Tanaka Takao, Yamamoto Daisuke, Sato Takaji, Tanaka Sunao, Usui Kazuya, Manabe Miki, Aoki Yui, Iwashima Yasuki, Saito Yoshihiro, Mino Yoshiki, Deguchi Hirofumi
Organization of Medical Education, Osaka Medical College, 2-7 Daigakuchou, Takatsuki, Osaka, Japan.
J Nutr Sci Vitaminol (Tokyo). 2011;57(2):192-6. doi: 10.3177/jnsv.57.192.
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.
聚（ADP - 核糖）聚合酶 -1（PARP -1）的过度激活已被证明会导致包括糖尿病在内的各种与应激相关的疾病。细胞烟酰胺腺嘌呤二核苷酸（NAD(+)）含量的缺乏，被PARP -1用于将ADP - 核糖部分添加到靶蛋白上，这会导致病理生理状况。三磷酸腺苷硫胺素（AThTP）在哺乳动物中含量很少；然而，这种代谢物的功能仍未明确。AThTP的结构类似于NAD(+)。最近的实验研究表明高剂量硫胺素治疗糖尿病并发症具有有益影响。这些发现促使我们推测AThTP可能调节PARP -1的活性。我们已经化学合成了AThTP，并评估了AThTP对重组PARP -1酶活性的影响。AThTP在10 µM时抑制PARP -1活性，并且PARP -1 - AThTP复合物的结构模型突出了AThTP结合位点。这些结果为AThTP作为PARP -1抑制剂的药理学重要性提供了新的见解。
