References of "Veiga-da-Cunha, Maria"
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See detailFailure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency
Veiga-da-Cunha, Maria; Chevalier, Nathalie; Stephenne, Xavier et al

in Proceedings of the National Academy of Sciences of the United States of America (2019), 116(4), 1241-1250

Neutropenia presents an important clinical problem in patients with G6PC3 or G6PT deficiency, yet why neutropenia occurs is unclear. We discovered that G6PC3 and G6PT collaborate to dephosphorylate a ... [more ▼]

Neutropenia presents an important clinical problem in patients with G6PC3 or G6PT deficiency, yet why neutropenia occurs is unclear. We discovered that G6PC3 and G6PT collaborate to dephosphorylate a noncanonical metabolite (1,5anhydroglucitol-6-phosphate; 1,5AG6P) which is produced when glucose-phosphorylating enzymes erroneously act on 1,5-anhydroglucitol, a food-derived polyol present in blood. In patients or mice with G6PC3 or G6PT deficiency, 1,5AG6P accumulates and inhibits the first step of glycolysis. This is particularly detrimental in neutrophils, since their energy metabolism depends almost entirely on glycolysis. Consistent with our findings, we observed that treatment with a 1,5anhydroglucitol-lowering drug treats neutropenia in G6PC3deficient mice. Our findings highlight that the elimination of noncanonical side products by metabolite-repair enzymes makes an important contribution to mammalian physiology. [less ▲]

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See detailNit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione
Peracchi, Alessio; Veiga-da-Cunha, Maria; Kuhara, Tomiko et al

in Proceedings of the National Academy of Sciences of the United States of America (2017), 1613736114

The mammalian gene Nit1 (nitrilase-like protein 1) encodes a protein that is highly conserved in eukaryotes and is thought to act as a tumor suppressor. Despite being ∼35% sequence identical to ω-amidase ... [more ▼]

The mammalian gene Nit1 (nitrilase-like protein 1) encodes a protein that is highly conserved in eukaryotes and is thought to act as a tumor suppressor. Despite being ∼35% sequence identical to ω-amidase (Nit2), the Nit1 protein does not hydrolyze efficiently α-ketoglutaramate (a known physiological substrate of Nit2), and its actual enzymatic function has so far remained a puzzle. In the present study, we demonstrate that both the mammalian Nit1 and its yeast ortholog are amidases highly active toward deaminated glutathione (dGSH; i.e., a form of glutathione in which the free amino group has been replaced by a carbonyl group). We further show that Nit1-KO mutants of both human and yeast cells accumulate dGSH and the same compound is excreted in large amounts in the urine of Nit1-KO mice. Finally, we show that several mammalian aminotransferases (transaminases), both cytosolic and mitochondrial, can form dGSH via a common (if slow) side-reaction and provide indirect evidence that transaminases are mainly responsible for dGSH formation in cultured mammalian cells. Altogether, these findings delineate a typical instance of metabolite repair, whereby the promiscuous activity of some abundant enzymes of primary metabolism leads to the formation of a useless and potentially harmful compound, which needs a suitable “repair enzyme” to be destroyed or reconverted into a useful metabolite. The need for a dGSH repair reaction does not appear to be limited to eukaryotes: We demonstrate that Nit1 homologs acting as excellent dGSH amidases also occur in Escherichia coli and other glutathione-producing bacteria. [less ▲]

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See detailA conserved phosphatase destroys toxic glycolytic side products in mammals and yeast
Collard, François; Baldin, Francesca; Gerin, Isabelle et al

in Nature Chemical Biology (2016), 12(8), 601-607

Metabolic enzymes are very specific. However, most of them show weak side activities toward compounds that are structurally related to their physiological substrates, thereby producing side products that ... [more ▼]

Metabolic enzymes are very specific. However, most of them show weak side activities toward compounds that are structurally related to their physiological substrates, thereby producing side products that may be toxic. In some cases, ‘metabolite repair enzymes’ eliminating side products have been identified. We show that mammalian glyceraldehyde 3-phosphate dehydrogenase and pyruvate kinase, two core glycolytic enzymes, produce 4-phosphoerythronate and 2-phospho-L-lactate, respectively. 4-Phosphoerythronate strongly inhibits an enzyme of the pentose phosphate pathway, whereas 2-phospho-L-lactate inhibits the enzyme producing the glycolytic activator fructose 2,6-bisphosphate. We discovered that a single, widely conserved enzyme, known as phosphoglycolate phosphatase (PGP) in mammals, dephosphorylates both 4-phosphoerythronate and 2-phospho-L-lactate, thereby preventing a block in the pentose phosphate pathway and glycolysis. Its yeast ortholog, Pho13, similarly dephosphorylates 4-phosphoerythronate and 2-phosphoglycolate, a side product of pyruvate kinase. Our work illustrates how metabolite repair enzymes can make up for the limited specificity of metabolic enzymes and permit high flux in central metabolic pathways. [less ▲]

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See detailEnzyme complexity in intermediary metabolism.
Van Schaftingen, Emile; Veiga-da-Cunha, Maria; Linster, Carole UL

in Journal of inherited metabolic disease (2015), 38(4), 721-7

A good appraisal of the function of enzymes is essential for the understanding of inborn errors of metabolism. However, it is clear now that the 'one gene, one enzyme, one catalytic function' rule ... [more ▼]

A good appraisal of the function of enzymes is essential for the understanding of inborn errors of metabolism. However, it is clear now that the 'one gene, one enzyme, one catalytic function' rule oversimplifies the actual situation. Genes often encode several related proteins, which may differ in their subcellular localisation, regulation or function. Furthermore, enzymes often show several catalytic activities. In some cases, this is because they are multifunctional, possessing two or more different active sites that catalyse different, physiologically related reactions. In enzymes with broad specificity or in multispecificity enzymes, a single type of catalytic site performs the same reaction on different physiological substrates at similar rates. Enzymes that act physiologically in only one reaction often show nonetheless substrate promiscuity: they act at low rates on compounds that resemble their physiological substrate(s), thus forming non-classical metabolites, which are in some cases eliminated by metabolite repair. In addition to their catalytic role, enzymes may have moonlighting functions, i.e. non-catalytic functions that are most often not related with their catalytic activity. Deficiency in such functions may participate in the phenotype of inborn errors of metabolism. Evolution has also made that some enzymes have lost their catalytic activity to become allosteric proteins. [less ▲]

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See detailEthylmalonyl-CoA decarboxylase, a new enzyme involved in metabolite proofreading
Linster, Carole UL; Noël, Gaëtane; Stroobant, Vincent et al

in Journal of Biological Chemistry (2011), 286(50), 42992-3003

A limited number of enzymes are known that play a role analogous to DNA proofreading by eliminating non-classical metabolites formed by side activities of enzymes of intermediary metabolism. Because few ... [more ▼]

A limited number of enzymes are known that play a role analogous to DNA proofreading by eliminating non-classical metabolites formed by side activities of enzymes of intermediary metabolism. Because few such "metabolite proofreading enzymes" are known, our purpose was to search for an enzyme able to degrade ethylmalonyl-CoA, a potentially toxic metabolite formed at a low rate from butyryl-CoA by acetyl-CoA carboxylase and propionyl-CoA carboxylase, two major enzymes of lipid metabolism. We show that mammalian tissues contain a previously unknown enzyme that decarboxylates ethylmalonyl-CoA and, at lower rates, methylmalonyl-CoA but that does not act on malonyl-CoA. Ethylmalonyl-CoA decarboxylase is particularly abundant in brown adipose tissue, liver, and kidney in mice, and is essentially cytosolic. Because Escherichia coli methylmalonyl-CoA decarboxylase belongs to the family of enoyl-CoA hydratase (ECH), we searched mammalian databases for proteins of uncharacterized function belonging to the ECH family. Combining this database search approach with sequencing data obtained on a partially purified enzyme preparation, we identified ethylmalonyl-CoA decarboxylase as ECHDC1. We confirmed this identification by showing that recombinant mouse ECHDC1 has a substantial ethylmalonyl-CoA decarboxylase activity and a lower methylmalonyl-CoA decarboxylase activity but no malonyl-CoA decarboxylase or enoyl-CoA hydratase activity. Furthermore, ECHDC1-specific siRNAs decreased the ethylmalonyl-CoA decarboxylase activity in human cells and increased the formation of ethylmalonate, most particularly in cells incubated with butyrate. These findings indicate that ethylmalonyl-CoA decarboxylase may correct a side activity of acetyl-CoA carboxylase and suggest that its mutation may be involved in the development of certain forms of ethylmalonic aciduria. [less ▲]

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