Insect Arylalkylamine N-Acyltransferases: Mechanism and Role in Fatty Acid Amide Biosynthesis

Abstract

Arylalkylamine N-acyltransferases (AANATs) catalyze the formation of an N-acylamide from an acyl-CoA thioester and an amine. One well known example is the production of N-acetylserotonin from acetyl-CoA and serotonin, a reaction in the melatonin biosynthetic pathway from tryptophan. AANATs have been identified from a variety of vertebrates and invertebrates. Considerable efforts have been devoted to the mammalian AANAT because a cell-permeable inhibitor specifically targeted against this enzyme could prove useful to treat diseases related to dysfunction in melatonin production. Insects are an interesting model for the study of AANATs because more than one isoform is typically expressed by a specific insect and the different insect AANATs (iAANATs) serve different roles in the insect cell. In contrast, mammals express only one AANAT. The major role of iAANATs seem to be in the production of N-acetyldopamine, a reaction important in the tanning and sclerotization of the cuticle. Metabolites identified in insects including N-acetylserotonin and long-chain N-fatty acyl derivatives of dopamine, histidine, phenylalanine, serotonin, tyrosine, and tryptophan are likely produced by an iAANAT. In vitro studies of specific iAANATs are consistent with this hypothesis. In this review, we highlight the current metabolomic knowledge of the N-acylated aromatic amino acids and N-acylated derivatives of the aromatic amino acids, the current mechanistic understanding of the iAANATs, and explore the possibility that iAANATs serve as insect “rhymezymes” regulating photoperiodism and other rhythmic processes in insects.

Gcn5-Related N-Acetyltransferases (GNATs) With a Catalytic Serine Residue Can Play Ping-Pong Too

“…Here, we showed this residue is critical for catalysis when either NANMO or polymyxin B are substrates. It has been suggested that serine can act as a general acid in other GNATs ( O’Flynn et al, 2018 ), but its high pKa makes it highly unlikely to act in this capacity. Based on the crystal structure of PA3944, there are no other residues in the active site that could act as a general acid and the only viably positioned residue that could act as a general base is E102.…”

“…Contrary to this perspective, several members of the GNAT superfamily actually utilize a range of catalytic mechanisms. For example, substrate-assisted catalysis has been proposed for some GNATs whereby the CoA thiolate or CoA adenine participates in the catalytic mechanism ( Farazi et al, 2001 ; O’Flynn et al, 2018 ). More intricate residue interactions have also been suggested in the cases of aminoglycoside acetyltransferase AAC(3′)-VIa and dopamine acetyltransferase (DAT).…”

“…Nevertheless, S205 in PaNAT appears equivalent to S148 in PA3944 and could conceivably act as a nucleophile. It should be noted that this serine is strictly conserved in the iAANATs as well but these enzymes utilize a proton wire catalytic mechanism ( O’Flynn et al, 2018 ). Therefore, the role of the conserved serine residue in catalysis is not pre-ordained strictly by conservation.…”

Anopheles metabolic proteins in malaria transmission, prevention and control: a review

“…Unlike humans that have one aaNAT, insects have multiple aaNAT, one of which is dopamine N-acetyltransferase (DAT) that is conserved in all insects. However, some aaNAT are insect specific (iaaNAT) and specific for certain genera and substrates, hence they can serve as possible targets for more specific insecticides [214]. O'Flynn et al [51] revealed that residues that make up the amine binding pocket and the CoA binding pocket of iaaNAT varied among different genera.…”

Knockdown of arylalkylamine N‐acetyltransferase‐like 2 in Drosophila melanogaster

“…Enzymes in the GNAT superfamily of N -acetyltransferases catalyze a similar reaction utilizing acetyl-CoA as the acyl-CoA donor to generate N -acetylamines (Ud-Din, Tikhomirova, & Roujeinikova, 2016; Vetting et al, 2005). Drosophila melanogaster produces FAAs (Jeffries et al, 2014; Tortoriello et al, 2013; Yoshinaga et al, 2007) and expresses a number of N -acetyl and N -acyltransferases (O’Flynn, Suarez, Hawley, & Merkler, 2018). Thus, D. melanogaster is a valuable model organism for the study of FAA biosynthesis.…”