MetRS-m (Aats-met, CG31322) encodes the Drosophila mitochondrial methionyl-tRNA synthetase, the ortholog of human MARS2. It is a nuclear-encoded class I aminoacyl-tRNA synthetase with an N-terminal mitochondrial transit peptide and the HIGH and KMSKS catalytic motifs, and it uses ATP to attach methionine to mitochondrial tRNA(Met) in the mitochondrial matrix, supplying Met-tRNA for initiation and elongation of mitochondrially encoded proteins. Hypomorphic missense alleles (V42D, S224L) cause reduced cell proliferation, Complex I deficiency, elevated reactive oxygen species, a mitochondrial unfolded protein response, glial lipid droplet accumulation and progressive photoreceptor degeneration, and null alleles are lethal; these defects are rescued by fly or human MARS2 cDNA, which established MARS2 as the gene mutated in autosomal recessive spastic ataxia with leukoencephalopathy (ARSAL).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000166 nucleotide binding | IEA GO_REF:0000002 | MODIFY | Summary: Nucleotide binding is true but uninformative; the bound nucleotide is ATP, a substrate of the aminoacylation reaction. Reason: InterPro-mapped parent term. The specific supported term is GO:0005524 ATP binding, which the gene already carries (KMSKS motif, ATP-binding residue at 320 by similarity). Proposed replacements: ATP binding Supporting Evidence: file:DROME/MetRS-m/MetRS-m-uniprot.txt /ligand="ATP" file:DROME/MetRS-m/MetRS-m-uniprot.txt Belongs to the class-I aminoacyl-tRNA synthetase family. |
| GO:0004812 aminoacyl-tRNA ligase activity | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general; MetRS-m is the mitochondrial methionyl-tRNA synthetase. Reason: The InterPro mapping gives the generic aminoacyl-tRNA ligase activity; the specific activity supported by orthology to MARS2, TIGR00398 metG membership and rescue of fly mutants by human MARS2 is GO:0004825 methionine-tRNA ligase activity, which the gene already carries. Proposed replacements: methionine-tRNA ligase activity Supporting Evidence: PMID:22448145 Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA synthetase, with 44% identity and 75% similarity to its human orthologue MARS2 file:DROME/MetRS-m/MetRS-m-uniprot.txt NCBIfam; TIGR00398; metG; 1. PMID:22448145 The fly and human cDNAs rescued the lethality associated with FB/Df and HV/Df, the strongest allelic combinations. |
| GO:0004825 methionine-tRNA ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core activity: MetRS-m charges mitochondrial tRNA(Met) with methionine. Reason: PAINT node PTN000235847 groups experimentally characterized MetRSs (yeast MSM1, human MARS2, Arabidopsis, Plasmodium, M. tuberculosis); MetRS-m sits in the mitochondrial MARS2 subfamily (PTHR43326:SF1) and retains HIGH/KMSKS motifs, so inheritance of the activity is sound. Supporting Evidence: file:DROME/MetRS-m/MetRS-m-uniprot.txt PANTHER; PTHR43326:SF1; METHIONINE--TRNA LIGASE, MITOCHONDRIAL; 1. PMID:22448145 Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA synthetase, with 44% identity and 75% similarity to its human orthologue MARS2 |
| GO:0004825 methionine-tRNA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core activity: MetRS-m charges mitochondrial tRNA(Met) with methionine. Reason: Combined InterPro/Rhea/EC mapping; consistent with family membership (TIGR00398 metG, PTHR43326:SF1) and the conserved class I catalytic motifs. Supporting Evidence: file:DROME/MetRS-m/MetRS-m-uniprot.txt NCBIfam; TIGR00398; metG; 1. file:DROME/MetRS-m/MetRS-m-uniprot.txt Belongs to the class-I aminoacyl-tRNA synthetase family. |
| GO:0004825 methionine-tRNA ligase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Core activity: MetRS-m charges mitochondrial tRNA(Met) with methionine. Reason: Transfer from human MARS2 (Q96GW9), the ortholog; strongly supported by functional complementation of fly mutants by human MARS2 cDNA. Supporting Evidence: PMID:22448145 Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA synthetase, with 44% identity and 75% similarity to its human orthologue MARS2 PMID:22448145 The fly and human cDNAs rescued the lethality associated with FB/Df and HV/Df, the strongest allelic combinations. |
| GO:0004825 methionine-tRNA ligase activity | TAS PMID:26761199 The aminoacyl-tRNA synthetases of Drosophila melanogaster. | ACCEPT | Summary: Core activity: MetRS-m charges mitochondrial tRNA(Met) with methionine. Reason: The Drosophila aaRS catalogue assigns CG31322 as the sole mitochondrial MetRS, ortholog of MARS2. No direct biochemical assay of the fly enzyme exists, but orthology plus cross-species rescue make the activity secure. Supporting Evidence: PMID:26761199 MetRS-mMethionyl-tRNA synthetase, mitochondrialCG31322M1MARS2 PMID:22448145 The fly and human cDNAs rescued the lethality associated with FB/Df and HV/Df, the strongest allelic combinations. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP is a substrate of the aminoacylation reaction; binding is part of the catalytic mechanism. Reason: Class I aaRS with a KMSKS motif and an ATP-binding residue (320, by similarity). True, but subsumed in the core ligase activity. Supporting Evidence: file:DROME/MetRS-m/MetRS-m-uniprot.txt /ligand="ATP" |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial localization is inherited within the mitochondrial MetRS clade. Reason: PTN000235848 is the mitochondrial MetRS node (yeast MSM1, human MARS2). The organelle claim holds: predicted N-terminal transit peptide (1-95), and the tagged human ortholog that rescues the mutant co-localizes with mito-GFP in fly neurons. Sub-compartment (matrix) is captured by separate rows. Supporting Evidence: file:DROME/MetRS-m/MetRS-m-uniprot.txt TRANSIT 1..95 PMID:22448145 Both proteins co-localize, indicating that MARS2 is indeed a mitochondrial protein. |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: Mitochondrion; consistent with the transit peptide and the mitochondrial MetRS identity. Reason: ARBA-based row, but the organelle claim is independently supported by the predicted transit peptide and orthology to MARS2. Root organelle term retained per policy. Supporting Evidence: file:DROME/MetRS-m/MetRS-m-uniprot.txt TRANSIT 1..95 PMID:22448145 Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA synthetase, with 44% identity and 75% similarity to its human orthologue MARS2 |
| GO:0005739 mitochondrion | TAS PMID:26761199 The aminoacyl-tRNA synthetases of Drosophila melanogaster. | ACCEPT | Summary: The fly aaRS catalogue classes MetRS-m as the mitochondrial MetRS. Reason: Traceable author statement from the catalogue review; supported by transit peptide and ortholog localization. Supporting Evidence: PMID:26761199 MetRS-mMethionyl-tRNA synthetase, mitochondrialCG31322M1MARS2 file:DROME/MetRS-m/MetRS-m-uniprot.txt TRANSIT 1..95 |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Mitochondrial matrix is where tRNA charging for mitochondrial translation occurs. Reason: UniProt subcellular location (by similarity to MARS2). Two independent lines agree: a cleavable N-terminal transit peptide and a function (charging tRNA for matrix-located mitoribosomes) that only makes sense in the matrix. Supporting Evidence: file:DROME/MetRS-m/MetRS-m-uniprot.txt TRANSIT 1..95 PMID:22448145 Since Aats-met/MARS2 is a mitochondrial translation factor |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Matrix localization by similarity to human MARS2. Reason: Consistent with the transit peptide and with its role in mitochondrial translation. Supporting Evidence: file:DROME/MetRS-m/MetRS-m-uniprot.txt TRANSIT 1..95 PMID:22448145 Since Aats-met/MARS2 is a mitochondrial translation factor |
| GO:0006418 tRNA aminoacylation for protein translation | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general; MetRS-m charges tRNA for mitochondrial, not cytosolic, translation. Reason: GO:0070127 tRNA aminoacylation for mitochondrial protein translation is the is_a descendant supported by the mitochondrial identity (transit peptide, MARS2 orthology, rescue by MARS2). Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:22448145 Since Aats-met/MARS2 is a mitochondrial translation factor file:DROME/MetRS-m/MetRS-m-uniprot.txt TRANSIT 1..95 |
| GO:0006431 obsolete methionyl-tRNA aminoacylation | IBA GO_REF:0000033 | MODIFY | Summary: Obsolete term that restates the ligase activity; replace with the mitochondrial aminoacylation process. Reason: GO:0006431 is now obsolete in GO (it restated the molecular function GO:0004825). The biology is correct; the process MetRS-m participates in is tRNA aminoacylation for mitochondrial protein translation (GO:0070127), with methionine specificity carried by GO:0004825. Same treatment as the obsolete aminoacylation rows in the DARS2 and TyrRS reviews. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000235847 SUPPORTS TRANSFER Node and MetRS charging biology are sound; only the process term is obsolete and unscoped for compartment. Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:22448145 Since Aats-met/MARS2 is a mitochondrial translation factor PMID:22448145 Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA synthetase, with 44% identity and 75% similarity to its human orthologue MARS2 |
| GO:0006431 obsolete methionyl-tRNA aminoacylation | IEA GO_REF:0000002 | MODIFY | Summary: Obsolete term that restates the ligase activity; replace with the mitochondrial aminoacylation process. Reason: GO:0006431 is now obsolete in GO (it restated the molecular function GO:0004825). The biology is correct; the process MetRS-m participates in is tRNA aminoacylation for mitochondrial protein translation (GO:0070127), with methionine specificity carried by GO:0004825. Same treatment as the obsolete aminoacylation rows in the DARS2 and TyrRS reviews. Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:22448145 Since Aats-met/MARS2 is a mitochondrial translation factor PMID:22448145 Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA synthetase, with 44% identity and 75% similarity to its human orthologue MARS2 |
| GO:0006431 obsolete methionyl-tRNA aminoacylation | ISS GO_REF:0000024 | MODIFY | Summary: Obsolete term that restates the ligase activity; replace with the mitochondrial aminoacylation process. Reason: GO:0006431 is now obsolete in GO (it restated the molecular function GO:0004825). The biology is correct; the process MetRS-m participates in is tRNA aminoacylation for mitochondrial protein translation (GO:0070127), with methionine specificity carried by GO:0004825. Same treatment as the obsolete aminoacylation rows in the DARS2 and TyrRS reviews. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:Q96GW9 SUPPORTS TRANSFER Human MARS2 is the true ortholog and rescues fly mutants; only the term is obsolete. Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:22448145 Since Aats-met/MARS2 is a mitochondrial translation factor PMID:22448145 Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA synthetase, with 44% identity and 75% similarity to its human orthologue MARS2 |
| GO:0006431 obsolete methionyl-tRNA aminoacylation | TAS PMID:26761199 The aminoacyl-tRNA synthetases of Drosophila melanogaster. | MODIFY | Summary: Obsolete term that restates the ligase activity; replace with the mitochondrial aminoacylation process. Reason: GO:0006431 is now obsolete in GO (it restated the molecular function GO:0004825). The biology is correct; the process MetRS-m participates in is tRNA aminoacylation for mitochondrial protein translation (GO:0070127), with methionine specificity carried by GO:0004825. Same treatment as the obsolete aminoacylation rows in the DARS2 and TyrRS reviews. Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:22448145 Since Aats-met/MARS2 is a mitochondrial translation factor PMID:22448145 Aats-met encodes the uncharacterized Drosophila mitochondrial methionyl-tRNA synthetase, with 44% identity and 75% similarity to its human orthologue MARS2 |
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Download this section (compressed HTML)Q: Does the fly MetRS-m charge the single mitochondrial tRNA(Met) used for both initiation (after formylation) and elongation, and do the V42D and S224L substitutions reduce catalytic rate, tRNA affinity or protein stability?
Q: Is mitochondrial translation measurably reduced in Aats-met mutant fly tissue, as it is in ARSAL patient cells?
Experiment: In vitro aminoacylation of transcribed Drosophila mt-tRNA(Met) with recombinant wild-type, V42D and S224L MetRS-m to measure kinetic parameters.
Experiment: 35S-methionine pulse labelling of mitochondrial translation products in Aats-met mutant larvae, with rescue by fly and human cDNAs.
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