6.1.1.5: isoleucine-tRNA ligase
This is an abbreviated version!
For detailed information about isoleucine-tRNA ligase, go to the full flat file.
Word Map on EC 6.1.1.5
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6.1.1.5
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synthetases
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aminoacyl-trna
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aminoacylation
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isoleucylation
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valyl-trna
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misactivated
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methionyl-trna
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leurs
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mischarged
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pseudomonic
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post-transfer
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noncognate
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valrs
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mupirocin-resistant
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misacylated
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anticodons
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aarss
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kmsks
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glnrs
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trna-dependent
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pretransfer
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lysyl-trna
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molecular biology
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medicine
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drug development
- 6.1.1.5
- synthetases
- aminoacyl-trna
- aminoacylation
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isoleucylation
- valyl-trna
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misactivated
- methionyl-trna
- leurs
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mischarged
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pseudomonic
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post-transfer
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noncognate
- valrs
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mupirocin-resistant
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misacylated
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anticodons
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aarss
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kmsks
- glnrs
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trna-dependent
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pretransfer
- lysyl-trna
- molecular biology
- medicine
- drug development
Reaction
Synonyms
EcIleRS, IARS2, Ile-tRNA synthetase, IleRS, ileS, ileS1, ileS2, IRS, Isoleucine translase, Isoleucine--tRNA ligase, Isoleucine-transfer RNA ligase, Isoleucine-tRNA synthetase, isoleucyl tRNA synthetase, Isoleucyl-transfer ribonucleate synthetase, Isoleucyl-transfer RNA synthetase, Isoleucyl-tRNA synthetase, mitochondrial isoleucyl-tRNA synthetase, More, mt isoleucyl-tRNA synthetase, mt-IleRS, Mupirocin resistance protein, ScIleRS, SgIleRS, Synthetase, isoleucyl-transfer ribonucleate
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General Information
General Information on EC 6.1.1.5 - isoleucine-tRNA ligase
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evolution
malfunction
physiological function
additional information
enzyme IleRS is a class I aaRS enzyme built around the conserved N-terminal Rossmann fold catalytic domain, which encloses the synthetic site. Phylogenetic analysis suggests that the ileS1 and ileS2 genes of contemporary bacteria are the descendants of genes that might have arisen by an ancient duplication event before the separation of bacteria and archaea. The accuracy of Ile-tRNAIle synthesis may be entirely ensured by the powerful post-transfer editing domain, which is absolutely conserved through evolution. The origin of discrimination against valine in the synthetic reaction is evolutionarily conserved in IleRS, overview
evolution
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phylogenetic analysis, the origin of discrimination against valine in the synthetic reaction is evolutionarily conserved in IleRS, overview
evolution
phylogenetic analysis, the origin of discrimination against valine in the synthetic reaction is evolutionarily conserved in IleRS, overview
evolution
the enzyme belongs to the class I amino acyl-tRNA synthetases (aaRS)
evolution
the enzyme belongs to the class I amino acyl-tRNA synthetases (aaRS)
evolution
Saccharomyces cerevisiae ATCC 204508 / S288c
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phylogenetic analysis, the origin of discrimination against valine in the synthetic reaction is evolutionarily conserved in IleRS, overview
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evolution
Streptococcus pneumoniae D39 / NCTC 7466
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the enzyme belongs to the class I amino acyl-tRNA synthetases (aaRS)
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constitutive high levels of mt isoleucyl-tRNA synthetase (mt-IleRS) are associated with reduced penetrance of the homoplasmic m.4277T>C mt-tRNAIle mutation, causing hypertrophic cardiomyopathy, which is paralleled by results in mutant transmitochondrial cybrids following overexpression of mt-IleRS. Interchangeable ability of three human mt-aaRS, namely mt-ValRS, mt-LeuRS and mt-IleRS, to suppress the mitochondrial functional defects associated with pathogenic homoplasmic mutations in mt-tRNAIle gene (MTTI). Transient overexpression of cognate mt-IleRS causes a 1.5fold increase in the viability of m.4277T>C MTTI mutant cybrids grown in galactose medium. The carboxy-terminal domain of human mt-leucyl-tRNA synthetase is both necessary and sufficient to improve the pathologic phenotype associated either with the mild mutations or with the severe m.3243A>G mutation in the mt-tRNALeu(UUR) gene. This small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNALeu(UUR) with high affinity and stability and, with lower affinity, with mt-tRNAIle
malfunction
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mutant ileS(T233P) allows tRNAIle mischarging while retaining wild-type Ile-tRNAIle synthesis activity. The growth rate of the ileS(T233P) strain BAL4571 is not significantly different from wild-type strain BAL4574. The ileS(T233P) strain is observed to exhibit a significant defect in formation of environmentally resistant spores. The sporulation defect ranges from 3fold to 30fold and is due to a delay in activation of early sporulation genes. The loss of aminoacylation quality control in the ileS(T233P) strain results in the inability to compete with a wild-type strain under selective conditions that require sporulation. The quality control-defective IleRS mutant is defective in expressing genes activated by the master regulator of sporulation, Spo0A. Phenotype, overview. Spo0A is the first transcription factor to become active, through phosphorylation by a phosphorelay, in the sporulation regulatory cascade
malfunction
mutations in the nuclear-encoded mitochondrial aminoacyltRNA synthetases are associated with a range of clinical phenotypes. A recessive disorder CAGSSS in three adult French-Canadian patients with a phenotype including cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, and skeletal dysplasia is caused by a single missense mutation P909L in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level is reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 are independently identified in a patient with a more severe mitochondrial phenotype diagnosed as Leigh syndrome. Phenotypes, overview
malfunction
under error-prone conditions Streptomyces griseus IleRS is able to rescue the growth of an Escherichia coli lacking functional IleRS, providing the first evidence that tRNA-dependent pre-transfer editing in IleRS is not essential for cell viability
malfunction
Bacillus subtilis BAL4574
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mutant ileS(T233P) allows tRNAIle mischarging while retaining wild-type Ile-tRNAIle synthesis activity. The growth rate of the ileS(T233P) strain BAL4571 is not significantly different from wild-type strain BAL4574. The ileS(T233P) strain is observed to exhibit a significant defect in formation of environmentally resistant spores. The sporulation defect ranges from 3fold to 30fold and is due to a delay in activation of early sporulation genes. The loss of aminoacylation quality control in the ileS(T233P) strain results in the inability to compete with a wild-type strain under selective conditions that require sporulation. The quality control-defective IleRS mutant is defective in expressing genes activated by the master regulator of sporulation, Spo0A. Phenotype, overview. Spo0A is the first transcription factor to become active, through phosphorylation by a phosphorelay, in the sporulation regulatory cascade
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hydrolytic editing activities are present in aminoacyl-tRNA synthetases possessing reduced amino acid discrimination in the synthetic reactions. Post-transfer hydrolysis of misacylated tRNA in class I editing enzymes, e.g. IleRS, occurs in a spatially separate domain inserted into the catalytic Rossmann fold. tRNA-dependent hydrolysis of noncognate valyl-adenylate by IleRS is largely insensitive to mutations in the editing domain of the enzyme and that noncatalytic hydrolysis after release is too slow to account for the observed rate of clearing. Pre-transfer editing in IleRS is an enzyme-catalyzed activity residing in the synthetic active site. Balance between pretransfer and post-transfer editing pathways is controlled by kinetic partitioning of the noncognate aminoacyl-adenylate, overview. In IleRS both pre- and post-transfer editing are important
physiological function
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the single trypanosomal IleRS gene is essential for normal growth and for charging of cytosolic and mitochondrial tRNAIle
physiological function
aminoacyl-tRNA synthetases provide the first step in protein synthesis quality control by discriminating cognate from noncognate amino acid and tRNA substrates. While substrate specificity is enhanced in many instances by cis- and transediting pathways, it has been revealed that in organisms such as Streptococcus pneumoniae some aminoacyl tRNA synthetases display significant tRNA mischarging activity. Pneumococcal IleRS mischarges tRNAIle with both Val and Leu in a tRNA sequence-dependent manner. IleRS substrate specificity is achieved in an editing-independent manner, indicating that tRNA mischarging is only significant under growth conditions where Ile is depleted. Adaptive misaminoacylation may contribute significantly to the viability of this pathogen during amino acid starvation
physiological function
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isoleucyl-tRNA synthetase (IleRS) is an aminoacyl-tRNA synthetase whose essential function is to aminoacylate tRNAIle with isoleucine. Like some other aminoacyl-tRNA synthetases, IleRS can mischarge tRNAIle and correct this misacylation through a separate post-transfer editing function, biological significance of this editing function. The quality control function of IleRS is required in Bacillus subtilis for efficient sporulation and editing by aminoacyl-tRNA synthetases may be important for survival under starvation/nutrient limitation conditions. Isoleucine-tRNA synthetase (IleRS) possesses quality control functions that discriminate between isoleucine, the non-cognate amino acid valine, and the non-proteinogenic amino acids, norvaline, a by-product of branched-chain amino acid synthesis, and homocysteine (Hcy), a by-product from degradation of S-adenosylhomocysteine by LuxS in bacteria
physiological function
isoleucyl-tRNA synthetase (IleRS) is responsible for decoding of isoleucine codons in all three domains of life. Besides isoleucine, IleRS also activates non-cognate valine with a discrimination factor as low as 200 and thus it requires editing to enhance accuracy of isoleucyltRNAIle (Ile-tRNAIle) synthesis. Enzyme IleRS is unusual among aminoacyl-tRNA synthetases in having a tRNA-dependent pre-transfer editing activity as an optional property. Some bacteria also have the enzymes (eukaryote-like) that cluster with eukaryotic IleRSs and exhibit low sensitivity to the antibiotic mupirocin. tRNA-dependent pre-transfer editing in IleRS is not essential for cell viability. Specificity of the editing pathways, overview
physiological function
isoleucyl-tRNA synthetase (IleRS) is responsible for decoding of isoleucine codons in all three domains of life. Besides isoleucine, IleRS also activates non-cognate valine with a discrimination factor as low as 200 and thus it requires editing to enhance accuracy of isoleucyltRNAIle (Ile-tRNAIle) synthesis. Enzyme IleRS is unusual among aminoacyl-tRNA synthetases in having a tRNA-dependent pre-transfer editing activity. The main tRNA-dependent pre-transfer editing pathway in ScIleRS is the enzyme-based aa-AMP hydrolysis. Specificity of the editing pathways, overview
physiological function
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isoleucyl-tRNA synthetase (IleRS) is responsible for decoding of isoleucine codons in all three domains of life. Besides isoleucine, IleRS also activates non-cognate valine with a discrimination factor as low as 200 and thus it requires editing to enhance accuracy of isoleucyltRNAIle (Ile-tRNAIle) synthesis. The eukaryote-like enzyme from Streptomyces griseus IleRS lacks the tRNA-dependent pre-transfer editing activity, an unusual capacity of isoleucyl-tRNA synthetases (IleRS). At the same time, its synthetic site displays the 103fold drop in sensitivity to antibiotic mupirocin relative to the yeast enzyme. Under error-prone conditions Streptomyces griseus IleRS is able to rescue the growth of an Escherichia coli lacking functional IleRS, providing the first evidence that tRNA-dependent pre-transfer editing in IleRS is not essential for cell viability
physiological function
the accuracy of protein synthesis relies on the capacity of aminoacyl-tRNA synthetases (aaRS) to couple cognate amino acids and tRNAs in a two-step reaction that defines the genetic code. In the first step, the amino acid is activated by condensation with ATP to form an enzyme-bound aminoacyl-adenylate (aa-AMP) intermediate with release of pyrophosphate. The second step comprises attack by the terminal 2'- or 3'-OH group of tRNA on the carbonyl carbon atom of aa-AMP, followed by transfer of the aminoacyl moiety to tRNA and release of AMP. The amino acid activation and transfer steps occur within the synthetic active site located in the catalytic domain. Enzyme IleRS possesses an inactivated post-transfer editing domain still capable of robust tRNA-dependent editing. The pretransfer editing activity resides within the synthetic site. Specific recognition of tRNAs by cognate aaRSs is ensured by a network of interactions, based on direct and indirect recognition elements that are embedded in all levels of tRNA structure. Noncognate amino acids that structurally and chemically resemble the cognate substrates are often not well-distinguished in the synthetic reactions alone, so that discrimination is based in part on inherent aaRS-based hydrolytic editing
physiological function
Bacillus subtilis BAL4574
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isoleucyl-tRNA synthetase (IleRS) is an aminoacyl-tRNA synthetase whose essential function is to aminoacylate tRNAIle with isoleucine. Like some other aminoacyl-tRNA synthetases, IleRS can mischarge tRNAIle and correct this misacylation through a separate post-transfer editing function, biological significance of this editing function. The quality control function of IleRS is required in Bacillus subtilis for efficient sporulation and editing by aminoacyl-tRNA synthetases may be important for survival under starvation/nutrient limitation conditions. Isoleucine-tRNA synthetase (IleRS) possesses quality control functions that discriminate between isoleucine, the non-cognate amino acid valine, and the non-proteinogenic amino acids, norvaline, a by-product of branched-chain amino acid synthesis, and homocysteine (Hcy), a by-product from degradation of S-adenosylhomocysteine by LuxS in bacteria
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physiological function
Saccharomyces cerevisiae ATCC 204508 / S288c
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isoleucyl-tRNA synthetase (IleRS) is responsible for decoding of isoleucine codons in all three domains of life. Besides isoleucine, IleRS also activates non-cognate valine with a discrimination factor as low as 200 and thus it requires editing to enhance accuracy of isoleucyltRNAIle (Ile-tRNAIle) synthesis. Enzyme IleRS is unusual among aminoacyl-tRNA synthetases in having a tRNA-dependent pre-transfer editing activity. The main tRNA-dependent pre-transfer editing pathway in ScIleRS is the enzyme-based aa-AMP hydrolysis. Specificity of the editing pathways, overview
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physiological function
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the single trypanosomal IleRS gene is essential for normal growth and for charging of cytosolic and mitochondrial tRNAIle
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physiological function
Streptococcus pneumoniae D39 / NCTC 7466
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aminoacyl-tRNA synthetases provide the first step in protein synthesis quality control by discriminating cognate from noncognate amino acid and tRNA substrates. While substrate specificity is enhanced in many instances by cis- and transediting pathways, it has been revealed that in organisms such as Streptococcus pneumoniae some aminoacyl tRNA synthetases display significant tRNA mischarging activity. Pneumococcal IleRS mischarges tRNAIle with both Val and Leu in a tRNA sequence-dependent manner. IleRS substrate specificity is achieved in an editing-independent manner, indicating that tRNA mischarging is only significant under growth conditions where Ile is depleted. Adaptive misaminoacylation may contribute significantly to the viability of this pathogen during amino acid starvation
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in mupirocin-resistant strains, e.g. evolved strain C12 that carried several copies of ileS, the antibiotic resistance leads also to reduced growth rates, these can be restored by the organism via increased expression of the original mutant ileS gene, also improving fitness while maintaining resistance, a process of adaptation initiated by common amplifications and followed by later acquisition of rare point mutations. A point mutation in one copy relaxes selection and allows loss of defective ileS copies, overview. Model for genetic adaptation of cells to the growth limitation caused by their MupR, overview
additional information
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thiaisoleucine-resistant parasites possess a mutation in the cytoplasmic isoleucyl-tRNA synthetase, mutational analysis, overview
additional information
a Rossmann fold peptide is loacted directly N-terminal to the strictly conserved HIGH motif. The class I IleRS Rossmann fold accommodates both synthetic and tRNA-dependent pretransfer hydrolysis pathways within the synthetic site. Residue Y59 acts as a gatekeeper of the IleRS synthetic site
additional information
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a Rossmann fold peptide is loacted directly N-terminal to the strictly conserved HIGH motif. The class I IleRS Rossmann fold accommodates both synthetic and tRNA-dependent pretransfer hydrolysis pathways within the synthetic site. Residue Y59 acts as a gatekeeper of the IleRS synthetic site
additional information
the simultaneous presence of Ile-tRNA and Ile-AMP can cause additional possibilities to proofreading mechanisms of the enzyme, existence of an additional activation step, formation of a new isoleucyl-AMP before the isoleucyl-tRNA is freed from the enzyme. The removal of Ile-tRNA is possible without the formation of Ile-AMP if both isoleucine and ATP are bound to the E-Ile-tRNA complex, but this route covers only 11% of the total formation of Ile-tRNA
additional information
three human mitochondrial aminoacyl-tRNA syntethases, namely leucyl-, valyl-, and isoleucyl-tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt-tRNAIle gene
additional information
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three human mitochondrial aminoacyl-tRNA syntethases, namely leucyl-, valyl-, and isoleucyl-tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt-tRNAIle gene