Inositol pyrophosphates have been shown to pyrophosphorylate proteins in eukaryotes in a non-enzymatic manner. We describe here that the inositol pyrophosphate diphosphoinositol pentakisphosphate (5-PP-IP7 ) can pyrophosphorylate the protein deacetylase SIRT1. In addition SIRT1 binds to the IP6 kinase enzymes that synthesize IP7 as well as inositol polyphosphate multikinase. We also demonstrate that alteration of pyrophosphate levels in mammalian cells culture can regulate SIRT1 activity towards its targets. We also generated mice in which the IP6K1 gene has been deleted. We show that these mice exhibit growth retardation, reduced insulin secretion and insulin hypersensitivity, and defects in spermiogenesis.
|Advisor:||Snyder, Solomon H.|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 69/04, Dissertation Abstracts International|
|Subjects:||Neurosciences, Cellular biology|
|Keywords:||Inositol pyrophosphate, Insulin secretion, Pyrophosphorylation, SIRT1|
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