Abstract
An important aspect of food security is the development of innovative insecticides, particularly ones that specifically target insect pests and exhibit minimal toxicity to mammals. The insect arylalkylamine N-acyltransferases (iAANATs) could serve as targets for novel insecticides that satisfy these criteria. There exists a wealth of structural and biochemical information for the iAANATs and iAANAT knockdown experiments show that these enzymes are critical to insect health. Herein, we have expressed, purified, and characterized two new iAANATs, one from Apis mellifera (honey bee, AmNAT1) and another from Diaphorina citri (Asian citrus psyllid, DcNAT). We discovered that diminazene, a compound used to treat livestock for trypanosomiasis and babesiosis, inhibits AmNAT1, DcNAT, and D. melanogaster DmAgmNAT with modest affinity, Ki values ranging from 0.8 μM to 200 μM. We found a series of guanidines, amidines, and a hydroxamate, structurally related to diminazene, also inhibit the iAANATs, including camostat, gabexate, nafamostate, and panobinostat. Significantly, we found DmAgmNAT is far more susceptible to inhibition by four of these five of these compounds. In particular, camostat, nafamostat, and gabexate inhibit DmAgmNAT with Ki values of 0.2-30 μM, but no inhibition of AmNAT1 and DcNAT was observed at 500 μM for any of the three. These results show that a species-specific inhibitor targeted against an iAANAT is a real possibility. Also, we report that adipoyl-CoA is a substrate for AmNAT1 and DcNAT and that succinoyl-CoA is a substrate for DcNAT. These results contribute to a growing body of data suggesting that N-dicarboxyacyl-amines are metabolites in insects and other organisms.
