Comparison of homologous angucycline modification enzymes from five closely related Streptomyces pathways (pga, cab, jad, urd, lan) allowed us to deduce the biosynthetic steps responsible for the three alternative outcomes: gaudimycin C, dehydrorabelomycin, and 11-deoxylandomycinone. The C-12b-hydroxylated urdamycin and gaudimycin metabolites appear to be the ancestral representatives from which landomycins and jadomysins have evolved as a result of functional divergence of the ketoreductase LanV and hydroxylase JadH, respectively. Specifically, LanV has acquired affinity for an earlier biosynthetic intermediate resulting in a switch in biosynthetic order and lack of hydroxyls at C-4a and C-12b, whereas in JadH, C-4a/C-12b dehydration has evolved into an independent secondary function replacing C-12b hydroxylation. Importantly, the study reveals that many of the modification enzymes carry several alternative, hidden, or ancestral catalytic functions, which are strictly dependent on the biosynthetic context.
|Number of pages||9|
|Journal||Chemistry and Biology|
|State||Published - May 25 2012|
Bibliographical noteFunding Information:
We thank Andriy Luzhetskyy and Andreas Bechthold for cosmid H2-26 and Streptomyces fradiae AO strain. This study was supported by the Academy of Finland (Grant 121688 to J.N., 127844 to P.M., and 136060 to M.M.-K.), the National Natural Science Foundation of China (Grant 31130001 to K.Y.), Turun Yliopistosäätiö (to K.D.K), and US National Institutes of Health (Grants CA091901 and CA102102 to J.R.). The Center for Scientific Computing is acknowledged for computational resources.
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Drug Discovery
- Clinical Biochemistry