Download MendeleyUncovering the Enzymes that Catalyze the Final Steps in Oxytetracycline Biosynthesis.
Wang, P., Bashiri, G., Gao, X., Sawaya, M.R., Tang, Y.(2013) J Am Chem Soc 135: 7138-7141
- PubMed: 23621493
- DOI: https://doi.org/10.1021/ja403516u
- Primary Citation of Related Structures:
4K2X - PubMed Abstract:
Tetracyclines are a group of natural products sharing a linearly fused four-ring scaffold, which is essential for their broad-spectrum antibiotic activities. Formation of the key precursor anhydrotetracycline 3 during oxytetracycline 1 biosynthesis has been previously characterized. However, the enzymatic steps that transform 3 into 1, including the additional hydroxylation at C5 and the final C5a-C11a reduction, have remained elusive. Here we report two redox enzymes, OxyS and OxyR, are sufficient to convert 3 to 1. OxyS catalyzes two sequential hydroxylations at C6 and C5 positions of 3 with opposite stereochemistry, while OxyR catalyzes the C5a-C11a reduction using F420 as a cofactor to produce 1. The crystal structure of OxyS was obtained to provide insights into the tandem C6- and C5-hydroxylation steps. The substrate specificities of OxyS and OxyR were shown to influence the relative ratio of 1 and tetracycline 2.
Organizational Affiliation:
Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, California 90095, USA.
