Tailoring enzymes involved in the biosynthesis of angucyclines contain latent context-dependent catalytic activities

Pekka Patrikainen, Pauli Kallio, Keqiang Fan, Karel D. Klika, Khaled A. Shaaban, Pekka Mäntsälä, Jürgen Rohr, Keqian Yang, Jarmo Niemi, Mikko Metsä-Ketelä

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)647-655
Number of pages9
JournalChemistry and Biology
Volume19
Issue number5
DOIs
StatePublished - May 25 2012

Bibliographical note

Funding 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

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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