Comeaux Evan Q, van Waardenburg Robert C A M
Department of Pharmacology and Toxicology, University of Alabama at Birmingham , Birmingham, AL , USA.
Drug Metab Rev. 2014 Nov;46(4):494-507. doi: 10.3109/03602532.2014.971957. Epub 2014 Oct 20.
DNA is subject to a wide range of insults, resulting from endogenous and exogenous sources that need to be metabolized/resolved to maintain genome integrity. Tyrosyl-DNA phosphodiesterase I (Tdp1) is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts. As a phospholipase D superfamily member Tdp1 utilizes two catalytic histidines each within a His-Lys-Asn motif. Tdp1 was discovered for its ability to hydrolyze the 3'-phospho-tyrosyl that in the cell covalently links DNA Topoisomerase I (Topo1) and DNA. Tdp1's list of substrates has since grown and can be divided into two groups: protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogs. Since many of Tdp1's substrates are generated by clinically relevant chemotherapeutics, Tdp1 became a therapeutic target for molecularly targeted small molecules. Tdp1's unique catalytic cycle allows for two different targeting strategies: (1) the intuitive inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of chemotherapeutically induced DNA adducts, thereby enhancing their toxicity and (2) stabilization of the Tdp1-DNA covalent reaction intermediate, prevents resolution of Tdp1-DNA adduct and increases the half-life of this potentially toxic DNA adduct. This concept is best illustrated by a catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy, and results in an increased stability of its Tdp1-DNA reaction intermediate. Here, we will discuss Tdp1 catalysis from a structure-function perspective, Tdp1 substrates and Tdp1 potential as a therapeutic target.
DNA会受到多种损伤，这些损伤源于内源性和外源性因素，需要进行代谢/修复以维持基因组完整性。酪氨酰-DNA磷酸二酯酶I（Tdp1）是一种真核生物DNA修复酶，可催化去除共价3'-DNA加合物。作为磷脂酶D超家族成员，Tdp1在每个His-Lys-Asn基序中利用两个催化性组氨酸。Tdp1因其能够水解细胞内共价连接DNA拓扑异构酶I（Topo1）和DNA的3'-磷酸酪氨酰而被发现。此后，Tdp1的底物列表不断增加，可分为两类：蛋白质-DNA加合物，如喜树碱稳定的Topo1-DNA加合物，以及修饰核苷酸，包括氧化核苷酸和链终止核苷类似物。由于Tdp1的许多底物是由临床相关化疗药物产生的，Tdp1成为分子靶向小分子的治疗靶点。Tdp1独特的催化循环允许两种不同的靶向策略：（1）直观地抑制Tdp1催化，以防止Tdp1介导的化疗诱导DNA加合物的修复，从而增强其毒性；（2）稳定Tdp1-DNA共价反应中间体，防止Tdp1-DNA加合物的分解，并增加这种潜在有毒DNA加合物的半衰期。常染色体隐性神经退行性疾病伴轴索性神经病的脊髓小脑共济失调的分子基础是一种催化性Tdp1突变体，它能增加其Tdp1-DNA反应中间体的稳定性，这一概念得到了最好的阐释。在这里，我们将从结构-功能的角度讨论Tdp1催化、Tdp1底物以及Tdp1作为治疗靶点的潜力。
