The red flour beetle (Tribolium castaneum) is one of the most common secondary pest of all grain commodities in the world. It has been held responsible for up to 20% of all grain storage contamination in the US, with this number rising to up to 50% in third world countries. This large-scale destruction results in substantial economic damage due to loss of the market price of product and decreased nutritional value. So far, against an arsenal of chemical species, this insect has avoided all attempts of control. One possible route to develop a novel type of insecticide for T. castaneum is based on the study of arylalkylamine N-acyltransferases (AANATs). These promiscuous enzymes (members of the GCN5-related N-acetyltransferase (GNAT) family) catalyze the N-acylation of biogenic amines to form N-acylarylalkylamines, and are vital to T. castaneum as they are involved in melanism, biogenic amine excretion, as well as hardening of the cuticle. In addition, the N-acylarylalkylamines have been suggested to act as potent neurotransmitters. For example, the acylation of serotonin is the rate limiting step in circadian rhythm. An AANAT-targeted insecticide would not only disrupt neural signaling, but would also inhibit cuticle development, decrease the structural stability, result in a non-conforming appearance (harming the insects’ ability to mate), and diminish the cuticle-mediated protection against injury and infection. Presented here is a mechanistic analysis , which was determined to catalyze the formation of short-chain N-acylarylalkylamines, with acetyl CoA functioning in the role of acyl-donor via an ordered sequential mechanism. Also presented is the first crystal structure of AANAT from T. castaneum, bound to acetyl CoA. These combined data not only gives new insight into the chemical mechanism behind this family of enzymes, but also confirms the hypothesis that despite high structural homology between AANATs from different organisms, a low sequence homology means insecticides could potentially be tailor-made to attack a particular insect, while quelling damage on other organisms.

Novel target for insecticide design: Mechanistic and structural analysis of arylalkylamine N-acetyltransferase from the red flour beetle

256th National Meeting (2018)

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