Exploring the substrate specificity of OxyB, a phenol coupling P450 enzyme involved in vancomycin biosynthesis
| Autor: | Nina Geib, John A. Robinson, Katja Zerbe, Odile Meyer, Katharina Woithe, Tanja Wörtz |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
chemistry.chemical_classification
Receptors Steroid Binding Sites Molecular Structure Chemistry Stereochemistry medicine.drug_class Organic Chemistry Tryptophan Substrate (chemistry) Peptide Tripeptide Glycopeptide antibiotic Thioester Biochemistry Substrate Specificity Cytochrome P-450 Enzyme System Phenols Vancomycin medicine Physical and Theoretical Chemistry Binding site Conjugate |
| Zdroj: | Organic & Biomolecular Chemistry. 6:2861 |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/b805956j |
| Popis: | OxyB is a cytochrome P450 enzyme that catalyzes the first oxidative phenol coupling reaction during vancomycin biosynthesis. The preferred substrate is a linear peptide linked as a C-terminal thioester to a peptide carrier protein (PCP) domain of the glycopeptide antibiotic non-ribosomal peptide synthetase. Previous studies have shown that OxyB can efficiently oxidize a model hexapeptide-PCP conjugate (R-Leu(1)-R-Tyr(2)-S-Asn(3)-R-Hpg(4)-R-Hpg(5)-S-Tyr(6)-S-PCP) (Hpg = 4-hydroxyphenylglycine) into a macrocyclic product by phenolic coupling of the aromatic rings in residues-4 and -6. In this work, the substrate specificity of OxyB has been explored using a series of N-terminally truncated peptides related in sequence to this model hexapeptide-PCP conjugate. Deletion of one or three residues from the N-terminus afforded a penta- (Ac-Tyr-Asn-Hpg-Hpg-Tyr-S-PCP) and a tri- (Ac-Hpg-Hpg-Tyr-S-PCP) peptide that were also efficiently transformed into the corresponding macrocyclic cross-linked product by OxyB. The tripeptide, representing the core of the macrocycle in vancomycin created by OxyB, is thus sufficient, as a thioester with the PCP domain, for phenol coupling to occur. The related tetrapeptide-PCP thioester was not cyclized by OxyB, neither was a related model hexapeptide containing tryptophan in place of tyrosine-6, nor were tripeptides (related to the natural product K-13) with the sequence Ac-Tyr-Tyr-Tyr-S-PCP cross-linked by OxyB. |
| Databáze: | OpenAIRE |
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