The Bacterial Heterotrimeric Amidotransferase GatCAB: functions, structures and mechanism-based inhibitors

Abstract

<small>tRNA-dependent amidotransferases (AdT) are essential enzymes for protein biosynthesis in many bacteria and in all archaea. As AdT is essential for a number of pathogenic bacteria, and it is absent from mammalian cytoplasm, it is considered as a putative target for novel inhibitors that could be lead compounds to develop a new class of antibiotics. Besides GatFAB of <em><em>Saccharomyces cerevisiae</em></em> mitochondria and GatAB of <em><em>Plasmodium falciparum</em></em> apicoplast, all reported AdT can be divided into two groups: heterodimeric GatDE and heterotrimeric GatCAB. The latter is required to catalyze the conversion of Glu-tRNA^{^Gln} and/or Asp-tRNA^{^Asn} into ^Gln-tRNA^Gln and/or ^Asn-tRNA^Asn in many pathogenic bacteria. Recently determined high resolution crystal structures of several GatCAB could be used to design new inhibitors. In this review, we highlight the essential role of AdT for the faithful translation of glutamine and/or asparagine codons, we describe important features of the crystal structures of several GatCAB as well as tRNA/AdT/aaRS complexes for the formation of ^Gln-tRNA^Asn and ^Asn-tRNA^Asn, we finally summarize discoveries of AdT inhibitors based on their analogy to glutamine, adesosine tripoliphosphate and 3’-end of tRNA.</small