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Drug Modulation of Water-Heme Interactions in Low-Spin P450 Complexes of CYP2C9d and CYP125A1

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dc.contributor.authorConner, Kip P.
dc.contributor.authorCruce, Alex A.
dc.contributor.authorKrzyaniak, Matthew D.
dc.contributor.authorSchimpf, Alina M.
dc.contributor.authorFrank, Daniel J.
dc.contributor.authorde Montellano, Paul Ortiz
dc.contributor.authorAtkins, William M.
dc.contributor.authorBowman, Michael K.
dc.contributor.otherUniversity of Washington
dc.contributor.otherUniversity of Washington Seattle
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.contributor.otherUniversity of California San Francisco
dc.date.accessioned2023-09-28T19:14:00Z
dc.date.available2023-09-28T19:14:00Z
dc.date.issued2015
dc.description.abstractAzoles and pyridines are commonly incorporated into small molecule inhibitor scaffolds that target cytochromes P450 (CYPs) as a strategy to increase drug binding affinity, impart isoform-dependent selectivity, and improve metabolic stability. Optical absorbance spectra of the CYP-inhibitor complex are widely used to infer whether these inhibitors are ligated directly to the heme iron as catalytically inert, low-spin (type II) complexes. Here, we show that the low-spin complex between a drug-metabolizing CYP2C9 variant and 4-(3-phenylpropyl)-1H-1,2,3-triazole (PPT) retains an axial water ligand despite exhibiting elements of classic type II optical behavior. Hydrogens of the axial water ligand are observed by pulsed electron paramagnetic resonance (EPR) spectroscopy for both inhibitor-free and inhibitor-bound species and show that inhibitor binding does not displace the axial water. A N-15 label incorporated into PPT is 0.444 nm from the heme iron, showing that PPT is also in the active site. The reverse type I inhibitor, LP10, of CYP125A1 from Mycobacterium tuberculosis, known from X-ray crystal structures to form a low-spin water-bridged complex, is found by EPR and by visible and near-infrared magnetic circular dichroism spectroscopy to retain the axial water ligand in the complex in solution.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationConner, K. P., Cruce, A. A., Krzyaniak, M. D., Schimpf, A. M., Frank, D. J., Ortiz de Montellano, P., Atkins, W. M., & Bowman, M. K. (2015). Drug Modulation of Water–Heme Interactions in Low-Spin P450 Complexes of CYP2C9d and CYP125A1. In Biochemistry (Vol. 54, Issue 5, pp. 1198–1207). American Chemical Society (ACS). https://doi.org/10.1021/bi501402k
dc.identifier.doi10.1021/bi501402k
dc.identifier.orcidhttps://orcid.org/0000-0003-3464-9409
dc.identifier.orcidhttps://orcid.org/0000-0003-0063-7557
dc.identifier.orcidhttps://orcid.org/0000-0001-5402-7426
dc.identifier.orcidhttps://orcid.org/0000-0002-9774-5580
dc.identifier.urihttps://ir.ua.edu/handle/123456789/11114
dc.languageEnglish
dc.language.isoen_US
dc.publisherAmerican Chemical Society
dc.subjectMAGNETIC CIRCULAR-DICHROISM
dc.subjectCRYSTAL-STRUCTURE
dc.subjectSTRUCTURAL BASIS
dc.subjectCYTOCHROME-P450 ENZYMES
dc.subjectALPHA-NAPHTHOFLAVONE
dc.subjectCOOPERATIVE BINDING
dc.subjectPULSED ENDOR
dc.subjectG-TENSOR
dc.subjectSPECTRA
dc.subjectIDENTIFICATION
dc.subjectBiochemistry & Molecular Biology
dc.titleDrug Modulation of Water-Heme Interactions in Low-Spin P450 Complexes of CYP2C9d and CYP125A1en_US
dc.typeArticle
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