2015
DOI: 10.1016/j.chembiol.2015.10.015
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Unraveling the B. pseudomallei Heptokinase WcbL: From Structure to Drug Discovery

Abstract: SummaryGram-negative bacteria utilize heptoses as part of their repertoire of extracellular polysaccharide virulence determinants. Disruption of heptose biosynthesis offers an attractive target for novel antimicrobials. A critical step in the synthesis of heptoses is their 1-O phosphorylation, mediated by kinases such as HldE or WcbL. Here, we present the structure of WcbL from Burkholderia pseudomallei. We report that WcbL operates through a sequential ordered Bi-Bi mechanism, loading the heptose first and th… Show more

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Cited by 8 publications
(13 citation statements)
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“…GHMP kinases belong to a wider structural fold that includes diverse proteins. These include several carbohydrate kinases: in addition to the galactokinase for which the family is named, these include N-acetylgalactosamine (GalNAc) kinase [84], galacturonic acid kinase [85], arabinose kinase [86], and one group of heptose-7-phosphate kinases [87]. Human galactokinase is important for galactose catabolism (via the Leloir pathway), and it has been suggested as a target for drug interventions to suppress galactosemia (caused by an accumulation of the product galactose-1-phosphate when the next Leloir pathway enzyme is absent) [10,[88][89][90]; or, for use in enzyme replacement therapy in the (rarer) galactosemias that is caused by a defect in galactokinase [91].…”
Section: Overview Of the Familymentioning
confidence: 99%
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“…GHMP kinases belong to a wider structural fold that includes diverse proteins. These include several carbohydrate kinases: in addition to the galactokinase for which the family is named, these include N-acetylgalactosamine (GalNAc) kinase [84], galacturonic acid kinase [85], arabinose kinase [86], and one group of heptose-7-phosphate kinases [87]. Human galactokinase is important for galactose catabolism (via the Leloir pathway), and it has been suggested as a target for drug interventions to suppress galactosemia (caused by an accumulation of the product galactose-1-phosphate when the next Leloir pathway enzyme is absent) [10,[88][89][90]; or, for use in enzyme replacement therapy in the (rarer) galactosemias that is caused by a defect in galactokinase [91].…”
Section: Overview Of the Familymentioning
confidence: 99%
“…One case of a kinase that can also use GTP and ITP with lower activity has been reported [33]. As with other carbohydrate kinases, a magnesium ion is also required for activity [87,98].…”
Section: Ghmp Kinase Specificitymentioning
confidence: 99%
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