# Effect of PAS-LuxR Family Regulators on the Secondary Metabolism of _Streptomyces_
## 3 Regulation of Related Product Biosynthesis by PAS-LuxR Family Regulators
### Regulation of the Nonpolyne Macrolides Biosynthesis by PAS-LuxR Family Regulators  
CFA-L-Ile, a phytotoxin, is produced by _S. scabies_ and causes the development of potato blast. The biosynthetic gene cluster of CFA-L-Ile contains 15 genes, and 13 of them are cotranscribed in a multicistron, while the two remaining genes, namely, PAS-LuxR family regulator gene _cfaR_ and partial ThiF family gene _orf1_, are transcribed in another transcript [14]. The _cfaR_ deletion strain has no or low-level transcripts for _cfaR5_, _cfaR6_, and _cfI_ compared with the wild-type strain. The cotranscribed gene _orf1_ of _cfaR_ is not affected in any way, indicating that _cfaR_ activates the transcription of approximately 27 kb transcripts from _cfaR1_ to _scab79721_, but it does not regulate itself. EMSA results show that CfaR only binds to the _cfaR1_ promoter region, further demonstrating that CfaR regulates the CFA-L-Ile pathway directly through a vertical regulatory system [49].  
Wuyiencin is an aminoglycosonic antibiotic produced by _S.uwyiensis_ CK-15, and a PAS-LuxR gene _wysR_ is present in the biosynthetic gene cluster. Wuyiencin is widely used for fungal control in crops and has low toxicity. The sequencing analysis of WysR (193 amino acids) revealed 84.27% identity with NysRIV and more than 60% identity with other PAS-LuxR family regulatory protein sequences. The transcript levels of _wysE_ (thioesterase), _wysR1_ (LAL family regulator), and _wysRIII_ (DeoR family regulator) were analyzed in the wuviencin biosynthetic gene cluster, and the results show that the transcript levels of _wysRIII_ and _wysE_ are remarkably lower in _wysR_ deletion strain than that in the wild-type strain, while the transcript levels of _wysR1_ remarkably increased compared with wild-type strains [16]. In the _wysR_ overexpressing strain, the transcript levels of _wysRIII_ and _wysE_ remarkably increased, whereas the transcript levels of _wysR1_ are significantly reduced compared with the wild-type strain [15]. Therefore, WysR directly or indirectly regulates the expression of other potential regulatory genes such as _wysRI_ and _wysRIII_  
\begin{table}
\begin{tabular}{c c c c c c c c} \hline \hline
**Regulator** & _Streptomyces_ & **Size** & **Product** & \begin{tabular}{c} **Type of** \\ **Product** \\ \end{tabular} & \
\begin{tabular}{c} **Target Genes** \\ **Overexpression Strain** \\ \end{tabular} &
\begin{tabular}{c} **Yield in** \\ **Overexpression Strain** \\ \end{tabular} & **Reference** \\ \hline PimM & _S. natalensis_ & & & & _pimS0_, _pimS1_, _pimS0_, _pimS1_, _pimS0_, _pimS1_, _pimS2_, _pimS3_, _pimS4_, _pimS4_, _pimS4_, _pimS4_, _pimS4_, _pimS5_, _pimS6_, _pimS7_, _pimS8_, _scaI_, _scaI  
to affect the transcription of early wuyiencin PKS genes and regulates _wysE_ to affect the late biosynthetic enzymes in wuyiencin production [16]. Moreover, WysR regulates wuyiencin biosynthesis and morphological development by influencing possible regulatory genes such as _bld_, _vuti_, _chp_, _rd1_, and _ram_ family genes, indicating its crucial role in the morphological development [15].