Chemical analyses of three lysergic acid amide-producing Aspergillus species and sequences for phylogenetic analyses of associated enzymes

Ergot alkaloids derived from lysergic acid have impacted humanity as
contaminants of crops and as the bases of pharmaceuticals prescribed to
treat dementia, migraines, and other disorders. Several plant-associated
fungi in the Clavicipitaceae produce lysergic acid derivatives, but many
of these fungi are difficult to culture and manipulate. Some Aspergillus
species, which may be more ideal experimental and industrial organisms,
contain an alternate branch of the ergot alkaloid pathway but none were
known to produce lysergic acid derivatives. We mined genomes of
Aspergillus species for ergot alkaloid synthesis (eas) gene clusters and
discovered three species––A. leporis, A. homomorphus, and A.
hancockii––had eas clusters indicative of the capacity to produce a
lysergic acid amide. In culture, A. leporis, A. homomorphus, and A.
hancockii produced lysergic acid amides, predominantly lysergic acid
α-hydroxyethylamide (LAH). Aspergillus leporis and A. homomorphus produced
high concentrations of LAH and secreted most of their ergot alkaloid yield
into the culture medium. Phylogenetic analyses indicated genes encoding
enzymes leading to the synthesis of lysergic acid were orthologous to
those of the lysergic acid amide-producing Clavicipitaceae; however, genes
to incorporate lysergic acid into an amide derivative evolved from
different ancestral genes in the Aspergillus species. Our data demonstrate
fungi outside the Clavicipitaceae produce lysergic acid amides and
indicate the capacity to produce lysergic acid evolved once, but the
ability to insert it into LAH evolved independently in Aspergillus species
and the Clavicipitaceae. The LAH-producing Aspergillus species may be
useful for study and production of these pharmaceutically important
compounds.