An Editing Activity That Prevents Mistranslation and Connection to Disease

Paul Schimmel

doi:10.1074/jbc.x800007200

Abstract

I believe that the genetic code was the greatest discovery of the 20th century (Fig. 1). The code was worked out during the period that I was a student: a medical student at Tufts University (I dropped out after a year), a graduate student at MIT and Cornell (with Gordon Hammes), and a postdoctoral student at Stanford University (with Paul Flory). My research as a student was centered on theoretical and experimental physical chemistry, as applied to biological systems. With Hammes, I had done a spectroscopic and thermodynamic analysis of ribonuclease and its interaction with one of its ligands. I also had done both experimental and theoretical analyses of kinetic relaxation spectroscopy, inspired in part by the pioneering work of Eigen, who himself had been a mentor of Hammes. (Eigen gave lectures at Cornell that I attended, and we spent time in conversation as well. In more recent years, we have seen each other on a regular basis and continued our conversations.) With Flory at Stanford, I worked on statistical mechanics of polypeptides. All of that graduate and postdoctoral work was exciting, particularly the mathematical side that I especially loved because of its elegance, rigor, and abstraction. However, while this sort of mental activity was going on, I kept thinking about the newly discovered genetic code and aminoacyl-tRNA synthetases.

Highlights

For each of the 20 amino acids, there is a separate enzyme and a family of isoaccepting tRNAs
This mouse is diminutive and has ataxia. It harbors a mutation in the editing site of alanyl-tRNA synthetase
Subtle errors of aminoacylation lead to pathologies caused by mistranslation (Fig. 4), i.e. the insertion into growing polypeptides of the wrong amino acid at a codon for valine (Fig. 2) or alanine (Fig. 3). (The erroneous insertion of amino acids into proteins synthesized in cells bearing an editing-defective tRNA synthetase was established by direct chemical and mass spectrometric analysis.) Significantly, the connection of defects in editing to pathology and disease came from years of work in simpler bacterial systems

Summary

Introduction

For each of the 20 amino acids, there is a separate enzyme and a family of isoaccepting tRNAs. REFLECTIONS: Editing Activity That Prevents Mistranslation that clears errors of aminoacylation.

Results

Conclusion