**1. Introduction**

Polyketides, a large group of secondary metabolites, are known to possess remarkable variety, not only in their structure, and but also in their function [1,2]. Polyketides exhibit a wide range of bioactivities such as antibacterial (e.g., tetracycline), antifungal (e.g., amphotericin B), anticancer (e.g., doxorubicin), antiviral (e.g., balticolid), immune-suppressing (e.g., rapamycin), anti-cholesterol (e.g., lovastatin), and anti-inflammatory activity (e.g., flavonoids) [3–9]. Some organisms can produce polyketides such as bacteria (e.g., tetracycline from *Streptomyces aureofaciens*) [10], fungi (e.g., lovastatin from *Phomopsis vexans*) [11], plants (e.g., emodin from *Rheum palmatum*) [12], protists (e.g., maitotoxin-1 from *Gambierdiscus australes*) [13], insects (e.g., stegobinone from *Stegobium paniceum*) [14], and mollusks (e.g., elysione from *Elysia viridis*) [15]. These organisms could use the polyketides they produce as protective compounds and for pheromonal communication in the case for insects.

Since the beginning of the 1940s, the history of antibiotics has greatly related to microorganisms. One of the groups of bacteria that produce many important antibiotics is Actinobacteria. Actinobacteria are Gram-positive, have high GC content, and comprise various genera known for their secondary metabolite production, such as *Streptomyces*, *Micromonospora*, *Kitasatospora*, *Nocardiopsis*, *Pseudonocardia*, *Nocardia*, *Actinoplanes*, *Saccharopolyspora*, and *Amycolatopsis* [16,17]. Their most important genus is *Streptomyces*, which has a filamentous form like fungi and has become a source of around two-thirds of all known natural antibiotics [18]. Among the antibiotics produced by *Streptomyces*, polyketides are one group of the very important compounds. Some examples of polyketides produced by *Streptomyces* are rapamycin (produced by *Streptomyces hygroscopicus*), oleandomycin (produced by *Streptomyces*

*antibioticus*), actinorhodin (produced by *Streptomyces coelicolor*A3(2)), daunorubicin (produced by *Streptomyces peucetius*) and caprazamycin (produced *by Streptomyces* sp. MK730-62F2) [19–23].

Biosynthesis of polyketides is very complex because the process involves multifunctional enzymes called polyketide synthases (PKSs). The mechanism of PKS is similar to fatty acid synthase (FAS). The process includes many enzymatic reactions with different enzymes such as acyltransferase (AT), which has a role in catalyzing the attachment of the substrate (e.g., acetyl or malonyl) to the acyl carrier protein (ACP), and ketosynthase (KS), which catalyzes the condensation of substrates attached in ACP. After condensation of the substrates, the reaction continues by incorporating ketoreductase (KR), which reduces keto ester, dehydratase (DH), which dehydrates the compound, and enoylreductase (ER), which reduces the carbon-carbon double bond in the molecule (Figure 1). Unlike in FAS, the process catalyzed by KR, DH, and ER is optional in PKSs, which can give the various structures of polyketides with keto groups, hydroxy groups, and/or double bonds in different locations of the molecule [24–26]. In *Streptomyces*, there are three types of PKSs (type I, type II, and type III) [27–29]. This review describes the biosynthesis of polyketides in *Streptomyces* with three distinct types of PKSs. The focus is only on the *Streptomyces* genus because it is one of the most important producers of bioactive compounds and one of the most well-studied microbes in terms of polyketide biosynthesis. To the best of our knowledge, this is the first review that describes the three types of PKSs that are involved in the biosynthesis of polyketides in *Streptomyces*.

**Figure 1.** Scheme of the reaction occurring in polyketide synthases (PKSs). ACP, acyl carrier protein; AT, acyltransferase; KS, ketosynthase; KR, ketoreductase; DH, dehydratase; ER, enoylreductase. Adapted with permission of Portland Press, from Vance, S.; Tkachenko, O.; Thomas, B.; Bassuni, M.; Hong, H.; Nietlispach, D.; Broadhurst, W. Sticky swinging arm dynamics: studies of an acyl carrier protein domain from the mycolactone polyketide synthase. *Biochem. J.* **2016**, *473*, 1097–1110 [30].
