# 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 Polyene Macrolide Biosynthesis by PAS-LuxR Family Regulators
#### 3.1.2 Network Regulatory System Formed with LAL and PAS-LuxR Family Regulators
Considering that FscRI can unidirectionally compensate for the deletion of FscRIII and FscRIV, and FscRIV can unidirectionally compensate for the deletion of FscRI, FscRIV can partially replace FscRII, while FscRI can partially replace FscRIII and FscRIV [37]. In addition to the abovementioned genes regulated by _fscRI_, the transcript of both _fscRI_ and the precursor synthesis gene _pabc_ decreased in _DfscRIV_, suggesting that _fscRI_ and _fscRIV_ have direct or indirect regulatory effects on the above genes and they regulate one another [38]. Therefore, the biosynthesis of candicidin is regulated by the regulatory network formed with the four regulators. In addition, some type I PKS biosynthetic pathways contain several LAL and PAS-LuxR family regulators, and the relationship between their regulatory roles has not been fully determined. A heptane macrolide amphoteric is produced by _S. nodosus_ and is commonly used clinically. Four regulators were also identified in the amphoteric pathway, including the three LAL family regulators AmphRI, AmphRII, AmphRII, and PAS-LuxR family regulator AmphRIV. Tetraene macrolide NPPA1 produced by _Pseudonocardiu autotrophic_ is 300-fold more water-soluble and 10-fold less hemolytic than nystatin A1 is, but its antimicrobial activity is 50-fold lower [39]. The increased antimicrobial activity NPPB1 was obtained with the inactivation of the enolase structure in the fifth module of its biosynthetic gene _nppC_, but its yield is less 10% than that of NppA1 [40]. The biosynthetic gene cluster contains six regulatory genes, namely, _nppRI_, _nppRII_, _nppRIII_, _nppRIV_, _nppRV_, and _nppRVI_, of which _nppRI_, _nppRIII_, and _nppRV_ encode LAL family regulators, and _nppRV_ encodes a PAS-LuxR family regulator. The sequence identities of NppRIV with _nysRIV_ and _pinM_ are 45.6% and 45%, respectively [41]. Two LAL family regulators encode genes, _salRI_ and _salRI_, and PAS-luxR family regulator encode gene _salRIII_, which is also present in the biosynthetic gene cluster of the polyether ion carrier salinomycin produced by _S. albus_ CCM4719. The sequence identities of _salRIII_ with _pteF_, _fscRI_, _nysRIV_, and _amplhRIV_ are 44%, 47%, 48%, and 50%, respectively [42]. PF1 and PF2 are polyene macrolides produced by _S. marokkomenis_ M10, and its structure is similar to that of candicidin. The regulators in the PF1 and PF2 pathway correspond to those of candicidin pathway, a PAS-LuxR family regulator MarRI to FscRI (98% identity), three LAL family regulators MarRII to FscRII (99% identity), MarRIII to FscRIII (97% identity), and MarRIV to FscRIV (97% identity) [43; 44]. Although the regulatory mechanisms of PAS-LuxR family and LAL family regulators in the above PKS pathway have not been reported, on the basis of the reported regulatory networks in the biosynthetic pathway of the same kind of substances, several of their regulators also play a similar regulatory role.