Mechanism of chiral proofreading during translation of the genetic code

摘要

Amino acids are ‘chiral’ molecules that come in two different forms, called D and L, which are mirror images of each other, similar to how our left and right hands are mirror images of each other. However, only one of these forms is used to make proteins the more abundant L-amino acids are linked together to make proteins, whereas the scarcer D-amino acids are not. This ‘homochirality’ is common to all life on Earth. The molecular machinery inside cells that manufactures proteins involves many enzymes that carry out different tasks. Among these is an enzyme called DTD (short for D-aminoacyl-tRNA deacylase), which prevents D-amino acids being incorporated into proteins. To do this, DTD must be able to recognise and remove the D forms of many different amino acids before they are taken to the growing protein by transfer RNA molecules. However, the details of this process are not fully understood. To investigate this mechanism, Ahmad et al. made crystals of the DTD enzyme in complex with a molecule that mimics a D-amino acid attached to a transfer RNA molecule. By studying this structure at a high resolution, Ahmad et al. were able to identify how the active site of DTD can specifically accommodate the ‘chiral centre’ of a complex made of a D-amino acid and a transfer RNA molecule. DTD is able to recognize D-amino acids because of a critical dipeptide that is inserted from one subunit of the DTD into the active site of another subunit of the enzyme. The effect of this dipeptide is to generate a binding pocket that is a perfect fit for the chiral centre of a complex that contains a D-amino acid and a transfer RNA molecule. Moreover, this pocket specifically excludes complexes that contain an L-amino acid. The crucial parts of DTD that form the binding pocket are highly conserved—that is, they are the same in a wide variety of organisms, from bacteria to mammals. This conservation suggests that DTD is crucial for ensuring homochirality throughout all forms of life. Intriguingly, DTD is particularly highly expressed in neurons which are abundant in D-amino acids this indicates that the DTD enzyme has an important physiological role, which will certainly be the focus of future work.