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Extradiol cleavage of L‐DOPA as strategy for natural product biosynthesis
Author(s) -
Jones Paige A.,
Johnson Nyjah M.,
Klugh Kameron L.,
Peterson Larryn W.,
Colabroy Keri L.
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r3491
Subject(s) - natural product , dioxygenase , context (archaeology) , synthon , chemistry , gene cluster , biosynthesis , biochemistry , stereochemistry , gene , computational biology , biology , paleontology
L‐DOPA dioxygenase was first discovered as part of a biosynthetic gene cluster to the natural product antibiotic, lincomycin. Within the larger biosynthetic context, L‐DOPA dioxygenase is part of a mini‐pathway to the synthon 3‐vinyl‐2,3‐pyrroline‐5‐carboxylic acid (VPCA). This synthon is elaborated and embedded within the final product structure of lincomycin, and also within the natural product structures of anthramycin, sibiromycin, tomaymycin and hormaomycin. Using the VPCA mini‐pathway as a starting point, we searched sequence space to identify 1) novel natural product pathways containing a VPCA synthon and 2) instances of L‐DOPA dioxygenase homologs that were not associated with a known VPCA containing natural product pathway, and that might provide new sources of natural product diversity and answer questions about the evolutionary origins of L‐DOPA dioxygenase. Using bioinformatic methods, including PSI‐BLAST, genome context analysis and structurally informed multiple‐sequence alignment, we identified a variety of known and novel natural product pathways that utilize an L‐DOPA dioxygenase ‐ many with the context of a VPCA synthon. Representative examples from these pathways were isolated and tested for iron binding and L‐DOPA dioxygenase activity.