# Effect of PAS-LuxR Family Regulators on the Secondary Metabolism of _Streptomyces_
## 3 Regulation of Related Product Biosynthesis by PAS-LuxR Family Regulators
### Regulatory Mechanisms of PAS-LuxR Family Regulators  
As the prototype of a PAS-LuxR family regulator, the regulatory mechanism of PimM in pimaricin biosynthesis has been widely studied. PimM affects the transcription of target genes by binding to their promoters [50]. A comprehensive study on PAS-LuxR regulators has been conducted in the biosynthesis of polyene macrolides of pimaricin, nystatin, amphoteric, and filipin. Results show that the expression of _amphRIV_, _nysRIV_, or _ptE_ in _pimM_ deletion strains can restore the production of pimaricin. The expression of _pimM_ in \(S\). _nodosus_ and \(S\). _avermitilis_ can increase the yield of amphoteric and filipin, respectively. The expression of _pimM_ in _ptE_ deletion strain can also restore the production of filipin [30]. GST-PimM could bind with the promoters of controlled biosynthetic genes of amphoteric (_amphA_, _amphDI_, _amphH_, _amphH_, and _amphDIII_), nystatin (_nysA_, _nysDI_, _nysI_, _nysH_, and _nysDIII_), filipin (_ptE_AI_), and pimaricin (_pimK_, _pimS2_, _pimI_, _pimA_, _pimE_, _pimS1_, and _pimD_). The binding site of the PAS-LuxR class regulator is located in a 16-bp palindromic conserved sequence 5\({}^{\prime}\)-CTVGGGAWWTCCCBAG-3\({}^{\prime}\) (V stands for A, C, or G; W stands for A or T; B stands for C, G or T) [50]. Therefore, PAS-LuxR family proteins are regulators with relatively conserved regulatory functions. The relatively conserved function of PAS-LuxR family regulators can be attributed to their regulatory role across gene clusters and antibiotic varieties. FscRI can regulate both candididin and antimycins across gene clusters in \(S\). _albus_ S4. In addition, FscRI is required for the heterologous expression of antimycin biosynthetic gene clusters in \(S\). _coelicolor_. Notably, the 16 bp binding sites of PAS-LuxR family regulator exist in the promoters of _antB2_, _antB1_, and _antC_, which are important genes in antimycin biosynthesis [51]. The increment of _pimM_ copies increased the production of candididin and antimycin at the same time in \(S\). _albus_ J1074 [52]. Following the above characteristic sequences, the potential binding sites of unspecified PAS-LuxR family regulators were searched, and the results show similar binding sites in the promoters of _nysDIII_, _nysH_, _nysH_, _nysA_, _nysRI_, and _nysRIV_ in the biosynthetic gene cluster of nystatin in \(S\). _noursei_ ATCC 11455, the promoters of _amphH_, _amphL_, _amphM_, _amphL_, _amphL_, _amphA_, and _amphB_ in the biosynthetic gene cluster of amphoteric in \(S\). _nodosus_, the promoters of _scnK_, _scnS4_, _scnS3_, _scnS2_, _scnl_, _scnl_, _scnA_, _scnB_, _scnC_, _scnF_, _scnS0_, _scnS1_, and _scnlD_ in the biosynthetic gene cluster of pimaricin in \(S\). _chattaoogensis_ L10, the promoters of _rdmA_, _rdmC_, _rdmF_, _rdmG_, _rdmH_, _rdmI_, _rdmK_, _rdmL_, and _rdmN_ in the biosynthetic gene cluster of reedsmycins in S.sp. strain OUC6819, and the promoters of _ptE_AI and _ptE_A2 in the biosynthetic gene cluster of filipin in \(S\). _avermitilis_. The sequence logo is shown in Figure 7. Therefore, the PAS-LuxR family regulators derived from different secondary metabolites in different _Streptomyces_ are functionally conserved and can be substituted for each other. However, these findings were all obtained from different strains. In \(S\). _alhyroscopicus_, although TtmRIV is present together with NysRIV, when _ttmRIV_ is deleted, tetramycin is no longer produced when nystatin production is enhanced [34]. Similarly, when _nysRIV_ is deleted, nystatin is no longer produced, and tetramycin production is enhanced (unpublished results). Therefore, NysRIV and TtmRIV cannot achieve functional substitution but can exhibit independent and precise regulation in \(S\). _ahyroscopicus_. Therefore, although TtmRIV and NysRIV belong to the same PAS-LuxR family regulators, their regulatory mechanisms differ.