Absolute stereochemistry of 2-hydroxyglutaric acid present in methanopterin

Solow, Barbara T.; White, Robert H.

doi:10.1002/(sici)1520-636x(1997)9:7<678::aid-chir7>3.0.co;2-3

Cited by 5 publications

(1 citation statement)

References 12 publications

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“…Unlike in some bacteria where it is involved in the synthesis of the cofactor methanopterin (Graupner et al 2000;Solow and White 1997) and possibly as a product of condensation of glyoxylate with propionyl-CoA (Reeves and Ajl 1962), L-2-hydroxyglutarate is not a known intermediate in any pathway present in mammals. Its presence in urine of patients with L-2-hydroxyglutaric aciduria, irrespective of their food intake (Barth et al 1992), indicates that this compound is formed endogenously.…”

Section: Origin Of L-2-hydroxyglutaratementioning

confidence: 99%

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

Rim

Vincent

Schaftingen

et al. 2007

J of Inher Metab Disea

132

129

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L-2-hydroxyglutaric aciduria is a metabolic disorder in which L-2-hydroxyglutarate accumulates as a result of a deficiency in FAD-linked L-2-hydroxyglutarate dehydrogenase, a mitochondrial enzyme converting L-2-hydroxyglutarate to alpha-ketoglutarate. The origin of the L-2-hydroxyglutarate, which accumulates in this disorder, is presently unknown. The oxidation-reduction potential of the 2-hydroxyglutarate/alpha-ketoglutarate couple is such that L-2-hydroxyglutarate could potentially be produced through the reduction of alpha-ketoglutarate by a NAD- or NADP-linked oxidoreductase. In fractions of rat liver cytosolic extracts that had been chromatographed on an anion exchanger we detected an enzyme reducing alpha-ketoglutarate in the presence of NADH. This enzyme co-purified with cytosolic L-malate dehydrogenase (cMDH) upon further chromatography on Blue Sepharose. Mitochondrial fractions also contained an NADH-linked, 'alpha-ketoglutarate reductase', which similarly co-purified with mitochondrial L-malate dehydrogenase (mMDH). Purified mMDH catalysed the reduction of alpha-ketoglutarate to L-2-hydroxyglutarate with a catalytic efficiency that was about 10(7)-fold lower than that observed with oxaloacetate. For the cytosolic enzyme, this ratio amounted to 10(8), indicating that this enzyme is more specific. Both cMDH and mMDH are highly active in tissues and alpha-ketoglutarate is much more abundant than oxaloacetate and more concentrated in mitochondria than in the cytosol. As a result of this, the weak activity of mMDH on alpha-ketoglutarate is sufficient to account for the amount of L-2-hydroxyglutarate that is excreted by patients deficient in FAD-linked L-2-hydroxyglutarate dehydrogenase. The latter enzyme appears, therefore, to be responsible for a 'metabolite repair' phenomenon and to belong to the expanding class of 'house-cleaning' enzymes.

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Section: Origin Of L-2-hydroxyglutaratementioning

confidence: 99%

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

Rim

Vincent

Schaftingen

et al. 2007

J of Inher Metab Disea

132

129

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Biosynthesis of the methanogenic cofactors

White

2001

Vitamins &Amp; Hormones

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Enzyme promiscuity, metabolite damage, and metabolite damage control systems of the tricarboxylic acid cycle

Niehaus

Hillmann

2020

The FEBS Journal

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Promiscuous enzymes and spontaneous chemical reactions can convert normal cellular metabolites into noncanonical or damaged metabolites. These damaged metabolites can be a useless drain on metabolism and may be inhibitory and/or reactive, sometimes leading to toxicity. Thus, mechanisms to prevent metabolite damage from occurring (metabolite damage preemption) or to convert damaged metabolites back to physiological forms (metabolite repair) are essential for sustained operation of metabolic networks. Some iconic examples of metabolite damage and its repair or preemption are associated with the tricarboxylic acid (TCA) cycle, and other metabolite damage control systems are likely to exist here due to the inherent promiscuity of TCA cycle enzymes and reactivity of TCA cycle intermediates. Here, we review known metabolite damage reactions and metabolite damage control systems associated with the TCA cycle. This includes a previously unrecognized metabolite damage control system – an oxaloacetate (OAA) enol‐keto tautomerase activity that is ‘built‐in’ to the TCA cycle. This activity is required to remove the highly inhibitory enol form of OAA and is likely to be critical for TCA cycle operation. By cataloging these instances, we show that metabolite damage and its repair or preemption is a prevalent feature of the TCA cycle and suggest many more metabolite damage control systems are likely to exist.

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Absolute stereochemistry of 2-hydroxyglutaric acid present in methanopterin

Cited by 5 publications

References 12 publications

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

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

Biosynthesis of the methanogenic cofactors

Enzyme promiscuity, metabolite damage, and metabolite damage control systems of the tricarboxylic acid cycle

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