Structural insights into CPT-11 activation by mammalian carboxylesterases - PubMed (original) (raw)
Structural insights into CPT-11 activation by mammalian carboxylesterases
Sompop Bencharit et al. Nat Struct Biol. 2002 May.
Abstract
Mammalian carboxylesterases cleave the anticancer prodrug CPT-11 (Irinotecan) into SN-38, a potent topoisomerase I poison, and 4-piperidino-piperidine (4PP). We present the 2.5 A crystal structure of rabbit liver carboxylesterase (rCE), the most efficient enzyme known to activate CPT-11 in this manner, in complex with the leaving group 4PP. 4PP is observed bound adjacent to a high-mannose Asn-linked glycosylation site on the surface of rCE. This product-binding site is separated from the catalytic gorge by a thin wall of amino acid side chains, suggesting that 4PP may be released through this secondary product exit pore. The crystallographic observation of a leaving group bound on the surface of rCE supports the 'back door' product exit site proposed for the acetylcholinesterases. These results may facilitate the design of improved anticancer drugs or enzymes for use in viral-directed cancer cotherapies.
Similar articles
- Structural constraints affect the metabolism of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) by carboxylesterases.
Wadkins RM, Morton CL, Weeks JK, Oliver L, Wierdl M, Danks MK, Potter PM. Wadkins RM, et al. Mol Pharmacol. 2001 Aug;60(2):355-62. doi: 10.1124/mol.60.2.355. Mol Pharmacol. 2001. PMID: 11455023 - Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies.
Yoon KJ, Krull EJ, Morton CL, Bornmann WG, Lee RE, Potter PM, Danks MK. Yoon KJ, et al. Mol Cancer Ther. 2003 Nov;2(11):1171-81. Mol Cancer Ther. 2003. PMID: 14617791 - Pharmacology of irinotecan.
Kuhn JG. Kuhn JG. Oncology (Williston Park). 1998 Aug;12(8 Suppl 6):39-42. Oncology (Williston Park). 1998. PMID: 9726089 Review. - Metabolism of CPT-11. Impact on activity.
Rivory LP. Rivory LP. Ann N Y Acad Sci. 2000;922:205-15. doi: 10.1111/j.1749-6632.2000.tb07039.x. Ann N Y Acad Sci. 2000. PMID: 11193896 Review.
Cited by
- In Silico Study of Camptothecin-Based Pro-Drugs Binding to Human Carboxylesterase 2.
Beierlein F, Horn AHC, Sticht H, Mokhir A, Imhof P. Beierlein F, et al. Biomolecules. 2024 Jan 27;14(2):153. doi: 10.3390/biom14020153. Biomolecules. 2024. PMID: 38397391 Free PMC article. - The Crystal Structure of Mouse Ces2c, a Potential Ortholog of Human CES2, Shows Structural Similarities in Substrate Regulation and Product Release to Human CES1.
Eisner H, Riegler-Berket L, Gamez CFR, Sagmeister T, Chalhoub G, Darnhofer B, Jazleena PJ, Birner-Gruenberger R, Pavkov-Keller T, Haemmerle G, Schoiswohl G, Oberer M. Eisner H, et al. Int J Mol Sci. 2022 Oct 28;23(21):13101. doi: 10.3390/ijms232113101. Int J Mol Sci. 2022. PMID: 36361897 Free PMC article. - Stereoselective hydrolysis of pyrethroid-like fluorescent substrates by human and other mammalian liver carboxylesterases.
Huang H, Fleming CD, Nishi K, Redinbo MR, Hammock BD. Huang H, et al. Chem Res Toxicol. 2005 Sep;18(9):1371-7. doi: 10.1021/tx050072+. Chem Res Toxicol. 2005. PMID: 16167828 Free PMC article. - Structural studies of a potent insect maturation inhibitor bound to the juvenile hormone esterase of Manduca sexta.
Wogulis M, Wheelock CE, Kamita SG, Hinton AC, Whetstone PA, Hammock BD, Wilson DK. Wogulis M, et al. Biochemistry. 2006 Apr 4;45(13):4045-57. doi: 10.1021/bi0521644. Biochemistry. 2006. PMID: 16566578 Free PMC article. - Herb-drug interactions: a literature review.
Hu Z, Yang X, Ho PC, Chan SY, Heng PW, Chan E, Duan W, Koh HL, Zhou S. Hu Z, et al. Drugs. 2005;65(9):1239-82. doi: 10.2165/00003495-200565090-00005. Drugs. 2005. PMID: 15916450 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Other Literature Sources