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In-frame deletion of ttmRIV led to abolishment of tetramycin and significant enhancement of nystatin A1, whose production reached 2.1-fold of the H42 parental strain. Gene complementation by an integrative plasmid carrying ttmRIV restored tetramycin biosynthesis revealed that ttmRIV was indispensable to tetramycin biosynthesis. Gene expression analysis of the H42 strain and its mutant strain \u0394ttmRIV via reverse transcriptase-PCR of the tetramycin gene cluster demonstrated that the expression levels of most biosynthetic genes were reduced in \u0394ttmRIV. Results of electrophoretic mobility shift assays showed that TtmRIV bound the putative promoters of several genes in the tetramycin pathway. Thus, TtmRIV is a pathway-specific positive regulator activating the transcription of the tetramycin gene cluster in S. ahygroscopicus. Providing an additional copy of ttmRIV under the control of the ermEp* promoter in the H42 strain boosted tetramycin A production to 3.3-fold.<\/jats:p>","DOI":"10.1007\/s10295-015-1660-3","type":"journal-article","created":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T09:40:07Z","timestamp":1438422007000},"page":"1273-1282","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Functional manipulations of the tetramycin positive regulatory gene <i>ttmRIV<\/i> to enhance the production of tetramycin A and nystatin A1 in <i>Streptomyces ahygroscopicus<\/i>"],"prefix":"10.1093","volume":"42","author":[{"given":"Hao","family":"Cui","sequence":"first","affiliation":[{"name":"grid.412561.5 0000000086454345 School of Life Science and Biopharmaceutics Shenyang Pharmaceutical Univerisity Shenhe District, Wenhua Road 103 110016 Shenyang Liaoning People\u2019s Republic of 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