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: Takao Tanaka, Daisuke Yamamoto, Takaji Sato, Sunao Tanaka, Kazuya Usui, Miki Manabe, Yui Aoki, Yasuki Iwashima, Yoshihiro Saito, Yoshiki Mino, Hirofumi Deguchi
• Journal: Journal of nutritional science and vitaminology (J Nutr Sci Vitaminol (Tokyo)) Vol. 57 Issue 2 Pg. 192-6 ( 2011) ISSN: 1881-7742 [Electronic] Japan
• PMID: 21697640 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors
• Recombinant Proteins
• adenosine thiamine triphosphate
• NAD
• Thiamine Triphosphate
• Adenosine Triphosphate
• Thiamine

Topics

• Adenosine Triphosphate (chemical synthesis, chemistry, pharmacology)
• Animals
• Binding Sites
• Diabetes Complications (drug therapy, metabolism)
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Models, Biological
• Molecular Structure
• NAD (chemistry, deficiency)
• Poly(ADP-ribose) Polymerase Inhibitors
• Recombinant Proteins
• Thiamine (therapeutic use)
• Thiamine Triphosphate (chemical synthesis, chemistry, pharmacology)