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Genetic analysis of the biosynthesis of pharmaceutically important dihydroergot alkaloids by heterologous expression of Claviceps gigantea genes in the fungus Neosartorya fumigata Ergot alkaloids are a family of secondary metabolites produced by several species of fungi. The structural similarities of ergot alkaloids to neurotransmitters give them the ability to help treat several neurological and cognitive diseases, such as dementia, Alzheimer’s and Parkinson’s disease. These pharmaceuticals are currently being synthesized from more complex ergot alkaloids, however they would be more efficiently synthesized from dihydroergot alkaloids. Understanding the genes involved in the synthesis of dihydroergot alkaloids, such as dihydrolysergol and dihydrolysergic acid, and elucidating their pathways will be beneficial. The Mexican maize ergot pathogen Claviceps gigantea has been reported to produce dihydrolysergol, which is an oxidized product of the precursor ergot alkaloid festuclavine. Due to the discovery of an ergot alkaloid synthesis gene, cloA, catalyzing multiple oxidations on a similar substrate, it was hypothesized that expression of C. gigantea cloA in a festuclavine-accumulating mutant of the model fungus Neosartorya fumigata would yield dihydrolysergol. HPLC and LC-MS analyses of the cloA transformed strains, demonstrated that the modified strain produced dihydrolysergic acid, the fully oxidized product of dihydrolysergol. Since dihydrolysergol was expected to be the pathway end product of C. gigantea, the genomic sequence data was analyzed and extracts of fieldgrown C. gigantea. The natural alkaloid analysis results supported the finding that dihydrolysergic acid is the end product of the C. gigantea pathway, rather than dihydrolysergol. C. gigantea is the first organism demonstrated to produce the pharmaceutically important compound dihydrolysergic acid as its pathway end product and heterologous expression of its cloA gene may serve as the basis of a more efficient approach to production of DHLA for pharmaceutical purposes. Additional attempts to increase the yield of dihydrolysergic acid in our modified strain, such as removal of introns, expression from an alternative promoter, and coexpression with an additional ergot alkaloid synthesis gene, easA, were conducted. The removal of introns and the alternative promoter had no significant effect on the yield of dihydrolysergic acid compared to the original cloA transformants in ANOVA (p = 0.58 and p = 0.76). However, the mutants expressing cloAeasA had conversion rates two-fold higher than the mutants expressing cloA (p = 0.01). The data illustrate that CloA of C. gigantea catalyzes a six-electron oxidation of festuclavine to dihydrolysergic acid.

Genetic Analysis of the Biosynthesis of Pharmaceutically Important Dihydroergot Alkaloids by Heterologous Expression of Claviceps gigantea Genes in the Fungus Neosartorya fumigata