*3.4. Biosynthesis of Fredericamycin*

Fredericamycin, isolated from *Streptomyces griseus* ATCC 49344, is an aromatic polyketide that contains a spirocyclic structure. It has moderate antitumor and cytotoxic activity in various cell lines. These bioactivities are suggested because of the blockage of topoisomerases I and II or the peptidyl-prolyl cis-trans isomerase Pin1 [83].

The biosynthesis of fredericamycin employs the minimal type II PKSs that contains KSα (FdmF and FdmS), KSβ (FdmG), and ACP (FdmH). There are two alternative mechanisms for chain initiation in the biosynthesis of fredericamycin. The first one requires acetyl-CoA and two malonyl-CoAs to produce the hexadienyl-priming unit. The second mechanism is by utilizing butyryl- or crotonyl-CoA and one malonyl-CoA to yield the hexadienyl-priming unit. The next step is carried out by processing twelve malonyl-CoAs as extender units to give the pentadecaketide intermediate, and then, the cyclases and oxygenases modify the intermediate compound into the final product [82,83,86].

#### **4. Polyketide Synthases Type III**

Unlike the type I and type II PKSs, the type III PKSs do not utilize ACP as an anchor for the production of polyketide metabolite. In this case, acyl-CoAs are used directly as substrates for generating polyketide compounds. In order to create polyketides, this system contains enzymes that construct homodimers and catalyzes many reactions such as priming, extension, and cyclization in an iterative way. With this fact, the type III PKSs are the simplest structures among the other types of PKSs. The type III PKSs found in bacteria were reported the first time in1999, and before that time, the type III PKSs were known only to be detected in plants [87–89].

Some studies previously revealed that type III PKSs could also be identified in the *Streptomyces* such as RppA, found in *Streptomyces griseus*, which is responsible in the synthesis of 1,3,6,8-tetrahydroxynaphthalene (THN) [90]. Gcs, identified in *Streptomyces coelicolor* A3(2), is reported to have an important role in the biosynthesis of germicidin [91]. SrsA*,* encoded by the *srsA* gene and isolated from *Streptomyces griseus*, is known to have an important role in the biosynthesis of phenolic lipids, i.e., alkylresorcinols and alkylpyrones [29].

The type III PKS Ken2, isolated from *Streptomyces violaceoruber*, was suggested to be involved in the production of 3,5-dihydroxyphenylglycine (3,5-DHPG). This compound is a nonproteinogenic amino acid needed for the formation of kendomycin and several other glycopeptide antibiotics such as balhimycin, chloroeremomycin, and also vancomycin [92]. Cpz6, encoded by the *cpz6* gene and isolated from *Streptomyces* sp. MK730–62F2, was reported to be engaged in the biosynthesis of caprazamycins by producing a group of new triketidepyrenes (presulficidins) [93]. Moreover, another finding also suggested that DpyA catalyzes the formation of alkyldihydropyrones in *Streptomyces reveromyceticus* (Figure 7) [94].

**Figure 7.** Some compounds produced by type III PKSs.
