Structural鈥揊unctional Studies of Burkholderia cenocepaciad-Glycero-尾-d-manno-heptose 7-Phosphate Kinase (HldA) and Characterization

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• 作者：Ting-Wai Lee ; Theodore B. Verhey ; Pavel A. Antiperovitch ; Dmytro Atamanyuk ; Nicolas Desroy ; Chrystelle Oliveira ; Alexis Denis ; Vincent Gerusz ; Elodie Drocourt ; Slade A. Loutet ; Mohamad A. Hamad ; Christian Stanetty ; Sara N. Andres ; Seiji Sugiman-Marangos ; Paul Kosma ; Miguel A. Valvano ; Francois Moreau ; Murray S. Junop
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 28, 2013
• 年：2013
• 卷：56
• 期：4
• 页码：1405-1417
• 全文大小：834K
• 年卷期：v.56,no.4(February 28, 2013)
• ISSN：1520-4804

文摘

As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural鈥揻unctional studies of d-glycero-尾-d-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.