Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan.

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dc.contributor.authorParikh, Sonia J*
dc.contributor.authorEdara, Sreeja*
dc.contributor.authorDeodhar, Shruti*
dc.contributor.authorSingh, Ajit K
dc.contributor.authorMaekawa, Keiko
dc.contributor.authorZhang, Qinghai
dc.contributor.authorGlass, Karen C
dc.contributor.authorShah, Manish B
dc.date.accessioned2024-07-30T15:23:17Z
dc.date.available2024-07-30T15:23:17Z
dc.date.issued2024-09
dc.descriptionClick on the Resource Link to access the article (may not be free).
dc.description.abstractThe human cytochrome P450 (CYP) 1, 2 and 3 families of enzymes are responsible for the biotransformation of a majority of the currently available pharmaceutical drugs. The highly polymorphic CYP2C9 predominantly metabolizes many drugs including anticoagulant S-warfarin, anti-hypertensive losartan, anti-diabetic tolbutamide, analgesic ibuprofen, etc. There are >80 single nucleotide changes identified in CYP2C9, many of which significantly alter the clearance of important drugs. Here we report the structural and biophysical analysis of two polymorphic variants, CYP2C9*14 (Arg125His) and CYP2C9*27 (Arg150Leu) complexed with losartan. The X-ray crystal structures of the CYP2C9*14 and *27 illustrate the binding of two losartan molecules, one in the active site near heme and another on the periphery. Both losartan molecules are bound in an identical conformation to that observed in the previously solved CYP2C9 wild-type complex, however, the number of losartan differs from the wild-type structure, which showed binding of three molecules. Additionally, isothermal titration calorimetry experiments reveal a lower binding affinity of losartan with *14 and *27 variants when compared to the wild-type. Overall, the results provide new insights into the effects of these genetic polymorphisms and suggests a possible mechanism contributing to reduced metabolic activity in patients carrying these alleles.
dc.description.grantGrant Funded
dc.description.sponsorshipR01 GM129338/GM/NIGMS NIH HHS/United States
dc.description.urihttps://doi.org/10.1016/j.jinorgbio.2024.112622
dc.description.urihttp://www.ncbi.nlm.nih.gov/pmc/articles/pmc11285081/
dc.identifier.citationParikh SJ, Edara S, Deodhar S, Singh AK, Maekawa K, Zhang Q, Glass KC, Shah MB. Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan. J Inorg Biochem. 2024 Sep;258:112622. doi: 10.1016/j.jinorgbio.2024.112622. Epub 2024 May 31. PMID: 38852293; PMCID: PMC11285081.
dc.identifier.issn0162-0134
dc.identifier.other38852293
dc.identifier.urihttps://hdl.handle.net/20.500.14303/594
dc.language.isoen
dc.publisherElsevier
dc.relation.ispartofJournal of Inorganic Biochemistry
dc.rightsThis Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). http://rightsstatements.org/vocab/InC/1.0/
dc.subjectCYP2C9*14
dc.subjectCYP2C9*27
dc.subjectCytochrome P450 2C9
dc.subjectIsothermal titration calorimetry
dc.subjectLosartan
dc.subjectX-ray crystallography
dc.titleStructural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan.
dc.typeArticle
local.departmentprogramDepartment of Pharmaceutical Sciences
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