Abstract
Polyketide synthases (PKS) catalyze stepwise condensation reactions of small carboxylic acid units to form structurally diverse natural products. The products, mainly found from microorganisms and plant, possess a wide range of important agriculture and pharmaceutical applications. PKS-encoding genes, located closely as a cluster, have been mined for immense information about polyketide biosynthesis and its regulation mechanisms. With the endeavor on genome projects, the increased availability of PKS gene data has enabled to discover new bioactive compound and to explore polyketide biosynthetic manner. The focus of the present thesis was the exploration the interrelationships between the fungal type I PKS genes, proteins and the corresponding metabolite structures from evolutionary perspectives. We created a wiki-based database to accommodate our publicly accessible and manually curated PKS gene data. With more than 400 PKS gene data in the database, we conducted a phylogenomic approach to investigate the distribution of iterative PKS genes from eight sequenced Aspergilli and other fungi. Their genealogy by the conserved ketosynthase (KS) domain unveiled the clear phylogenetic classification within three large groups of non-reducing PKS, two partial-reducing PKS groups nested with bacterial PKSs and PKS-nonribosomal peptide synthase (NRPS) respectively, and more than 10 small groups of reducing PKSs. In addition, polyphyly of PKS-NRPS hybrid genes raised questions regarding the recruitment of the elegant conjugation machinery. Overall, high rates of gene duplication and divergence for type I PKSs were frequent. In order to design a more efficient and easier genetically manipulated heterologous system for the expression of fungal PKS genes, we addressed the genetic robustness mechanism in yeast. Especially, we focused on the exploration on the role of transcriptional compensation in genetic robustness. A set of non-homologous synthetic-lethal gene pairs was assessed with various type data in yeast. We considered the functional buffering of non-homologous genes can be characterized by three features: (i) synthetic-lethal interaction, (ii) the ratio of shared common interacting partners, and (iii) the degree of co-regulation. The results also suggested that transcriptional reprogramming may plays a limited role in functional compensation among non-homologous genes. As stated above, our assessment aids in understanding the phylogenetic relationship of fungal PKSs and the mechanism of functional compensation in yeast. The PKS wiki-database will further integrate various types of polyketide information and facilitate the identification and the application of new bioactive products.