# Fungal Pigments and Their Roles Associated with Human Health
## 3 Biosynthesis of Fungal Pigments
### Polyktetide Synthetic Pathways  
The polyktetide synthetic pathway is involved in producing many fungal pigments with human health relevance. For example, there is increasing evidence that fungal pigments such as melanin, quinones, flavins, ankaflavin, and azaphilones, all relevant to human health [5; 6], involve the polyktetide synthesis pathway [86; 87]. This pathway has been studied in diverse fungal species, including those in the genera _Monascus_, _Fusarium_, _Alternaria_, and _Epicoccum_[64]. The core polyktetide synthetic pathway is shown in Figure 6. Fungal pigments are produced by this pathway via repetitive Claisen condensations of an acyl-coenzyme A (CoA) starting unit with malonyl-CoA elongation units in a manner analogous to fatty acid biosynthesis. The polyktetide pathway generates either aromatic ketides or fatty acids. The extending chain of the aromatic ketides is stabilized by cyclization reactions and partial reduction. However, in the fatty acids, the carbonyl groups of the chain are reduced prior to the addition of the next C\({}_{2}\) group. One of the major differences between the two metabolic routes is that polyktetides have varied degrees of \(\beta\)-keto processing. Specifically, some are not or only partially reduced, giving rise to the formation of (poly-)cyclic aromatic compounds. On the other hand, they may be significantly reduced, yielding linear or macrocyclic, non-aromatic carbon skeletons. Figure 5: Chemical structure of the pigment sclerootin produced by _Penicillium sclerootin_ 2 AV2. Figure 6: Mechanisms of fungal polyktetide biosynthesis. Aromatic ketides of this pathway include tetra-, hepta-, octa- and higher number ketides. Fungi possess a variety of pigments of the octaketide origin based on the anthra-9,10-quinone backbone with both rings being substituted. Anthraquinones are representatives of this type of pigment. In many cases anthraquinones are found in fungi in the corresponding colourless reductive states (anthranol, anthrone, anthrahydroquinone, and oxanthrone derivatives) that may be present in the forms of diverse glycoside conjugants. However, many naturally occurring, coloured anthraquinones are oligomers made by the coupling of two or more anthraquinone molecules. These oligomers differ in the number and positions from which monomers and amino acids are ligated to generate a diversity of fungal pigments [88; 89]. A large number of enzymes have been identified in the fungal polyketide synthesis pathway. These include a core set of enzymes, including ketosynthase (KS), acyl transferase (AT), and acyl carrier protein (ACP) domains. Further, optional \(\beta\)-keto processing steps may be catalyzed by keto reductase (KR), dehydatase (DH) and enoyl reductase (ER) domains. Other optional ancillary domains involve cyclase (CYC) [90] and methyl transferase (MT) activities [91]. Based on their architecture and the presence or absence of additional \(\beta\)-keto processing domains, fungal PKSs are categorized into non-reducing or aromatic (NR-PKS), partially reducing (PR-PKS), and highly reducing PKS (HR-PKS). The synthesized fungal polyketides can vary in their chain length, the degree of \(\beta\)-keto processing, and cyclization. Moreover, the tremendous structural diversity of polyketides is further obtained from derivatization of the polyketide carbon backbone by alkylation, acylation, and oxygenation, and by post-PKS modification or tailoring. Genome sequence analyses so far have revealed that all genes essential for fungal polyketide biosynthesis are clustered, including the PKS genes, genes encoding enzymes associated with tailoring, as well as regulatory genes [92]. While most fungal polyketide pigments are synthesized as aromatic ketides, the biosynthesis of azaphilones uses both the polyketide pathway and the fatty acid synthesis pathway.