Dokument: Functional analysis of CYP4B1 enzymes from apes and humans uncovers evolutionary hot spots for adaptations of the catalytical function
| Titel: | Functional analysis of CYP4B1 enzymes from apes and humans uncovers evolutionary hot spots for adaptations of the catalytical function | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=72612 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20260317-131750-2 | |||||||
| Kollektion: | Publikationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Texte » Artikel, Aufsatz | |||||||
| Medientyp: | Text | |||||||
| Autoren: | Hüsken, Saskia [Autor] Röder, Annika [Autor] Ptok, Johannes [Autor] Meyer, Anne E. [Autor] Schwarz, Yannick [Autor] Floss, Doreen M. [Autor] Girhard, Marco [Autor] Hanenberg, Helmut [Autor] Wiek, Constanze [Autor] Georg, Mats [Autor] | |||||||
| Dateien: |
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| Beschreibung: | A hallmark of the highly conserved CYP4B1 enzyme in mammals is the capability to bioactivate both xenobiotic and endobiotic substrates. However, due to a single amino acid change (p.P427S) within the evolutionary conserved meander region no catalytic activity of the native human CYP4B1 has been identified so far. To identify at which point in human evolution the loss of CYP4B1 activity had occurred, we evaluated the activities of CYP4B1 orthologs from 14 primate genera against 4-ipomeanol and perilla ketone in human liver cells. The activity of recombinant CYP4B1 proteins isolated from E. coli was also tested against 4-ipomeanol and lauric acid. Surprisingly, CYP4B1 already became catalytically inactive at the split between apes and monkeys; all tested CYP4B1 orthologs from monkeys were able to bioactivate both protoxins and to hydroxylate lauric acid. Amino acid analysis of the CYP4B1 orthologs revealed four additional evolutionary changes, each affecting the function of ape and human enzymes: p.V71G specific for Denisovans, p.R106C, p.R244H, and an exon deletion found only in the gorilla CYP4B1. Systematic functional analyses proved the negative impact of the genetic changes on CYP4B1 activity and showed that reversion of the mutations restored enzyme activity. The occurrence of five independent inactivating genetic changes in the same gene of closely related species is a clear indication of the importance of inactivating CYP4B1 in apes and humans. Elucidating the evolutionary trigger(s) for CYP4B1 inactivation in our ancestors will ultimately improve our understanding of primate evolution. | |||||||
| Rechtliche Vermerke: | Originalveröffentlichung:
Hüsken, S., Röder, A., Ptok, J., Meyer, A. E., Georg, M., Schwarz, Y., Roos, C., Mätz-Rensing, K., Hutter, M. C., Floß, D. M., Rettie, A. E., Girhard, M., Hanenberg, H., & Wiek, C. (2025). Functional analysis of CYP4B1 enzymes from apes and humans uncovers evolutionary hot spots for adaptations of the catalytical function. PLoS Genetics, 21(6), Article e1011750. https://doi.org/10.1371/journal.pgen.1011750 | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 17.03.2026 | |||||||
| Dateien geändert am: | 17.03.2026 |
