From molecular genetics and secondary metabolism to molecular metabolites and secondary genetics

Secondary metabolites constitute a huge array of low molecular weight natural products that cannot be easily defined. Largely produced by bacteria, fungi, and green plants, they tend to be synthesized after active growth has ceased, in families of similar compounds, often at the same time as species-specific morphological characters become apparent. Although, in many cases, the function that the secondary metabolite performs in the producing organism is unknown, the bioactivity of these compounds has been exploited since prehistoric times as drugs, poisons, food flavoring agents, and so forth. In fungi, the polyketide family is the largest known group of secondary metabolite compounds. Polyketides are synthesized from acetate by a mechanism analogous to fatty acid biosynthesis but involving changes in oxidation level and stereochemistry during the chain-elongation process. The fungal polyketide biosynthetic pathways for aflatoxin and patulin have emerged as model systems. The use of blocked mutants has been an essential part of the research approach for both pathways. Molecular methods of studying fungal secondary metabolites were first used with penicillin and cephalosporin, both of which are amino acid derived. Most of the basic molecular work on polyketides was done with streptomycete-derived compounds; however, enough fungal data are now available to compare fungal and streptomycete polyketide synthases, as well as to map the genes involved in a number of polyketide pathways from both groups. The traditional dogma, derived from classical genetics, that genes for fungal pathways are unlinked, has been overturned. In addition, cloning of structural genes facilitates the formation of hybrid molecules, and we are on the brink of understanding certain regulatory functions. Key words: fungal metabolism, secondary metabolism, polyketide, β-lactam, product discovery.