UA cloudflare authentication

 

1,2,3-Triazole-Heme Interactions in Cytochrome P450: Functionally Competent Triazole-Water-Heme Complexes

Simple item page
dc.contributor.authorConner, Kip P.
dc.contributor.authorVennam, Preethi
dc.contributor.authorWoods, Caleb M.
dc.contributor.authorKrzyaniak, Matthew D.
dc.contributor.authorBowman, Michael K.
dc.contributor.authorAtkins, William M.
dc.contributor.otherUniversity of Washington
dc.contributor.otherUniversity of Washington Seattle
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.date.accessioned2023-09-28T19:14:28Z
dc.date.available2023-09-28T19:14:28Z
dc.date.issued2012
dc.description.abstractIn comparison to imidazole (IMZ) and 1,2,4-triazole (1,2,4-TRZ), the isosteric 1,2,3-triazole (1,2,3-TRZ) is unrepresented among cytochrome P450 (CYP) inhibitors. This is surprising because 1,2,3-TRZs are easily obtained via "click" chemistry. To understand this underrepresentation of 1,2,3-TRZs among CYP inhibitors, thermodynamic and density functional theory computational studies were performed with unsubstituted IMZ, 1,2,4-TRZ, and 1,2,3-TRZ. The results indicate that the lower affinity of 1,2,3-TRZ for the heme iron includes a large unfavorable entropy term likely originating in solvent-1,2,3-TRZ interactions; the difference is not solely due to differences in the enthalpy of heme-ligand interactions. In addition, the 1,2,3-TRZ fragment was incorporated into a well-established CYP3A4 substrate and mechanism-based inactivator, 17-alpha-ethynylestradiol (17EE), via click chemistry. This derivative, 17-click, yielded optical spectra consistent with low-spin ferric heme iron (type II) in contrast to 17EE, which yields a high-spin complex (type I). Furthermore, the rate of CYP3A4-mediated metabolism of 17-click was comparable to that of 17EE, with a different regioselectivity. Surprisingly, continuous-wave electron paramagnetic resonance (EPR) and HYSCORE EPR spectroscopy indicate that 17-click does not displace water from the sixth axial ligand position of CYP3A4 as expected for a type II ligand. We propose a binding model in which 17-click pendant 1,2,3-TRZ hydrogen bonds with the sixth axial water ligand. The results demonstrate the potential for 1,2,3-TRZ to form metabolically labile water-bridged low-spin heme complexes, consistent with recent evidence that nitrogenous type II ligands of CYPs can be efficiently metabolized. The specific case of [CYP3A4 center dot 17-click] highlights the risk of interpreting CYP-ligand complex structure on the basis of optical spectra.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationConner, K. P., Vennam, P., Woods, C. M., Krzyaniak, M. D., Bowman, M. K., & Atkins, W. M. (2012). 1,2,3-Triazole–Heme Interactions in Cytochrome P450: Functionally Competent Triazole–Water–Heme Complexes. In Biochemistry (Vol. 51, Issue 32, pp. 6441–6457). American Chemical Society (ACS). https://doi.org/10.1021/bi300744z
dc.identifier.doi10.1021/bi300744z
dc.identifier.orcidhttps://orcid.org/0000-0003-3464-9409
dc.identifier.urihttps://ir.ua.edu/handle/123456789/11142
dc.languageEnglish
dc.language.isoen_US
dc.publisherAmerican Chemical Society
dc.subjectSPIN-STATE
dc.subjectCONFORMATIONAL FLEXIBILITY
dc.subjectCRYSTAL-STRUCTURE
dc.subjectCLICK CHEMISTRY
dc.subjectBINDING
dc.subjectMETABOLISM
dc.subject3A4
dc.subjectMECHANISM
dc.subjectTAUTOMERISM
dc.subjectSPECTRA
dc.subjectBiochemistry & Molecular Biology
dc.title1,2,3-Triazole-Heme Interactions in Cytochrome P450: Functionally Competent Triazole-Water-Heme Complexesen_US
dc.typeArticle
dc.typetext

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
10.1021bi300744z.pdf
Size:
3.02 MB
Format:
Adobe Portable Document Format
Download

Collections

Research and Publications - Department of Chemistry & Biochemistry