title: Adenosine thiamine triphosphate (AThTP) inhibits poly(ADP-ribose) polymerase-1 (PARP-1) activity.
abstract: 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.
authors.affiliation: Organization of Medical Education, Osaka Medical College, 2-7 Daigakuchou, Takatsuki, Osaka, Japan. t.tanaka.md@gmail.com
authors.forename: Takao
authors.initials: T
authors.lastname: Tanaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamoto
authors.forename: Takaji
authors.initials: T
authors.lastname: Sato
authors.forename: Sunao
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kazuya
authors.initials: K
authors.lastname: Usui
authors.forename: Miki
authors.initials: M
authors.lastname: Manabe
authors.forename: Yui
authors.initials: Y
authors.lastname: Aoki
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Iwashima
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Mino
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Deguchi
mesh_terms: D000255:Adenosine Triphosphate / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D048909:Diabetes Complications / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D009243:NAD / Q000737:chemistry / Q000172:deficiency*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; D013831:Thiamine / Q000627:therapeutic use; D013838:Thiamine Triphosphate / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; C519454:adenosine thiamine triphosphate; D009243:NAD; D013838:Thiamine Triphosphate; D000255:Adenosine Triphosphate; D013831:Thiamine