the result of impaired biosynthesis, while secondary deficiencies can arise due to other factors affecting NAD + homeostasis, such as increased NAD + consumption or dietary deficiency of its vitamin B3 precursors. NAD + depletion can manifest in a wide variety of pathological phenotypes, ranging from rare inherited defects, characterized by congenital malformations, retinal degeneration, and/or encephalopathy, to more common multifactorial, often age-related, diseases. Here, we discuss NAD + biochemistry and metabolism and provide an overview of the etiology and pathological consequences of alterations of the NAD + metabolism in humans. Finally, we discuss the state of the art of the potential therapeutic implications of NAD + repletion for boosting health as well as treating rare and common diseases, and the possibilities to achieve this by means of the different NAD +enhancing agents.

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Section: Primary Deficiencies Of Nad + Synthesismentioning

confidence: 99%

NAD ⁺ homeostasis in human health and disease

et al. 2021

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“…One of the two oldest known metabolite repair mechanisms allows hydrated forms of NADH and NADPH to be reconverted to regular NAD(P)H. An ATP-dependent dehydratase activity was shown in 1956 to repair a damaged form of NADH, called NADHX [59], that is formed by a side-reaction of GAPDH [27,60] (Figure 1, pathway 5; Figure 3). Later it was found that NAD(P)HX is a hydrated form of NAD(P)H in which the hydroxyl group on C6 of the nicotinamide ring is in the S or the R orientation [27].…”

Section: Acyp1 Can Eliminate Side-products Of Gapdhmentioning

confidence: 99%

Metabolite Repair Enzymes Control Metabolic Damage in Glycolysis

Bommer

Schaftingen

Veiga‐da‐Cunha

2020

Trends in Biochemical Sciences

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Hundreds of metabolic enzymes work together smoothly in a cell. These enzymes are highly specific. Nevertheless, under physiological conditions, many perform side-reactions at low rates, producing potentially toxic side-products. An increasing number of metabolite repair enzymes are being discovered that serve to eliminate these noncanonical metabolites. Some of these enzymes are extraordinarily conserved, and their deficiency can lead to diseases in humans or embryonic lethality in mice, indicating their central role in cellular metabolism. We discuss how metabolite repair enzymes eliminate glycolytic side-products and prevent negative interference within and beyond this core metabolic pathway. Extrapolating from the number of metabolite repair enzymes involved in glycolysis, hundreds more likely remain to be discovered that protect a wide range of metabolic pathways.

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“…This reaction may for example be caused by a side activity of glyceraldehyde-3-phosphate dehydrogenase. 39,40 But it may also be spontaneous, and this is particularly true for NADPH, which is converted to NADPHX at a rate of 10% per hour at 37 C. 41 The enzyme that reverses this damage by removing a water molecule from NAD(P)HX in an ATP-dependent manner was first described in 1956. 42 Yet, it was only recently that its sequence was identified.…”

Section: Deficiency In Two Super-conserved Repair Enzymes Leads To a New Metabolic Diseasementioning

confidence: 99%

“…This is true for the pyridine nucleotides, NAD and NADP, which under their reduced form (NADH and NADPH), are rather easily converted to hydrated forms (called NADHX and NADPHX), that is, to forms that have undergone a water addition reaction. This reaction may for example be caused by a side activity of glyceraldehyde‐3‐phosphate dehydrogenase . But it may also be spontaneous, and this is particularly true for NADPH, which is converted to NADPHX at a rate of 10% per hour at 37°C …”

Section: Deficiency In Two Super‐conserved Repair Enzymes Leads To a New Metabolic Diseasementioning

confidence: 99%

Inborn errors of metabolite repair

Veiga‐da‐Cunha

Schaftingen

Bommer

2019

J of Inher Metab Disea

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It is traditionally assumed that enzymes of intermediary metabolism are extremely specific and that this is sufficient to prevent the production of useless and/or toxic side-products. Recent work indicates that this statement is not entirely correct. In reality, enzymes are not strictly specific, they often display weak side activities on intracellular metabolites (substrate promiscuity) that resemble their physiological substrate or slowly catalyse abnormal reactions on their physiological substrate (catalytic promiscuity). They thereby produce non-classical metabolites that are not efficiently metabolised by conventional enzymes. In an increasing number of cases, metabolite repair enzymes are being discovered that serve to eliminate these non-classical metabolites and prevent their accumulation. Metabolite repair enzymes also eliminate non-classical metabolites that are formed through spontaneous (ie, not enzyme-catalysed) reactions. Importantly, genetic deficiencies in several metabolite repair enzymes lead to 'inborn errors of metabolite repair', such as L-2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria, 'ubiquitous glucose-6-phosphatase' (G6PC3) deficiency, the neutropenia present in Glycogen Storage Disease type Ib or defects in the enzymes that repair the hydrated forms of NADH or NADPH. Metabolite repair defects may be difficult to identify as such, because the mutated enzymes are non-classical enzymes that act on nonclassical metabolites, which in some cases accumulate only inside the cells, and at rather low, yet toxic, concentrations. It is therefore likely that many additional metabolite repair enzymes remain to be discovered and that many diseases of metabolite repair still await elucidation. K E Y W O R D S1,5-anhydroglucitol-6-phosphate, D-2-hydroxyglutaric aciduria, enzyme promiscuity, G6PC3, G6PT, galactose, inborn errors of metabolism, metabolite repair, NADP(H)X, neutropenia, PGM1, SGLT2 inhibitor, UGP2Abbreviations: D2HGDH, D-2-hydroxyglutarate dehydrogenase; G6PC3, ubiquitous glucose-6-phosphatase; G6PT, glucose-6-phosphate translocase of the endoplasmic

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The Action of Glyceraldehyde-3-Phosphate Dehydrogenase on Reduced Diphosphopyridine Nucleotide

Cited by 97 publications

References 19 publications

NAD ⁺ homeostasis in human health and disease

NAD ⁺ homeostasis in human health and disease

Metabolite Repair Enzymes Control Metabolic Damage in Glycolysis

Inborn errors of metabolite repair

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The Action of Glyceraldehyde-3-Phosphate Dehydrogenase on Reduced Diphosphopyridine Nucleotide

Cited by 97 publications

References 19 publications

NAD + homeostasis in human health and disease

NAD + homeostasis in human health and disease

Metabolite Repair Enzymes Control Metabolic Damage in Glycolysis

Inborn errors of metabolite repair

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NAD ⁺ homeostasis in human health and disease

NAD ⁺ homeostasis in human health and disease