Targeting the Large Subunit of Human Ribonucleotide Reductase for Cancer Chemotherapy

Pharmaceuticals

Sanath R. Wijerathna¹  Md. Faiz Ahmad¹  Hai Xu¹  James W. Fairman¹  Andrew Zhang¹  Prem Singh Kaushal¹  Qun Wan¹  Jianying Kiser¹ 

[1] Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA

关键词: ribonucleotide reductase;    gemcitabine;    clofarabine;    cladrabine;    P6;    P7;    Cyc 10;    dATP;    ATP;    allosteric regulation;    specificity cross-talk;    nucleotides;   

DOI  :  10.3390/ph4101328

来源: mdpi

【 摘 要 】

Ribonucleotide reductase (RR) is a crucial enzyme in de novo DNA synthesis, where it catalyses the rate determining step of dNTP synthesis. RRs consist of a large subunit called RR1 (α), that contains two allosteric sites and one catalytic site, and a small subunit called RR2 (β), which houses a tyrosyl free radical essential for initiating catalysis. The active form of mammalian RR is an α_nβ_m hetero oligomer. RR inhibitors are cytotoxic to proliferating cancer cells. In this brief review we will discuss the three classes of RR, the catalytic mechanism of RR, the regulation of the dNTP pool, the substrate selection, the allosteric activation, inactivation by ATP and dATP, and the nucleoside drugs that target RR. We will also discuss possible strategies for developing a new class of drugs that disrupts the RR assembly.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.