Journal article 186 views 9 downloads
Unravelling the role of transient redox partner complexes in P450 electron transfer mechanics
,
Jarrod A. Smith,
Zdzislaw Wawrzak,
Steven Kelly ,
Galina I. Lepesheva
Scientific Reports, Volume: 12, Issue: 1
Swansea University Authors:
David Lamb , Steven Kelly
-
PDF | Version of Record
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License
Download (3.68MB)
DOI (Published version): 10.1038/s41598-022-20671-0
Abstract
The molecular evolution of cytochromes P450 and associated redox-driven oxidative catalysis remains a mystery in biology. It is widely believed that sterol 14α-demethylase (CYP51), an essential enzyme of sterol biosynthesis, is the ancestor of the whole P450 superfamily given its conservation across...
| Published in: | Scientific Reports |
|---|---|
| ISSN: | 2045-2322 |
| Published: |
Springer Science and Business Media LLC
2022
|
| Online Access: |
Check full text
|
| URI: | https://cronfa.swan.ac.uk/Record/cronfa61474 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract: |
The molecular evolution of cytochromes P450 and associated redox-driven oxidative catalysis remains a mystery in biology. It is widely believed that sterol 14α-demethylase (CYP51), an essential enzyme of sterol biosynthesis, is the ancestor of the whole P450 superfamily given its conservation across species in different biological kingdoms. Herein we have utilized X-ray crystallography, molecular dynamics simulations, phylogenetics and electron transfer measurements to interrogate the nature of P450-redox partner binding using the naturally occurring fusion protein, CYP51-ferredoxin found in the sterol-producing bacterium Methylococcus capsulatus. Our data advocates that the electron transfer mechanics in the M. capsulatus CYP51-ferredoxin fusion protein involves an ensemble of ferredoxin molecules in various orientations and the interactions are transient. Close proximity of ferredoxin, however, is required to complete the substrate-induced large-scale structural switch in the P450 domain that enables proton-coupled electron transfer and subsequent oxygen scission and catalysis. These results have fundamental implications regarding the early evolution of electron transfer proteins and for the redox reactions in the early steps of sterol biosynthesis. They also shed new light on redox protein mechanics and the subsequent diversification of the P450 electron transfer machinery in nature. |
|---|---|
| Item Description: |
Data availability:Te atomic coordinates and structure factors have been deposited in the Protein Data Bank (http://wwwpdb.org) under the accession number 7SNM. Te ferredoxin model and the pdb fles obtained upon molecular dynamics simulations are available at request. All other data included in this article or its online Supplementary Material. |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
The study was supported by National Institutes of Health grants R01 GM067871 (G.I.L.) and by The Royal Society (to D.C.L.). Funding at Swansea University supported by the European Regional Development Fund/ Welsh European Funding Ofce via the BEACON project (SLK). |
| Issue: |
1 |