Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
Vascul Pharmacol. 2010 Sep-Oct;53(3-4):77-87. doi: 10.1016/j.vph.2010.06.003. Epub 2010 Jul 12.
Poly(ADP-ribose) polymerases (PARPs) are a family of cell signaling enzymes present in eukaryotes, which are involved in the poly(ADP-ribosylation) of DNA binding proteins. While an 18 member superfamily of PARPs has been identified, however PARP-1 the most abundant isoform accounts for more than 90% of its functions. PARP-1 works as DNA damage nick sensor, which uses NAD(+) to form polymers of ADP-ribose (PAR) and nicotinamide. Three consequences of the activation of PARP-1 are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of proinflammatory genes. Consequently, pharmacological inhibition of PARP has the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). Through this article we have tried to develop a brief and simplified picture of the principal physiological and pathophysiological roles governed by PARP-1 and its therapeutic implications.
聚（ADP-核糖）聚合酶（PARPs）是真核生物中存在的细胞信号酶家族，参与 DNA 结合蛋白的聚（ADP-核糖）化。虽然已经鉴定出 PARP 的 18 个成员超家族，但 PARP-1 是最丰富的同工型，占其功能的 90%以上。PARP-1 作为 DNA 损伤缺口传感器，利用 NAD（+）形成 ADP-核糖（PAR）和烟酰胺的聚合物。PARP-1 激活的三个后果对药物开发特别重要：第一，其在 DNA 修复中的作用；第二，其耗尽细胞能量库的能力，最终导致细胞功能障碍和坏死；第三，其促进促炎基因转录的能力。因此，PARP 的药理学抑制有可能增强某些 DNA 损伤抗癌药物的细胞毒性，减少细胞坏死（例如，在中风或心肌梗死中），并下调炎症和组织损伤的多个同时途径（例如，在循环休克、结肠炎或糖尿病并发症中）。通过本文，我们试图对 PARP-1 及其治疗意义所控制的主要生理和病理生理作用形成一个简短而简化的描述。
