Eukaryotic cytosolic and mitochondrial phenylalanyl-tRNA synthetases catalyze the charging of tRNA with the meta-tyrosine.
The accumulation of proteins damaged by reactive oxygen species (ROS), conventionally regarded as having pathological potentials, is associated with age-related diseases such as Alzheimer's, atherosclerosis, and cataractogenesis. Exposure of the aromatic amino acid phenylalanine to ROS-generating systems produces multiple isomers of tyrosine: m-tyrosine (m-Tyr), o-tyrosine (o-Tyr), and the standard p-tyrosine (Tyr). Previously it was demonstrated that exogenously supplied, oxidized amino acids could be incorporated into bacterial and eukaryotic proteins. It is, therefore, likely that in many cases, in vivo-damaged amino acids are available for de novo synthesis of proteins. Although the involvement of aminoacyl-tRNA synthetases in this process has been hypothesized, the specific pathway by which ROS-damaged amino acids are incorporated into proteins remains unclear. We provide herein evidence that mitochondrial and cytoplasmic phenylalanyl-tRNA synthetases (HsmtPheRS and HsctPheRS, respectively) catalyze direct attachment of m-Tyr to tRNA(Phe), thereby opening the way for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into eukaryotic proteins. Crystal complexes of mitochondrial and bacterial PheRSs with m-Tyr reveal the net of highly specific interactions within the synthetic and editing sites.
Klipcan
Liron
L
Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
Moor
Nina
N
Kessler
Naama
N
Safro
Mark G
MG
D055162:Biocatalysis; D020134:Catalytic Domain; D003600:Cytosol / Q000201:enzymology*; D005057:Eukaryotic Cells / Q000201:enzymology*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D010652:Phenylalanine-tRNA Ligase / Q000737:chemistry / Q000378:metabolism*; D017433:Protein Structure, Secondary; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism; D055672:Static Electricity; D013379:Substrate Specificity; D046249:Transfer RNA Aminoacylation; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*
D012346:RNA, Transfer, Amino Acyl; D014443:Tyrosine; C015566:3-tyrosine; D010652:Phenylalanine-tRNA Ligase