The gamma-butyrolactone receptors BulR1 and BulR2 of Streptomyces tsukubaensis: tacrolimus (FK506) and butyrolactone synthetases production control

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• 作者：Zahra Salehi-Najafabadi (1) (2) (4)
  Carlos Barreiro (2)
  Antonio Rodríguez-García (1) (2)
  Anthony Cruz (3)
  Gustavo E. López (3)
  Juan F. Martín (1) (2)
  
• 关键词：Streptomyces ; Tacrolimus ; FK506 ; Immunosuppressant ; Secondary metabolite ; Butyrolactone
• 刊名：Applied Microbiology and Biotechnology
• 出版年：2014
• 出版时间：June 2014
• 年：2014
• 卷：98
• 期：11
• 页码：4919-4936
• 全文大小：
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• 作者单位：Zahra Salehi-Najafabadi (1) (2) (4)
  Carlos Barreiro (2)
  Antonio Rodríguez-García (1) (2)
  Anthony Cruz (3)
  Gustavo E. López (3)
  Juan F. Martín (1) (2)
  
  1. área de Microbiología, Departamento de Biología Molecular, Fac. CC. Biológicas y Ambientales, Universidad de León, Campus de Vegazana s/n, 24071, León, Spain
  2. Instituto de Biotecnología de León (INBIOTEC), Parque Científico de León, Avda. Real 1, 24006, León, Spain
  4. Department of Biological Sciences, Lehman College of the City University of New York, Bronx, NY, 10468, USA
  3. Department of Chemistry, Lehman College of the City University of New York, Bronx, NY, 10468, USA
  
• ISSN：1432-0614

文摘

Streptomyces tsukubaensis is a well-established industrial tacrolimus producer strain, but its molecular genetics is very poorly known. This information shortage prevents the development of tailored mutants in the regulatory pathways. A region (named bul) contains several genes involved in the synthesis and control of the gamma-butyrolactone autoregulator molecules. This region contains ten genes (bulA, bulZ, bulY, bulR2, bulS2, bulR1, bulW, bluB, bulS1, bulC) including two γ-butyrolactone receptor homologues (bulR1, bulR2), two putative gamma-butyrolactone synthetase homologues (bulS1, bulS2) and two SARP regulatory genes (bulY, bulZ). Analysis of the autoregulatory element (ARE)-like sequences by electrophoretic mobility shift assays and footprinting using the purified BulR1 and BulR2 recombinant proteins revealed six ARE regulatory sequences distributed along the bul cluster. These sequences showed specific binding of both BulR1 (the gamma-butyrolactone receptor) and BulR2, a possible pseudo γ-butyrolactone receptor. The protected region in all cases covered a 28-nt sequence with a palindromic structure. Optimal docking area analysis of BulR1 proved that this protein can be presented as either monomer or dimer but not oligomers and that it binds to the conserved ARE sequence in both strands. The effect on tacrolimus production was analysed by deletion of the bulR1 gene, which resulted in a strong decrease of tacrolimus production. Meanwhile, the ΔbulR2 mutation did not affect the biosynthesis of this immunosuppressant.