Catalytic potential of a fungal indole prenyltransferase toward β-carbolines, harmine and harman, and their prenylation effects on antibacterial activity

The prenylation of compounds has attracted much attention, since it often adds bioactivity to non-prenylated compounds. We employed an enzyme assay with CdpNPT, an indole prenyltransferase from Aspergillus fumigatus with two naturally occurring β-carbolines, harmine (3) and harman (4) as prenyl acceptors, in the presence of dimethylallyl diphosphate (DMAPP) as the prenyl donor. The enzyme accepted these two prenyl acceptor substrates to produce 6-(3′,3′-dimethylallyl)harmine (5) from 3 and 9-(3′,3′-dimethylallyl)harman (6) and 6-(3′,3′-dimethylallyl)harman (7) from 4. The X-ray crystal structure analysis of the CdpNPT (38–440) truncated mutant complexed with 4, and docking simulation studies of DMAPP to the crystal structure of the CdpNPT (38–440) mutant, suggested that CdpNPT could employ the two-step prenylation mechanism to produce 7, while the enzyme produced 6 with either one- or two-step prenylation mechanisms. Furthermore, the antibacterial assays revealed that the 3′,3′-dimethylallylation of 3 and 4, as well as harmol (1), at C-6 enhanced the activities against Staphylococcus aureus and Bacillus subtilis.