# Effect of PAS-LuxR Family Regulators on the Secondary Metabolism of _Streptomyces_
## 1 Introduction  
Secondary _Streptomyces_ metabolites appear in the late stages of growth, when nutrients are insufficient and growth rates are reduced; they provide more than half of all antibiotics in clinical use [1]. The secondary metabolism of _Streptomyces_ is a complex process that is closely linked to the complex differentiation of cells. Thus, various regulatory approaches are used for the metabolic process in _Streptomyces_ in which different regulators interact and form a large and complex regulatory network that is rare in prokaryotes. Depending on the source, the different regulatory factors of a bacterium can be divided into internal and external (e.g., environmental) factors. Environmental factors include carbon, nitrogen, and phosphate, which are essential nutrients for the primary metabolism of the bacterium and serve as regulatory substances on the secondary metabolism of the bacterium. Regulatory substances from the bacterium itself typically include small molecules, such as highly phosphorylated guanosine acids (ppGpp), \(\gamma\)-butyrolactone, small proteins such as \(\sigma\)-factors, and regulatory proteins encoded by regulatory genes' biosynthetic gene clusters. The regulatory genes in the biosynthesis of secondary metabolites in _Streptomyces_ can be divided into those that contain only a DNA binding domain (DBD) and those that have an additional signal recognition or energy conversion region in addition to the DBD. Most of the regulators in _Streptomyces_ contain an additional region [2]. According to the range of regulation, most regulators are pathway-specific, while a few regulators are pleiotropic regulators. Depending on the structure and function of the regulatory proteins, they can be classified as tetracycline repression (TetR), xenobiotic response element (XRE), _Streptomyces_ antibiotic regulatory protein (SARP), multiple antibiotic resistance regulator (MarR), largeATP-binding regulators of the LuxR (LAL), PAS-LuxR, and other families [3]. More than 100 TetR family regulators have been identified, rendering it the largest family of regulators available [4]. XRE family regulators are the second most common family and are commonly found in bacteria such as _Serratia marcescens_, _Streptomyces_, and _Pseudomonas aeruginosa_[5]. SARP regulators were the first family to be identified and studied, but they are only found in _Actinomycetes_ and mostly in _Streptomyces_[6]. MarR family regulators are commonly found in the genomes of _Streptomyces_ with an average of 50 MarR family regulators per genome [7], and only one conserved structural domain was found for binding to DNA in its structure [6]. The LAL family is a large class of regulators that bind to ATP, typically consisting of 900-1000 amino acids. The PAS-LuxR family, a late class of regulators, combines an N-terminal PAS domain with a C-terminal helix-turn-helix (HTH) motif of the LuxR type. PAS domain, a signal module that monitors changes in light, redox potential, oxygen energy level of a cell, and small ligands was first found in eukaryotes and was named after homology to the Drosophila period protein (Per), the aryl hydrocarbon receptor nuclear translocator protein (ARNT), and the Drosophila single-minded protein (Sim) [8]. Similar to other families, the PAS-LuxR family regulators control secondary metabolic processes by influencing the transcription of functional genes. However, considering the presence of PAS, this regulator may play a regulatory role by sensing extracellular environmental changes. In addition, in terms of regulatory mode, the binding site of PAS-LuxR regulators contains a 16-bp palindrome-like region and adjusts to the consensus CTVGGGAWWTCCCBAG (V represents A, C, or G; W stands for A or T; B stands for C, G, or T), which is located in the -35 region in promoters of the regulated genes [9].