Aminoacyl-tRNA synthetases

Abstract

The aminoacyl-tRNA synthetases are an essential and universally distributed family of enzymes that plays a critical role in protein synthesis, pairing tRNAs with their cognate amino acids for decoding mRNAs according to the genetic code. Synthetases help to ensure accurate translation of the genetic code by using both highly accurate cognate substrate recognition and stringent proofreading of noncognate products. While alterations in the quality control mechanisms of synthetases are generally detrimental to cellular viability, recent studies suggest that in some instances such changes facilitate adaption to stress conditions. Beyond their central role in translation, synthetases are also emerging as key players in an increasing number of other cellular processes, with far-reaching consequences in health and disease. The biochemical versatility of the synthetases has also proven pivotal in efforts to expand the genetic code, further emphasizing the wide-ranging roles of the aminoacyl-tRNA synthetase family in synthetic and natural biology.

Keywords: aminoacyl-tRNA synthetases; protein translation; tRNA.

FIGURE 1.

The aminoacylation reaction. In the first step (A), the amino acid (blue) is activated with ATP (red) in the synthetase active site (not depicted), forming the aminoacyl-AMP and releasing PP_i. (B) The amino acid is transferred to the tRNA (green) and AMP is released (depicted in the image transfer to the 3′-OH characteristic of class I aaRS, while in class II transfer happens at the 2′-OH with a 3′-OH attack in the second step).

FIGURE 2.

Indirect aminoacylation pathways. (A) Asn and Gln. tRNA^Asn is mysaspartylated by a ND-AspRS. The resultant Asp-tRNA^Asn is converted to Asn-tRNA^Asn by the glutamine-dependent amidotransferase (AdT). The process is similar for Gln-tRNA^Gln. (B) Cysteine. tRNA^Cys is charged with O-phosphoserine by dedicated synthetases and further modified to cysteine by SepCysS to yield Cys-tRNA^Cys. (C) Selenocysteine. SelA (Bacteria) or PSTK followed by Sep-tRNA:Sec-tRNA synthase (Archaea and Eukarya) modify a previously charged SertRNA^Sec from serine to selenocysteine.

FIGURE 3.

The editing pathways. Schematic overview of the editing pathways used by the synthetases. In the figure above, the events are in italics, while the editing paths are in bold. The pathways are divided between pretransfer and posttransfer pathways. In the pretransfer editing, the activated noncognate aminoacyl-adenylate may be released from the enzyme and hydrolyze spontaneously or be edited within the active site or a specialized active site. Upon transfer to the tRNA, the aminoacyl-tRNA can be translocated to the editing site or released and cleared by a dedicated trans-editing factor. The cognate aminoacyl-tRNA binds the elongation factors and proceeds to translation in the ribosome.

FIGURE 4.

The multisynthetase complex. Schematic representation of the multisynthetase complex showing the differences of complexity between mammalian (A) and yeast (B). Mammalian MSC is a massive complex composed of nine synthetases and three accessory proteins, while the yeast counterpart is composed of two synthetases and a connecting protein. For the sake of simplicity, interactions are not shown; neither is the possible homodimerization of some of the components. The spatial arrangements and sizes of the components do not necessarily reflect their relative positions in the complexes.