13 research outputs found
Synthesis and decoding of selenocysteine and human health
Selenocysteine, the 21st amino acid, has been found in
25 human selenoproteins and selenoenzymes important
for fundamental cellular processes ranging from selenium
homeostasis maintenance to the regulation of the overall
metabolic rate. In all organisms that contain selenocysteine,
both the synthesis of selenocysteine and its incorporation
into a selenoprotein requires an elaborate synthetic and
translational apparatus, which does not resemble the canonical
enzymatic system employed for the 20 standard
amino acids. In humans, three synthetic enzymes, a specialized
elongation factor, an accessory protein factor, two
catabolic enzymes, a tRNA, and a stem-loop structure in
the selenoprotein mRNA are critical for ensuring that only
selenocysteine is attached to selenocysteine tRNA and that
only selenocysteine is inserted into the nascent polypeptide
in response to a context-dependent UGA codon. The
abnormal selenium homeostasis and mutations in selenoprotein
genes have been causatively linked to a variety of
human diseases, which, in turn, sparked a renewed interest
in utilizing selenium as the dietary supplement to either
prevent or remedy pathologic conditions. In contrast, the
importance of the components of the selenocysteine-synthetic
machinery for human health is less clear. Emerging
evidence suggests that enzymes responsible for selenocysteine
formation and decoding the selenocysteine UGA
codon, which by extension are critical for synthesis of the
entire selenoproteome, are essential for the development
and health of the human organism
Synthesis and decoding of selenocysteine and human health
Selenocysteine, the 21st amino acid, has been found in
25 human selenoproteins and selenoenzymes important
for fundamental cellular processes ranging from selenium
homeostasis maintenance to the regulation of the overall
metabolic rate. In all organisms that contain selenocysteine,
both the synthesis of selenocysteine and its incorporation
into a selenoprotein requires an elaborate synthetic and
translational apparatus, which does not resemble the canonical
enzymatic system employed for the 20 standard
amino acids. In humans, three synthetic enzymes, a specialized
elongation factor, an accessory protein factor, two
catabolic enzymes, a tRNA, and a stem-loop structure in
the selenoprotein mRNA are critical for ensuring that only
selenocysteine is attached to selenocysteine tRNA and that
only selenocysteine is inserted into the nascent polypeptide
in response to a context-dependent UGA codon. The
abnormal selenium homeostasis and mutations in selenoprotein
genes have been causatively linked to a variety of
human diseases, which, in turn, sparked a renewed interest
in utilizing selenium as the dietary supplement to either
prevent or remedy pathologic conditions. In contrast, the
importance of the components of the selenocysteine-synthetic
machinery for human health is less clear. Emerging
evidence suggests that enzymes responsible for selenocysteine
formation and decoding the selenocysteine UGA
codon, which by extension are critical for synthesis of the
entire selenoproteome, are essential for the development
and health of the human organism
Peptidyl-CCA deacylation on the ribosome promoted by induced fit and the O3′-hydroxyl group of A76 of the unacylated A-site tRNA
The last step in ribosome-catalyzed protein synthesis is the hydrolytic release of the newly formed polypeptide from the P-site bound tRNA. Hydrolysis of the ester link of the peptidyl-tRNA is stimulated normally by the binding of release factors (RFs). However, an unacylated tRNA or just CCA binding to the ribosomal A site can also stimulate deacylation under some nonphysiological conditions. Although the sequence of events is well described by biochemical studies, the structural basis of the mechanism underlying this process is not well understood. Two new structures of the large ribosomal subunit of Haloarcula marismortui complexed with a peptidyl-tRNA analog in the P site and two oligonucleotide mimics of unacylated tRNA, CCA and CA, in the A site show that the binding of either CA or CCA induces a very similar conformational change in the peptidyl-transferase center as induced by aminoacyl-CCA. However, only CCA positions a water molecule appropriately to attack the carbonyl carbon of the peptidyl-tRNA and stabilizes the proper orientation of the ester link for hydrolysis. We, thus, conclude that both the ability of the O3′-hydroxyl group of the A-site A76 to position the water and the A-site CCA induced conformational change of the PTC are critical for the catalysis of the deacylation of the peptidyl-tRNA by CCA, and perhaps, an analogous mechanism is used by RFs
The Mechanism of Pre-transfer Editing in Yeast Mitochondrial Threonyl-tRNA Synthetase
Background: The mechanism of pre-transfer
editing by which aaRSs regulate translational
fidelity is not well understood.
Results: Yeast mitochondrial ThrRS, MST1,
hydrolyzes seryl adenylate at the aminoacylation
active site more rapidly than the cognate
threonyl adenylate.
Conclusion: MST1 discriminates against serine
and reduces mischarging of threonine tRNA by
employing pre-transfer editing.
Significance: The mechanism of misactivation
and pre-transfer editing of serine by ThrRS is
provided
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Human SepSecS or SLA/LP: selenocysteine formation and autoimmune hepatitis
Selenocysteine, the 21st genetically encoded amino acid, is the major form of the antioxidant trace element selenium in the human body. In eukaryotes and archaea its synthesis proceeds through a phosphorylated intermediate in a tRNA-dependent fashion. The final step of selenocysteine formation is catalyzed by O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS) that converts phosphoseryl-tRNASec to selenocysteinyl-tRNASec. The human SepSecS protein is also known as soluble liver antigen/liver pancreas (SLA/LP), which represents one of the antigens of autoimmune hepatitis. Here we review the discovery of human SepSecS and the current understanding of the immunogenicity of SLA/LP in autoimmune hepatitis