Reference

Crystal Structures of Epothilone D-bound, Epothilone B-bound, and Substrate-free Forms of Cytochrome P450epoK

Crystal Structures of Epothilone D-bound, Epothilone B-bound, and Substrate-free Forms of Cytochrome P450epoK. Nagano, Shingo; Li, Huiying; Shimizu, Hideaki; Nishida, Clinton; Ogura, Hiroshi; Ortiz de Montellano, Paul R.; Poulos, Thomas L. (Department of Molecular Biology & Biochemistry, and the Program in Macromolecular Structure, University of California, Irvine, Irvine, CA 92697-3900, USA). Journal of Biological Chemistry, 278(45), 44886-44893 (English) 2003 American Society for Biochemistry and Molecular Biology. CODEN: JBCHA3. ISSN: 0021-9258. DOCUMENT TYPE: Journal CA Section: 7 (Enzymes) Section cross-reference(s): 6, 75 Epothilones are potential anticancer drugs that stabilize microtubules by binding to tubulin in a manner similar to paclitaxel. Cytochrome P 450epoK, a heme contg. monooxygenase involved in epothilone biosynthesis in the myxobacterium Sorangium cellulosum, catalyzes the epoxidn. of epothilones C and D into epothilones A and B, resp. The 2.10-, 1.93-, and 2.65-? crystal structures reported here for the epothilone D-bound, epothilone B-bound, and substrate-free forms, resp., are the first crystal structures of an epothilone-binding protein. Although the substrate for P 450epoK is the largest of a P 450 whose x-ray structure is known, the structural changes along with substrate binding or product release are very minor and the overall fold is similar to other P 450s.There are some commonly used reagents with their cas registry numbers 264147-17-3 and 189453-10-9 in this article. The epothilones are positioned with the macrolide ring roughly perpendicular to the heme plane and I helix, and the thiazole moiety provides key interactions that very likely are crit. in detg. substrate specificity. Interestingly, there are strong parallels between the epothilone/P 450epoK and paclitaxel/tubulin interactions. Based on structural similarities, a plausible epothilone tubulin-binding mode is proposed. .

Epothilones: Mechanism of action and biologic activity

Epothilones: Mechanism of action and biologic activity. Goodin, Susan; Kane, Michael P.; Rubin, Eric H. (Department of Medicine, Department of Pharmacology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, NJ, USA). Journal of Clinical Oncology, 22(10), 2015-2025 (English) 2004 American Society of Clinical Oncology. CODEN: JCONDN. ISSN: 0732-183X. DOCUMENT TYPE: Journal; General Review CA Section: 1 (Pharmacology) A review. Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Although the mechanisms by which perturbation of microtubule function leads to selective death of cancer cells remain unclear, several new microtubule-targeting compds. are undergoing clin. testing. In part, these efforts focus on overcoming some of the problems assocd. with taxane-based therapies, including formulation and administration difficulties and susceptibility to resistance conferred by P-glycoprotein. 33069-62-4 and 189453-10-9 are cas registry numbers of chemicals which are used as reagents here. Epothilones have emerged from these efforts as a promising new class of anticancer drugs. Preclin. studies indicate that epothilones bind to and stabilize microtubules in a manner similar but not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor models. Clin. phase I and early phase II data are available for BMS-247550, BMS-310705, EPO906, and KOS-862. The results suggest that these compds. have a broad range of antitumor activity at doses and schedules assocd. with tolerable side effects. .