Philip M Potter

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We present the first crystal structures of a human protein bound to analogs of cocaine and heroin. Human carboxylesterase 1 (hCE1) is a broad-spectrum bioscavenger that catalyzes the hydrolysis of heroin and cocaine, and the detoxification of organophosphate chemical weapons, such as sarin, soman and tabun. Crystal structures of the hCE1 glycoprotein in(More)
Carboxylesterases (CE) are ubiquitous enzymes found in both human and animal tissues and are responsible for the metabolism of xenobiotics. This includes numerous natural products, as well as a many clinically used drugs. Hence, the activity of these agents is likely dependent upon the levels and location of CE expression. We have recently identified benzil(More)
Human carboxylesterase 1 (hCE1) exhibits broad substrate specificity and is involved in xenobiotic processing and endobiotic metabolism. We present and analyze crystal structures of hCE1 in complexes with the cholesterol-lowering drug mevastatin, the breast cancer drug tamoxifen, the fatty acyl ethyl ester (FAEE) analogue ethyl acetate, and the novel hCE1(More)
Our understanding of the detailed recognition and processing of clinically useful therapeutic agents has grown rapidly in recent years, and we are now able to begin to apply this knowledge to the rational treatment of disease. Mammalian carboxylesterases (CEs) are enzymes with broad substrate specificities that have key roles in the metabolism of a wide(More)
The recently introduced camptothecin-derived chemotherapeutic agents have demonstrated remarkable promise in cancer therapy and as such have been approved for use in humans for the treatment of ovarian, lung, and colon cancer. CPT-11 is a prodrug that is activated by esterases to yield the potent topoisomerase I inhibitor, SN-38. Considerable success has(More)
Hydrolytic metabolism of pyrethroid insecticides in humans is one of the major catabolic pathways that clear these compounds from the body. Rodent models are often used to determine the disposition and clearance rates of these esterified compounds. In this study the distribution and activities of esterases that catalyze pyrethroid metabolism have been(More)
O6-methylguanine-DNA methyltransferase (MGMT) is a ubiquitous protein responsible for repair of O6-alkylguanine, a mutagenic, carcinogenic and toxic lesion. To characterize the elements responsible for the regulation of the MGMT gene, a 2.6 kb Sstl fragment isolated from a genomic clone, was shown to contain 5' flanking sequences of the gene. The promoter(More)
Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11)] is metabolized by esterases to yield the potent topoisomerase I poison 7-ethyl-10-hydroxycamptothecin. One of the major side effects observed with CPT-11 is gastrointestinal toxicity, and we supposed that this might be due to local activation of CPT-11 within the gut.(More)
We have isolated a cDNA encoding a rabbit carboxylesterase (CE; EC 3.1.1.1) that converts the camptothecin-derived prodrug irinotecan (CPT-11) to the potent topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin. NH2-terminal amino acid sequencing of a purified rabbit CE allowed the design of redundant oligonucleotides to perform PCR from rabbit liver(More)
Enzyme activation of prodrugs to improve the therapeutic index of specific anticancer agents is an attractive alternative to current chemotherapy regimens. This study addresses the potential for activating irinotecan (CPT-11) with recombinant carboxylesterases (CEs). CEs are a ubiquitous class of enzymes thought to be involved in the detoxification of(More)