Abstract
Myxobacteria, especially members of the genus Sorangium, are known for their biotechnological potential as producers of pharmaceutically valuable secondary metabolites. The biosynthesis of several of those myxobacterial compounds includes cytochrome P450 activity. Although class I cytochrome P450 enzymes occur wide-spread in bacteria and rely on ferredoxins and ferredoxin reductases as essential electron mediators, the study of these proteins is often neglected. Therefore, we decided to search in the Sorangium cellulosum So ce56 genome for putative interaction partners of cytochromes P450. In this work we report the investigation of eight myxobacterial ferredoxins and two ferredoxin reductases with respect to their activity in cytochrome P450 systems. Intriguingly, we found not only one, but two ferredoxins whose ability to sustain an endogenous So ce56 cytochrome P450 was demonstrated by CYP260A1-dependent conversion of nootkatone. Moreover, we could demonstrate that the two ferredoxins were able to receive electrons from both ferredoxin reductases. These findings indicate that S. cellulosum can alternate between different electron transport pathways to sustain cytochrome P450 activity.
Highlights
The cytochrome P450 (CYP)2 enzymes constitute a superfamily of external monooxygenases
Bioinformatic Analysis—Searching the genome of S. cellulosum So ce56 for possible interaction partners of cytochrome P450 systems revealed the presence of eight putative ferredoxin genes and two putative ferredoxin reductase genes
All of the ferredoxin genes are distributed over the whole chromosome and are not in the neighborhood of either one of the putative ferredoxin reductase genes or one of the 21 cytochrome P450 genes in S. cellulosum So ce56
Summary
The cytochrome P450 (CYP) enzymes constitute a superfamily of external monooxygenases. Even the identification of the correct interaction partners remains challenging because the encoding genes are frequently located at genomic loci distant to the cytochrome P450 genes [6, 7] Members of both the [2Fe-2S] and the non-[2Fe-2S] ferredoxins have been reported to sustain cytochrome P450 catalyzed reactions. Sorangium cellulosum So ce is a genome-sequenced myxobacterial model strain Because of their biotechnological potential as producers of secondary metabolites, the myxobacteria attract attention from both the academic community and the pharmaceutical industry. Epothilone is one of so far seven known myxobacterial compounds, the biosynthesis of which involves cytochromes P450 [15] Besides the epothilones, these are the antifungal leupyrrins [16] and the cytotoxic spirangienes [17] ( from S. cellulosum), the antibiotic myxovirescin from Myxococcus [18], the electron transport inhibitor stigmatellin [19] and the antibiotic aurafuron [20] from Stigmatella aurantiaca, and the antifungal ajudazols from Chondromyces crocatus [21]. In light of the significance of S. cellulosum as a viable source of bioactive secondary metabolites [14] and the role of cytochromes P450 in the synthesis of natural products [2], it is of great interest to elucidate the function of these enzymes
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