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EnglishThe cytochrome P450 OleP catalyzes the epoxidation of aliphatic carbons on both the aglycone 8.8a-deoxyoleandolide (DEO) and the monoglycosylated L-olivosyl-8.8a-deoxyoleandolide (L-O-DEO) intermediates of oleandomycin biosynthesis. We investigated the substrate versatility of the enzyme. X-ray and equilibrium binding data show that the aglycone DEO loosely fits the OleP active site, triggering the closure that prepares it for catalysis only on a minor population of enzyme. The open-to-closed state transition allows solvent molecules to accumulate in a cavity that forms upon closure, mediating protein–substrate interactions. In silico docking of the monoglycosylated L-O-DEO in the closed OleP–DEO structure shows that the L-olivosyl moiety can be hosted in the same cavity, replacing solvent molecules and directly contacting structural elements involved in the transition. X-ray structures of aglycone-bound OleP in the presence of L-rhamnose confirm the cavity as a potential site for sugar binding. All considered, we propose L-O-DEO as the optimal substrate of OleP, the L-olivosyl moiety possibly representing the molecular wedge that triggers a more efficient structural response upon substrate binding, favoring and stabilizing the enzyme closure before catalysis. OleP substrate versatility is supported by structural solvent molecules that compensate for the absence of a glycosyl unit when the aglycone is bound.
Dissecting the cytochrome P450 OleP substrate specificity: evidence for a preferential substrate / Parisi, Giacomo; Freda, Ida; Exertier, Cecile; Cecchetti, Cristina; Gugole, Elena; Cerutti, Gabriele; D'Auria, Lucia; Macone, Alberto; Vallone, Beatrice; Savino, Carmelinda; Montemiglio, Linda Celeste. - In: BIOMOLECULES. - ISSN 2218-273X. - (2020). [10.3390/biom10101411]
| Titolo: | Dissecting the cytochrome P450 OleP substrate specificity: evidence for a preferential substrate | |
| Autori: | PARISI, GIACOMO (Co-primo) FREDA, IDA (Co-primo) EXERTIER, CECILE (Co-primo) CECCHETTI, CRISTINA (Secondo) MONTEMIGLIO, LINDA CELESTE (Corresponding author) | |
| Data di pubblicazione: | 2020 | |
| Rivista: | ||
| Citazione: | Dissecting the cytochrome P450 OleP substrate specificity: evidence for a preferential substrate / Parisi, Giacomo; Freda, Ida; Exertier, Cecile; Cecchetti, Cristina; Gugole, Elena; Cerutti, Gabriele; D'Auria, Lucia; Macone, Alberto; Vallone, Beatrice; Savino, Carmelinda; Montemiglio, Linda Celeste. - In: BIOMOLECULES. - ISSN 2218-273X. - (2020). [10.3390/biom10101411] | |
| Handle: | http://hdl.handle.net/11573/1441957 | |
| Appartiene alla tipologia: | 01a Articolo in rivista |
File allegati a questo prodotto
| File | Note | Tipologia | Licenza | |
|---|---|---|---|---|
| biomolecules-10-01411.pdf | Versione editoriale (versione pubblicata con il layout dell'editore) |  | Open Access Visualizza/Apri |
http://hdl.handle.net/11573/1441957
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