High diversity of polyketide synthase genes and the melanin biosynthesis gene cluster in Penicillium marneffei

Abstract

Despite the unique phenotypic properties and clinical importance of Penicillium marneffei, the polyketide synthase genes in its genome have never been characterized. Twenty‐three putative polyketide synthase genes and two putative polyketide synthase nonribosomal peptide‐synthase hybrid genes were identified in the P. marneffei genome, a diversity much higher than found in other pathogenic thermal dimorphic fungi, such as Histoplasma capsulatum (one polyketide synthase gene) and Coccidioides immitis (10 polyketide synthase genes). These genes were evenly distributed on the phylogenetic tree with polyketide synthase genes of Aspergillus and other fungi, indicating that the high diversity was not a result of lineage‐specific gene expansion through recent gene duplication. The melanin‐biosynthesis gene cluster had gene order and orientations identical to those in the Talaromyces stipitatus (a teleomorph of Penicillium emmonsii) genome. Phylogenetically, all six genes of the melanin‐biosynthesis gene cluster in P. marneffei were also most closely related to those in T. stipitatus, with high bootstrap supports. The polyketide synthase gene of the melanin‐biosynthesis gene cluster (alb1) in P. marneffei was knocked down, which was accompanied by loss of melanin pigment production and reduced ornamentation in conidia. The survival of mice challenged with the alb1 knockdown mutant was significantly better than those challenged with wild‐type P. marneffei (P < 0.005). The sterilizing doses of hydrogen peroxide, leading to a 50% reduction in survival of conidia, were 11 min for wild‐type P. marneffei and 6 min for the alb1 knockdown mutant of P. marneffei, implying that the melanin‐biosynthesis gene cluster contributed to virulence through decreased susceptibility to killing by hydrogen peroxide.

Unraveling the Molecular Basis of Temperature-Dependent Genetic Regulation in Penicillium marneffei

“…Six genes related to the biosynthesis of DHN-melanin were clustered together (60,61) and genetically regulated by the expression of brlA (64). Our previous study revealed the existence of this gene cluster in P. marneffei (22). RNA-seq data from this study showed that all six genes in the cluster are significantly downregulated at 37°C (Fig.…”

“…Only in the past decade have studies focused on the molecular mechanisms of phase transition with the application of novel genetic approaches in P. marneffei (20)(21)(22). To date, more than 40 P. marneffei genes have been cloned or experimentally characterized (23)(24)(25)(26)(27).…”

Characterization of a fungal thioesterase having claisen cyclase and deacetylase activities in melanin biosynthesis

“…The THN skeleton is synthesized by multidomain nonreducing iterative polyketide synthases (NR-PKSs). In some cases, melanin genes are clustered at one genetic locus, but they can also be dispersed throughout the genome (Woo, et al, 2010). Although nonessential, melanin pigments are important for survival and longevity.…”

Draft Genome Sequence of Penicillium marneffei Strain PM1

“…Genes encoding Mp1p homologues were identified and used for construction of a highly discriminative multilocus sequence typing scheme for P. marneffei (9). Twenty-three putative polyketide synthase (PKS) genes and two putative PKS-nonribosomal peptide synthase hybrid genes were identified, a diversity much higher than those of other pathogenic thermal dimorphic fungi, such as Histoplasma capsulatum (one PKS gene) and Coccidioides immitis (10 PKS genes) (11). Further in-depth analysis would uncover additional clues that explain the virulent and thermal dimorphic behaviors of this unique Penicillium species.…”