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targeting the large subunit of human ribonucleotide reductase for cancer chemotherapy针对人类核苷酸还原酶大亚基对癌症化疗.pdf

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targeting the large subunit of human ribonucleotide reductase for cancer chemotherapy针对人类核苷酸还原酶大亚基对癌症化疗

Pharmaceuticals 2011, 4, 1328-1354; doi:10.3390/ph4101328 OPEN ACCESS Pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Targeting the Large Subunit of Human Ribonucleotide Reductase for Cancer Chemotherapy Sanath R. Wijerathna 1,*, Md. Faiz Ahmad 1, Hai Xu 1, James W. Fairman 1, Andrew Zhang 1, Prem Singh Kaushal 1, Qun Wan 1, Jianying Kiser 1 and Chris G. Dealwis 1,2,* 1 Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA 2 Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, OH 44106, USA * Authors to whom correspondence should be addressed; E-Mail: sxw199@ (S.R.W.); chris.dealwis@ (C.G.D.); Tel.:+1-216-368-3337 (S.R.W.); +1-216-368-1652 (C.G.D.); Fax: +1-216-368-1300 (S.R.W.); +1-216-368-1300 (C.G.D.). Received: 21 September 2011; in revised form: 27 September 2011 / Accepted: 30 September 2011 / Published: 13 October 2011 Abstract: 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 β hetero oligomer. RR inhibitors are cytotoxic n m to proliferating cancer cells. In this brief review we will discuss the t