Show simple item record

dc.contributor.authorHanzlik, Robert P.
dc.contributor.authorFang, Jianwen
dc.contributor.authorKoen, Yakov M.
dc.date.accessioned2011-10-31T15:19:51Z
dc.date.available2011-10-31T15:19:51Z
dc.date.issued2009-06-12
dc.identifier.citationJianwen Fang, Yakov Koen and Robert P. Hanzlik, "Bioinformatic analysis of xenobiotic reactive metabolite target proteins and their interacting partners." BMC Chemical Biology 2009, 9:5 (12 June 2009). PMID: 19523227 http://dx.doi.org/10.1186/1472-6769-9-5
dc.identifier.urihttp://hdl.handle.net/1808/8312
dc.description.abstractBackground Protein covalent binding by reactive metabolites of drugs, chemicals and natural products can lead to acute cytotoxicity. Recent rapid progress in reactive metabolite target protein identification has shown that adduction is surprisingly selective and inspired the hope that analysis of target proteins might reveal protein factors that differentiate target- vs. non-target proteins and illuminate mechanisms connecting covalent binding to cytotoxicity. Results Sorting 171 known reactive metabolite target proteins revealed a number of GO categories and KEGG pathways to be significantly enriched in targets, but in most cases the classes were too large, and the "percent coverage" too small, to allow meaningful conclusions about mechanisms of toxicity. However, a similar analysis of the directlyinteracting partners of 28 common targets of multiple reactive metabolites revealed highly significant enrichments in terms likely to be highly relevant to cytotoxicity (e.g., MAP kinase pathways, apoptosis, response to unfolded protein). Machine learning was used to rank the contribution of 211 computed protein features to determining protein susceptibility to adduction. Protein lysine (but not cysteine) content and protein instability index (i.e., rate of turnover in vivo) were among the features most important to determining susceptibility. Conclusion As yet there is no good explanation for why some low-abundance proteins become heavily adducted while some abundant proteins become only lightly adducted in vivo. Analyzing the directly interacting partners of target proteins appears to yield greater insight into mechanisms of toxicity than analyzing target proteins per se. The insights provided can readily be formulated as hypotheses to test in future experimental studies.
dc.language.isoen_US
dc.publisherBioMed Central
dc.rights© 2009 Fang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttp://creativecommons.org/licenses/by/2.0
dc.titleBioinformatic analysis of xenobiotic reactive metabolite target proteins and their interacting partners
dc.typeArticle
kusw.kuauthorFang, Jianwen
kusw.kuauthorKoen, Yakov M.
kusw.kuauthorHanzlik, Robert P.
kusw.kudepartmentDepartment of Medicinal Chemistry
kusw.oastatusfullparticipation
dc.identifier.doi10.1186/1472-6769-9-5
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

© 2009 Fang et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as: © 2009 Fang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.