ID   FMT_HUMAN               Reviewed;         389 AA.
AC   Q96DP5; B7Z734;
DT   27-JAN-2003, integrated into UniProtKB/Swiss-Prot.
DT   27-JAN-2003, sequence version 2.
DT   14-DEC-2022, entry version 174.
DE   RecName: Full=Methionyl-tRNA formyltransferase, mitochondrial;
DE            Short=MtFMT;
DE            EC=2.1.2.9 {ECO:0000269|PubMed:21907147, ECO:0000269|PubMed:25288793};
DE   Flags: Precursor;
GN   Name=MTFMT; Synonyms=FMT, FMT1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE
RP   [LARGE SCALE MRNA] OF 11-389 (ISOFORM 1).
RC   TISSUE=Neuroblastoma, and Synovium;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16572171; DOI=10.1038/nature04601;
RA   Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA   Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA   FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA   Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA   Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA   DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA   Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA   Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA   Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA   O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA   Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA   Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT   "Analysis of the DNA sequence and duplication history of human chromosome
RT   15.";
RL   Nature 440:671-675(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Brain, and Mammary gland;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   VARIANTS COXPD15 LEU-125 AND LEU-209, FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=21907147; DOI=10.1016/j.cmet.2011.07.010;
RA   Tucker E.J., Hershman S.G., Koehrer C., Belcher-Timme C.A., Patel J.,
RA   Goldberger O.A., Christodoulou J., Silberstein J.M., McKenzie M.,
RA   Ryan M.T., Compton A.G., Jaffe J.D., Carr S.A., Calvo S.E.,
RA   RajBhandary U.L., Thorburn D.R., Mootha V.K.;
RT   "Mutations in MTFMT underlie a human disorder of formylation causing
RT   impaired mitochondrial translation.";
RL   Cell Metab. 14:428-434(2011).
RN   [5]
RP   VARIANTS MC1DN27 LEU-209 AND 332-ARG--GLU-389 DEL.
RX   PubMed=22499348; DOI=10.1136/jmedgenet-2012-100846;
RA   Haack T.B., Haberberger B., Frisch E.M., Wieland T., Iuso A., Gorza M.,
RA   Strecker V., Graf E., Mayr J.A., Herberg U., Hennermann J.B., Klopstock T.,
RA   Kuhn K.A., Ahting U., Sperl W., Wilichowski E., Hoffmann G.F., Tesarova M.,
RA   Hansikova H., Zeman J., Plecko B., Zeviani M., Wittig I., Strom T.M.,
RA   Schuelke M., Freisinger P., Meitinger T., Prokisch H.;
RT   "Molecular diagnosis in mitochondrial complex I deficiency using exome
RT   sequencing.";
RL   J. Med. Genet. 49:277-283(2012).
RN   [6]
RP   CHARACTERIZATION OF VARIANTS COXPD15 LEU-125 AND LEU-209, FUNCTION, AND
RP   CATALYTIC ACTIVITY.
RX   PubMed=25288793; DOI=10.1074/jbc.m114.610626;
RA   Sinha A., Koehrer C., Weber M.H., Masuda I., Mootha V.K., Hou Y.M.,
RA   RajBhandary U.L.;
RT   "Biochemical characterization of pathogenic mutations in human
RT   mitochondrial methionyl-tRNA formyltransferase.";
RL   J. Biol. Chem. 289:32729-32741(2014).
CC   -!- FUNCTION: Methionyl-tRNA formyltransferase that formylates methionyl-
CC       tRNA in mitochondria and is crucial for translation initiation.
CC       {ECO:0000269|PubMed:21907147, ECO:0000269|PubMed:25288793}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6S)-10-formyltetrahydrofolate + L-methionyl-tRNA(fMet) =
CC         (6S)-5,6,7,8-tetrahydrofolate + H(+) + N-formyl-L-methionyl-
CC         tRNA(fMet); Xref=Rhea:RHEA:24380, Rhea:RHEA-COMP:9952, Rhea:RHEA-
CC         COMP:9953, ChEBI:CHEBI:15378, ChEBI:CHEBI:57453, ChEBI:CHEBI:57454,
CC         ChEBI:CHEBI:78530, ChEBI:CHEBI:78844; EC=2.1.2.9;
CC         Evidence={ECO:0000269|PubMed:25288793};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24381;
CC         Evidence={ECO:0000269|PubMed:21907147};
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:O77480}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q96DP5-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q96DP5-2; Sequence=VSP_057059, VSP_057060;
CC   -!- DOMAIN: Composed of an N- and a C-terminal domain. The N-terminal
CC       domain carries the tetrahydrofolate (THF)-binding site and the C-
CC       terminal domain is presumably involved in positioning the Met-tRNA
CC       substrate for the formylation reaction.
CC   -!- DISEASE: Combined oxidative phosphorylation deficiency 15 (COXPD15)
CC       [MIM:614947]: An autosomal recessive, mitochondrial, neurologic
CC       disorder characterized by features of Leigh syndrome and combined
CC       oxidative phosphorylation deficiency. Clinical features include mild
CC       global developmental delay, white matter abnormalities, ataxia,
CC       incoordination, speech and reading difficulties, T2-weighted
CC       hyperintensities in the basal ganglia, corpus callosum, and brainstem.
CC       {ECO:0000269|PubMed:21907147, ECO:0000269|PubMed:25288793}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Mitochondrial complex I deficiency, nuclear type 27 (MC1DN27)
CC       [MIM:618248]: A form of mitochondrial complex I deficiency, the most
CC       common biochemical signature of mitochondrial disorders, a group of
CC       highly heterogeneous conditions characterized by defective oxidative
CC       phosphorylation, which collectively affects 1 in 5-10000 live births.
CC       Clinical disorders have variable severity, ranging from lethal neonatal
CC       disease to adult-onset neurodegenerative disorders. Phenotypes include
CC       macrocephaly with progressive leukodystrophy, non-specific
CC       encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh
CC       syndrome, Leber hereditary optic neuropathy, and some forms of
CC       Parkinson disease. MC1DN27 transmission pattern is consistent with
CC       autosomal recessive inheritance. {ECO:0000269|PubMed:22499348}.
CC       Note=The disease is caused by variants affecting the gene represented
CC       in this entry.
CC   -!- SIMILARITY: Belongs to the Fmt family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH16630.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC       Sequence=AAH33687.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC       Sequence=BAB70984.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AK055688; BAB70984.1; ALT_INIT; mRNA.
DR   EMBL; AK301390; BAH13470.1; -; mRNA.
DR   EMBL; AC013553; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC103691; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC016630; AAH16630.2; ALT_INIT; mRNA.
DR   EMBL; BC033687; AAH33687.1; ALT_INIT; mRNA.
DR   CCDS; CCDS45280.1; -. [Q96DP5-1]
DR   RefSeq; NP_640335.2; NM_139242.3. [Q96DP5-1]
DR   AlphaFoldDB; Q96DP5; -.
DR   SMR; Q96DP5; -.
DR   BioGRID; 125820; 96.
DR   IntAct; Q96DP5; 5.
DR   STRING; 9606.ENSP00000220058; -.
DR   DrugBank; DB00116; Tetrahydrofolic acid.
DR   iPTMnet; Q96DP5; -.
DR   PhosphoSitePlus; Q96DP5; -.
DR   BioMuta; MTFMT; -.
DR   DMDM; 27923776; -.
DR   EPD; Q96DP5; -.
DR   jPOST; Q96DP5; -.
DR   MassIVE; Q96DP5; -.
DR   MaxQB; Q96DP5; -.
DR   PaxDb; Q96DP5; -.
DR   PeptideAtlas; Q96DP5; -.
DR   ProteomicsDB; 6828; -.
DR   ProteomicsDB; 76304; -. [Q96DP5-1]
DR   Antibodypedia; 25895; 169 antibodies from 14 providers.
DR   DNASU; 123263; -.
DR   Ensembl; ENST00000220058.9; ENSP00000220058.4; ENSG00000103707.10. [Q96DP5-1]
DR   Ensembl; ENST00000543678.1; ENSP00000443754.1; ENSG00000103707.10. [Q96DP5-2]
DR   Ensembl; ENST00000558460.5; ENSP00000452646.1; ENSG00000103707.10. [Q96DP5-1]
DR   GeneID; 123263; -.
DR   KEGG; hsa:123263; -.
DR   MANE-Select; ENST00000220058.9; ENSP00000220058.4; NM_139242.4; NP_640335.2.
DR   UCSC; uc002aof.5; human. [Q96DP5-1]
DR   AGR; HGNC:29666; -.
DR   CTD; 123263; -.
DR   DisGeNET; 123263; -.
DR   GeneCards; MTFMT; -.
DR   GeneReviews; MTFMT; -.
DR   HGNC; HGNC:29666; MTFMT.
DR   HPA; ENSG00000103707; Low tissue specificity.
DR   MalaCards; MTFMT; -.
DR   MIM; 611766; gene.
DR   MIM; 614947; phenotype.
DR   MIM; 618248; phenotype.
DR   neXtProt; NX_Q96DP5; -.
DR   OpenTargets; ENSG00000103707; -.
DR   Orphanet; 319524; Combined oxidative phosphorylation defect type 15.
DR   Orphanet; 255241; Leigh syndrome with leukodystrophy.
DR   PharmGKB; PA142671304; -.
DR   VEuPathDB; HostDB:ENSG00000103707; -.
DR   eggNOG; KOG3082; Eukaryota.
DR   GeneTree; ENSGT00390000017828; -.
DR   HOGENOM; CLU_033347_0_0_1; -.
DR   InParanoid; Q96DP5; -.
DR   OMA; FMPELHA; -.
DR   OrthoDB; 963177at2759; -.
DR   PhylomeDB; Q96DP5; -.
DR   TreeFam; TF323405; -.
DR   BRENDA; 2.1.2.9; 2681.
DR   PathwayCommons; Q96DP5; -.
DR   Reactome; R-HSA-5368286; Mitochondrial translation initiation.
DR   SignaLink; Q96DP5; -.
DR   BioGRID-ORCS; 123263; 141 hits in 1079 CRISPR screens.
DR   ChiTaRS; MTFMT; human.
DR   GeneWiki; MTFMT; -.
DR   GenomeRNAi; 123263; -.
DR   Pharos; Q96DP5; Tbio.
DR   PRO; PR:Q96DP5; -.
DR   Proteomes; UP000005640; Chromosome 15.
DR   RNAct; Q96DP5; protein.
DR   Bgee; ENSG00000103707; Expressed in left ventricle myocardium and 168 other tissues.
DR   ExpressionAtlas; Q96DP5; baseline and differential.
DR   Genevisible; Q96DP5; HS.
DR   GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR   GO; GO:0004479; F:methionyl-tRNA formyltransferase activity; IDA:UniProtKB.
DR   GO; GO:0071951; P:conversion of methionyl-tRNA to N-formyl-methionyl-tRNA; IDA:UniProtKB.
DR   CDD; cd08646; FMT_core_Met-tRNA-FMT_N; 1.
DR   InterPro; IPR005794; Fmt.
DR   InterPro; IPR005793; Formyl_trans_C.
DR   InterPro; IPR002376; Formyl_transf_N.
DR   InterPro; IPR036477; Formyl_transf_N_sf.
DR   InterPro; IPR011034; Formyl_transferase-like_C_sf.
DR   InterPro; IPR041711; Met-tRNA-FMT_N.
DR   Pfam; PF02911; Formyl_trans_C; 1.
DR   Pfam; PF00551; Formyl_trans_N; 1.
DR   SUPFAM; SSF50486; FMT C-terminal domain-like; 1.
DR   SUPFAM; SSF53328; Formyltransferase; 1.
DR   TIGRFAMs; TIGR00460; fmt; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Disease variant; Mitochondrion;
KW   Primary mitochondrial disease; Protein biosynthesis; Reference proteome;
KW   Transferase; Transit peptide.
FT   TRANSIT         1..?
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000255"
FT   CHAIN           ?..389
FT                   /note="Methionyl-tRNA formyltransferase, mitochondrial"
FT                   /id="PRO_0000010093"
FT   VAR_SEQ         141..144
FT                   /note="GILN -> SFQF (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_057059"
FT   VAR_SEQ         145..389
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_057060"
FT   VARIANT         5
FT                   /note="V -> A (in dbSNP:rs2946655)"
FT                   /id="VAR_059289"
FT   VARIANT         125
FT                   /note="S -> L (in COXPD15; loss of methionyl-tRNA
FT                   formyltransferase activity; dbSNP:rs397514614)"
FT                   /evidence="ECO:0000269|PubMed:21907147,
FT                   ECO:0000269|PubMed:25288793"
FT                   /id="VAR_069303"
FT   VARIANT         209
FT                   /note="S -> L (in COXPD15 and MC1DN27; decreased methionyl-
FT                   tRNA formyltransferase activity; dbSNP:rs201431517)"
FT                   /evidence="ECO:0000269|PubMed:21907147,
FT                   ECO:0000269|PubMed:22499348, ECO:0000269|PubMed:25288793"
FT                   /id="VAR_069304"
FT   VARIANT         332..389
FT                   /note="Missing (in MC1DN27)"
FT                   /evidence="ECO:0000269|PubMed:22499348"
FT                   /id="VAR_081461"
SQ   SEQUENCE   389 AA;  43832 MW;  EBBE92142AB954E0 CRC64;
     MRVLVRRCWG PPLAHGARRG RPSPQWRALA RLGWEDCRDS RVREKPPWRV LFFGTDQFAR
     EALRALHAAR ENKEEELIDK LEVVTMPSPS PKGLPVKQYA VQSQLPVYEW PDVGSGEYDV
     GVVASFGRLL NEALILKFPY GILNVHPSCL PRWRGPAPVI HTVLHGDTVT GVTIMQIRPK
     RFDVGPILKQ ETVPVPPKST AKELEAVLSR LGANMLISVL KNLPESLSNG RQQPMEGATY
     APKISAGTSC IKWEEQTSEQ IFRLYRAIGN IIPLQTLWMA NTIKLLDLVE VNSSVLADPK
     LTGQALIPGS VIYHKQSQIL LVYCKDGWIG VRSVMLKKSL TATDFYNGYL HPWYQKNSQA
     QPSQCRFQTL RLPTKKKQKK TVAMQQCIE
//