title: Initiation of actinorhodin export in Streptomyces coelicolor.
abstract: Many microorganisms produce molecules having antibiotic activity and expel them into the environment, presumably enhancing their ability to compete with their neighbours. Given that these molecules are often toxic to the producer, mechanisms must exist to ensure that the assembly of the export apparatus accompanies or precedes biosynthesis. Streptomyces coelicolor produces the polyketide antibiotic actinorhodin in a multistep pathway involving enzymes encoded by genes that are clustered together. Embedded within the cluster are genes for actinorhodin export, two of which, actR and actA resemble the classic tetR and tetA repressor/efflux pump-encoding gene pairs that confer resistance to tetracycline. Like TetR, which represses tetA, ActR is a repressor of actA. We have identified several molecules that can relieve repression by ActR. Importantly (S)-DNPA (an intermediate in the actinorhodin biosynthetic pathway) and kalafungin (a molecule related to the intermediate dihydrokalafungin), are especially potent ActR ligands. This suggests that along with the mature antibiotic(s), intermediates in the biosynthetic pathway might activate expression of the export genes thereby coupling export to biosynthesis. We suggest that this could be a common feature in the production of many bioactive natural products.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
authors.forename: Kapil
authors.initials: K
authors.lastname: Tahlan
authors.forename: Sang Kyun
authors.initials: SK
authors.lastname: Ahn
authors.forename: Anson
authors.initials: A
authors.lastname: Sing
authors.forename: Tetyana D
authors.initials: TD
authors.lastname: Bodnaruk
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Willems
authors.forename: Alan R
authors.initials: AR
authors.lastname: Davidson
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nodwell
mesh_terms: D000880:Anthraquinones / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D015374:Biosensing Techniques; D004269:DNA, Bacterial / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D008024:Ligands; D005810:Multigene Family; D009154:Mutation; D009281:Naphthalenes / Q000378:metabolism; D009285:Naphthoquinones / Q000378:metabolism; D011714:Pyrans / Q000378:metabolism; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D048372:Streptomyces coelicolor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013752:Tetracycline / Q000494:pharmacology; D000095622:Benzoisochromanequinones
chemical_list: D000880:Anthraquinones; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D008024:Ligands; D009281:Naphthalenes; D009285:Naphthoquinones; D011714:Pyrans; D012097:Repressor Proteins; D013752:Tetracycline; C408422:4-dihydro-9-hydroxy-1-methyl-10-oxo-3-H-naphtho-(2,3-c)-pyran-3-acetic acid; C034811:tetracycline resistance-encoding transposon repressor protein; C013079:kalafungin; D000095622:Benzoisochromanequinones; C013390:actinorhodin