Adenosine Thiamine Triphosphate (AThTP) Inhibits Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activity
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概要
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Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) has been demonstrated to result in various stress-related diseases, including diabetes mellitus. Deficiency of cellular nicotinamide adenine dinucleotide (NAD+) content, consumed by PARP-1 to add ADP-ribose moieties onto target proteins, contributes to pathophysiological conditions. Adenosine thiamine triphosphate (AThTP) exists in small amounts in mammals; however, the function(s) of this metabolite remains unresolved. The structure of AThTP resembles NAD+. Recent experimental studies demonstrate beneficial impacts of high-dose thiamine treatment of diabetic complications. These findings have led us to hypothesize that AThTP may modulate the activity of PARP-1. We have chemically synthesized AThTP and evaluated the effect of AThTP on recombinant PARP-1 enzyme activity. AThTP inhibited the PARP-1 activity at 10 μM, and a structural model of the PARP-1-AThTP complex highlighted the AThTP binding site. The results provide new insights into the pharmacological importance of AThTP as an inhibitor of PARP-1.
著者
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YAMAMOTO Daisuke
Biomedical Computation Center, Osaka Medical College
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Usui Kazuya
Laboratory of Biology, Hokkaido University of Education
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Manabe Miki
Laboratory Of Pharmacotherapy Osaka University Of Pharmaceutical Sciences
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Saito Yoshihiro
Laboratory Of Bio-analytical Chemistry Osaka University Of Pharmaceutical Sciences
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Sato Takaji
Laboratory Of Bio-analytical Chemistry Osaka University Of Pharmaceutical Sciences
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TANAKA Takao
Organization of Medical Education, Osaka Medical College
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TANAKA Sunao
Human Health Sciences, Graduate School of Medicine Kyoto University
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AOKI Yui
Laboratory of Analytical Chemistry, Osaka University of Pharmaceutical Sciences
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IWASHIMA Yasuki
Laboratory of Analytical Chemistry, Osaka University of Pharmaceutical Sciences
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MINO Yoshiki
Laboratory of Analytical Chemistry, Osaka University of Pharmaceutical Sciences
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DEGUCHI Hirofumi
Organization of Medical Education, Osaka Medical College
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