title: Structural insight into inositol pyrophosphate turnover.
abstract: The diphosphoinositol polyphosphates ("inositol pyrophosphates"; PP-InsPs) regulate many cellular processes in eukaryotes, including stress responses, apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, telomere maintenance, insulin signaling and neutrophil activation. Thus, the enzymes that control the metabolism of the PP-InsPs serve important cell signaling roles. In order to fully characterize how these enzymes are regulated, we need to determine the atomic-level architecture of their active sites. Only then can we fully appreciate reaction mechanisms and their modes of regulation. In this review, we summarize published information obtained from the structural analysis of a human diphosphoinositol polyphosphate phosphohydrolase (DIPP), and a human diphosphoinositol polyphosphate kinase (PPIP5K). This work includes the analysis of crystal complexes with substrates, products, transition state analogs, and a novel phosphonoacetate substrate analog.
authors.affiliation: Inositol Signaling Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, PO Box 12233, NC 27709, USA. Shears@niehs.nih.gov
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Shears
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Weaver
authors.forename: Huanchen
authors.initials: H
authors.lastname: Wang
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D011756:Diphosphates / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D011756:Diphosphates; D007295:Inositol Phosphates; D017856:Phosphotransferases (Phosphate Group Acceptor); C519580:PPIP5K1 protein, human; C562140:PPIP5K2 protein, human; D017766:Acid Anhydride Hydrolases; C116368:diphosphoinositol polyphosphate phosphohydrolase; D010746:Phosphonoacetic Acid