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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 detailsiRNA screen identifies QPCT as a druggable target for Huntington's disease.
Jimenez-Sanchez, Maria; Lam, Wun; Hannus, Michael et al

in Nature chemical biology (2015), 11(5), 347354

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity ... [more ▼]

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone alphaB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development. [less ▲]

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See detailMetabolite damage and its repair or pre-emption
Linster, Carole UL; Van Schaftingen, E.; Hanson, A. D.

in Nature Chemical Biology (2013), 9(2), 72-80

It is increasingly evident that metabolites suffer various kinds of damage, that such damage happens in all organisms, and that cells have dedicated systems for damage repair and containment. Firstly ... [more ▼]

It is increasingly evident that metabolites suffer various kinds of damage, that such damage happens in all organisms, and that cells have dedicated systems for damage repair and containment. Firstly, chemical biology is demonstrating that diverse metabolites are damaged by side-reactions of ‘promiscuous’ enzymes or by spontaneous chemical reactions, that the products are useless or toxic, and that the unchecked buildup of these products can be devastating. Secondly, genetic and genomic evidence from pro- and eukaryotes is implicating a network of novel, conserved enzymes that repair damaged metabolites or somehow pre-empt damage. Metabolite (i.e. small molecule) repair is analogous to macromolecule (DNA and protein) repair and appears from comparative genomic evidence to be equally widespread. Comparative genomics also implies that metabolite repair could be the function of many conserved protein families lacking known activities. How – and how well – cells deal with metabolite damage impacts fields ranging from medical genetics to metabolic engineering. [less ▲]

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