# Effect of PAS-LuxR Family Regulators on the Secondary Metabolism of _Streptomyces_
## 4 Application of PAS-LuxR Family Regulators  
PAS-LuxR family regulators influence the biosynthesis of target products by regulating the transcription of target genes. On the basis of this feature, the production of metabolites can be changed by the over-expression of PAS-LuxR family regulator genes in the biosynthetic gene cluster or knocking out them in the non-target gene cluster. As shown in Table 1, the production of pimaricin is completely eliminated by blocking _pimM_ in _S. natalensis_. After _pimM_ complementation, pimaricin production could be restored to the wild-type level, and PimM overexpression could reach 2.4 times of the wild-type level. Upon the overexpression of ScnRII in _S. chattanoogensis_, compared with the wild-type strain, the yield of pimaricin on YSG medium is 3.3 times higher and that of pimaricin on YEME medium is 4.6 times higher. When _shnM_ is overexpressed in _S.lydicus_, the production rates of pimaricin in the overexpressing strains containing ermEp* promoter, native promoter, and ermEp*- native promoter are 2.4, 1.9, and 3 times higher than those in the wild-type strain, respectively, on the YEME medium without sucrose. On the YSG medium, _sltM_ overexpressing strains containing ermEp*-native promoter produced 2.1 times more pimaricin than wild-type strains do [25]. _S. alngroscopicus_ produces two polyene macrolides, namely, tetramycin and nystain. In the \(ttmRIV\) deletion strain, nystain production increased 2.1 times, and a high-production nystain strain was obtained [46]. When the \(ttmRIV\) gene was overexpressed, the yield of tetramycin A was 3.33 times that of the wild-type strain, but the yield of tetramycin B did not change, because the \(ttmD\) gene, which is responsible for the transformation of tetramycin A to tetramycin B, is not regulated by TtmRIV. When \(nysRIV\) was disrupted, the yield of nystain was completely eliminated, and the yield of tetramycin increased by 1.28 times. In _S. aureofuscus_ SYAU0709, blocking AurJ3M resulted in stopped the production of aureofuscin, and the overexpression of AurJ3M could increase the production of aureofuscin by six times [54]. The \(pteF\) deletion mutant resulted in a 38% loss of filipin yield and delayed spore formation in the starting strain. The complementation of \(pteF\) restored the yield to wild-type levels and restored the rate of spore formation. The heterologous complementation of \(pimM\) to the deletion mutant strain of \(pteF\) fully restored filipin to wild-type levels. The overexpression of the \(amphRIV\) gene in the _S. nodosus_\(\Delta amphNM\) mutant strain resulted in an approximately three-fold increase in the yield of the related derivative [55]. The loss of \(rdmF\) also completely deprives the yield of reedsmycin, in which the level was almost restored to wild-type levels after complementation, and the overexpression of \(rdmF\) resulted in 2.5 times increase in reedsmycin yield [33]. PAS-LuxR transcriptional activators share the similarity regulatory pattern. By contrast, the overexpression of NppRIV in the _P. autotrophic_ reduces NPP production [40]. This phenomenon may be related to the different regulatory networks composed of six regulators present in _P. autotrophic_. For nonpolyene products, neither \(\Delta cfaR\Delta PAS\) nor \(\Delta cfaR\Delta LuxR\) produces CFA-L-Ile in _S. scabies. cfaR+orf1_ overexpression strains produced more than 10 times the yield of \(cfaR\) overexpression strains, whereas the overexpression of \(orf1\) alone did not remarkably affect the yield of CFA-L-Ile [49]. \(wysR\) gene deletion resulted in the complete disappearance of wuyiencin yield. Subsequently, the wild-type level was restored after complementation, and the overexpression of \(wysR\) resulted in an increase in wuyiencin yield with a value that was thrice that of the wild-type yield [15]. Aside from improving the product yield and species, PAS-LuxR family regulators are also used to regulate the heterologous expression of gene clusters.