# Recent Advances in the Heterologous Biosynthesis of Natural Products from _Streptomyces_
## 1 Introduction  
_Streptomyces_ is a group of filamentous, Gram-positive bacteria with a high GC (guanine-cytosine) content in their genomes. The secondary metabolites or natural products of _Streptomyces_, such as antibiotic, anticancer, antitumor, antiviral, and immune suppressive compounds, are some of the industrially important compounds that are used for biotechnological applications [1]. _Streptomyces_ is the main source of novel secondary metabolites, including polyketides, peptides, terpenoids, alkaloids, and saccharides [2, 3, 4, 5, 6]. Some natural secondary metabolites from _Streptomyces_ are shown in Figure 1.  
Figure 1: Natural secondary metabolites synthesized in _Streptomyces_: avermectin, pentalene from _Streptomyces avermitilis_[2,7], doxorubicin and geosmin from _Streptomyces peucetius_ ATCC 27952 [8,9], oxazolomycin from _Streptomyces albus_ JA3453 [10], germicidin from _Streptomyces livalians_ TK24 [11], isoaficanol from _Streptomyces malasisensis_[4], echinomycin from _Streptomyces lasiliensis_ ATCC 35851 [12], bosamycin from _Streptomyces_ sp. 120454 [3], cyclizidine from _Streptomyces_ sp. HNA39 [13], legoinimide from _Streptomyces_ sp. CT37 [6], avilamycin from _Streptomyces viridochromogenes_ Tu57 [5,14], and hygromycin from _Streptomyces hygroscopic_[15]. Previous studies showed that natural products have greater chemical diversity and a more extensive chemical space than synthetic compounds [16]. The structure of natural products is also more complex than the structure of synthetic compounds. Therefore, natural products are useful templates for developing relevant bioactive compound classes [17]. Many chemical synthetic drugs cause several side effects when curing disease. In contrast, natural products are produced by living cells and they may avoid the side effects caused by synthetic drugs [18]. Furthermore, bacterial resistance emerges as a current problem for treatment; therefore, discovering novel drugs is required and the exploration of natural products is one solution [19]. Genome sequences and genome mining revealed that _Streptomyces_ contains many secondary metabolite biosynthetic gene clusters (BGCs); however, some BGCs of native strains are silent or cryptic under laboratory conditions [20]. The heterologous expression is a powerful strategy for discovering uncharacterized BGCs or increasing the production of many secondary metabolites BGCs. For example, hybrubins were successfully explored via the heterologous expression of the _hbn_ BGC from _Streptomyces variabilis_ Snt24 in _S. Iividans_ SBT5 [21]. The yield of pikromycin from the heterologous expression in _S. Iividans_ TK21 showed a 2.1-fold increase compared to the production of pikromycin from the parental _Streptomyces__venzeuelae_ ATCC 15439 [22]. The BGCs vary in size from a small size to large sizes, such as 12 kb for the kocurin BGC [23], 60 kb for the pikromycin BGC [22], 65 kb for the daptomycin BGC [24], 90 kb for the meridamycin BGC [25], and 141 kb for the vancomycin BGC [26]. Depending on the size of the BGC, several cloning methods and vector systems have been developed for the heterologous expression of BGCs. Many techniques are applied for cloning target BGCs, such as the Gibson assembly [27], site-specific recombination-based tandem assembly (SSRTA) [28], the bacterial artificial chromosomal (BAC) system [2], and the transformation-associated recombination (TAR) system [29]. The selection of hosts and other elements for heterologous expression depends on the targeted products. In this review, we provide insight into the systematic approach for the heterologous production of secondary metabolites from _Streptomyces_ in _Streptomyces_ and other hosts, such as _Escherichia coli_, _Pseudomonas putida_, _Saccharomyces cerevisiae_, _Bacillus subtilis_, _Corynebacterium glutamicum_, and _Rhodococcus erythropopis_. The tools for genome analysis assist with precisely identifying and cloning BGCs.