ID   AL1L2_MOUSE             Reviewed;         923 AA.
AC   Q8K009; E9QLV8;
DT   15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT   27-JUL-2011, sequence version 2.
DT   24-JAN-2024, entry version 159.
DE   RecName: Full=Mitochondrial 10-formyltetrahydrofolate dehydrogenase {ECO:0000305|PubMed:33168096};
DE            Short=Mitochondrial 10-FTHFDH;
DE            Short=mtFDH;
DE            EC=1.5.1.6 {ECO:0000269|PubMed:33168096};
DE   AltName: Full=Aldehyde dehydrogenase family 1 member L2 {ECO:0000303|PubMed:33168096};
GN   Name=Aldh1l2 {ECO:0000303|PubMed:33168096,
GN   ECO:0000312|MGI:MGI:2444680};
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=C57BL/6J;
RX   PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA   Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA   Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA   Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA   Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA   Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA   Eichler E.E., Ponting C.P.;
RT   "Lineage-specific biology revealed by a finished genome assembly of the
RT   mouse.";
RL   PLoS Biol. 7:E1000112-E1000112(2009).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=FVB/N; TISSUE=Salivary 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   [3]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Brown adipose tissue, Heart, Pancreas, and Spleen;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [4]
RP   SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-681, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Embryonic fibroblast;
RX   PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA   Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA   Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT   "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT   pathways.";
RL   Mol. Cell 50:919-930(2013).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND DISRUPTION
RP   PHENOTYPE.
RX   PubMed=33168096; DOI=10.1186/s40246-020-00291-3;
RA   Krupenko N.I., Sharma J., Pediaditakis P., Helke K.L., Hall M.S., Du X.,
RA   Sumner S., Krupenko S.A.;
RT   "Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial
RT   folate enzyme to deregulation of a lipid metabolism observed in rare human
RT   disorder.";
RL   Hum. Genomics 14:41-41(2020).
CC   -!- FUNCTION: Mitochondrial 10-formyltetrahydrofolate dehydrogenase that
CC       catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate
CC       to tetrahydrofolate and carbon dioxide. {ECO:0000269|PubMed:33168096}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6R)-10-formyltetrahydrofolate + H2O + NADP(+) = (6S)-5,6,7,8-
CC         tetrahydrofolate + CO2 + H(+) + NADPH; Xref=Rhea:RHEA:10180,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC         ChEBI:CHEBI:57453, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC         ChEBI:CHEBI:195366; EC=1.5.1.6;
CC         Evidence={ECO:0000269|PubMed:33168096};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10181;
CC         Evidence={ECO:0000269|PubMed:33168096};
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000305|PubMed:33168096}.
CC   -!- DOMAIN: The N-terminal hydrolase domain has an NADP-independent
CC       formyltetrahydrofolate hydrolase activity, releasing formate and
CC       tetrahydrofolate. {ECO:0000250|UniProtKB:P28037}.
CC   -!- DOMAIN: The C-terminal aldehyde dehydrogenase domain has an NADP-
CC       dependent dehydrogenase activity. It catalyzes the oxidation of
CC       formate, released by the hydrolysis of formyltetrahydrofolate, into
CC       CO2. {ECO:0000250|UniProtKB:P28037}.
CC   -!- DOMAIN: The carrier domain is phosphopantetheinylated and uses the 4'-
CC       phosphopantetheine/4'-PP swinging arm to transfer the formyl group
CC       released by the N-terminal formyltetrahydrofolate hydrolase activity to
CC       the C-terminal aldehyde dehydrogenase domain that catalyzes its NADP-
CC       dependent oxidation into CO2. The overall NADP-dependent physiological
CC       reaction requires the 3 domains (N-terminal hydrolase, C-terminal
CC       aldehyde dehydrogenase and carrier domains) to convert
CC       formyltetrahydrofolate into tetrahydrofolate and CO2.
CC       {ECO:0000250|UniProtKB:Q3SY69}.
CC   -!- PTM: Phosphopantetheinylation at Ser-375 by AASDHPPT is required for
CC       the formyltetrahydrofolate dehydrogenase activity.
CC       {ECO:0000250|UniProtKB:Q3SY69}.
CC   -!- DISRUPTION PHENOTYPE: Homozygous knockout mice lacking Aldh1l2 are
CC       viable and fertile and no embryonic lethality is observed
CC       (PubMed:33168096). They do not display phenotypic differences in terms
CC       of growth, food consumption and development (PubMed:33168096). 10-
CC       formyl-THF and dihydrofolate accumulate in the liver of the knockout
CC       mice. It is associated with a decrease in levels of NADPH and ATP
CC       specifically in the mitochondrion (PubMed:33168096). Male knockout mice
CC       accumulate more fats in the liver which is associated with impaired
CC       beta-oxidation of fatty acids (PubMed:33168096).
CC       {ECO:0000269|PubMed:33168096}.
CC   -!- SIMILARITY: In the N-terminal section; belongs to the GART family.
CC       {ECO:0000305}.
CC   -!- SIMILARITY: In the C-terminal section; belongs to the aldehyde
CC       dehydrogenase family. ALDH1L subfamily. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AC113014; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC034531; AAH34531.1; -; mRNA.
DR   CCDS; CCDS24077.1; -.
DR   RefSeq; NP_705771.2; NM_153543.2.
DR   AlphaFoldDB; Q8K009; -.
DR   SMR; Q8K009; -.
DR   BioGRID; 229719; 4.
DR   STRING; 10090.ENSMUSP00000020497; -.
DR   iPTMnet; Q8K009; -.
DR   PhosphoSitePlus; Q8K009; -.
DR   SwissPalm; Q8K009; -.
DR   jPOST; Q8K009; -.
DR   MaxQB; Q8K009; -.
DR   PaxDb; 10090-ENSMUSP00000020497; -.
DR   PeptideAtlas; Q8K009; -.
DR   ProteomicsDB; 296161; -.
DR   Pumba; Q8K009; -.
DR   Antibodypedia; 30615; 108 antibodies from 22 providers.
DR   DNASU; 216188; -.
DR   Ensembl; ENSMUST00000020497.14; ENSMUSP00000020497.8; ENSMUSG00000020256.15.
DR   GeneID; 216188; -.
DR   KEGG; mmu:216188; -.
DR   UCSC; uc007gkh.2; mouse.
DR   AGR; MGI:2444680; -.
DR   CTD; 160428; -.
DR   MGI; MGI:2444680; Aldh1l2.
DR   VEuPathDB; HostDB:ENSMUSG00000020256; -.
DR   eggNOG; KOG2452; Eukaryota.
DR   GeneTree; ENSGT00940000158018; -.
DR   InParanoid; Q8K009; -.
DR   OMA; NEQVFMA; -.
DR   OrthoDB; 2291791at2759; -.
DR   PhylomeDB; Q8K009; -.
DR   TreeFam; TF354242; -.
DR   Reactome; R-MMU-196757; Metabolism of folate and pterines.
DR   BioGRID-ORCS; 216188; 4 hits in 77 CRISPR screens.
DR   ChiTaRS; Aldh1l2; mouse.
DR   PRO; PR:Q8K009; -.
DR   Proteomes; UP000000589; Chromosome 10.
DR   RNAct; Q8K009; Protein.
DR   Bgee; ENSMUSG00000020256; Expressed in parotid gland and 167 other cell types or tissues.
DR   ExpressionAtlas; Q8K009; baseline and differential.
DR   GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR   GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR   GO; GO:0004029; F:aldehyde dehydrogenase (NAD+) activity; IBA:GO_Central.
DR   GO; GO:0016155; F:formyltetrahydrofolate dehydrogenase activity; IMP:UniProtKB.
DR   GO; GO:0009258; P:10-formyltetrahydrofolate catabolic process; IMP:UniProtKB.
DR   GO; GO:0009058; P:biosynthetic process; IEA:InterPro.
DR   GO; GO:0006635; P:fatty acid beta-oxidation; IMP:UniProtKB.
DR   GO; GO:0046655; P:folic acid metabolic process; IMP:UniProtKB.
DR   GO; GO:0006740; P:NADPH regeneration; IMP:UniProtKB.
DR   GO; GO:0006730; P:one-carbon metabolic process; IEA:UniProtKB-KW.
DR   CDD; cd07140; ALDH_F1L_FTFDH; 1.
DR   CDD; cd08703; FDH_Hydrolase_C; 1.
DR   CDD; cd08647; FMT_core_FDH_N; 1.
DR   Gene3D; 1.10.1200.10; ACP-like; 1.
DR   Gene3D; 3.10.25.10; Formyl transferase, C-terminal domain; 1.
DR   Gene3D; 3.40.50.170; Formyl transferase, N-terminal domain; 1.
DR   InterPro; IPR011407; 10_FTHF_DH.
DR   InterPro; IPR036736; ACP-like_sf.
DR   InterPro; IPR016161; Ald_DH/histidinol_DH.
DR   InterPro; IPR016163; Ald_DH_C.
DR   InterPro; IPR016160; Ald_DH_CS_CYS.
DR   InterPro; IPR029510; Ald_DH_CS_GLU.
DR   InterPro; IPR016162; Ald_DH_N.
DR   InterPro; IPR015590; Aldehyde_DH_dom.
DR   InterPro; IPR005793; Formyl_trans_C.
DR   InterPro; IPR037022; Formyl_trans_C_sf.
DR   InterPro; IPR002376; Formyl_transf_N.
DR   InterPro; IPR036477; Formyl_transf_N_sf.
DR   InterPro; IPR011034; Formyl_transferase-like_C_sf.
DR   InterPro; IPR001555; GART_AS.
DR   InterPro; IPR009081; PP-bd_ACP.
DR   InterPro; IPR006162; Ppantetheine_attach_site.
DR   PANTHER; PTHR11699; ALDEHYDE DEHYDROGENASE-RELATED; 1.
DR   PANTHER; PTHR11699:SF131; MITOCHONDRIAL 10-FORMYLTETRAHYDROFOLATE DEHYDROGENASE; 1.
DR   Pfam; PF00171; Aldedh; 1.
DR   Pfam; PF02911; Formyl_trans_C; 1.
DR   Pfam; PF00551; Formyl_trans_N; 1.
DR   Pfam; PF00550; PP-binding; 1.
DR   PIRSF; PIRSF036489; 10-FTHFDH; 1.
DR   SUPFAM; SSF47336; ACP-like; 1.
DR   SUPFAM; SSF53720; ALDH-like; 1.
DR   SUPFAM; SSF50486; FMT C-terminal domain-like; 1.
DR   SUPFAM; SSF53328; Formyltransferase; 1.
DR   PROSITE; PS00070; ALDEHYDE_DEHYDR_CYS; 1.
DR   PROSITE; PS00687; ALDEHYDE_DEHYDR_GLU; 1.
DR   PROSITE; PS50075; CARRIER; 1.
DR   PROSITE; PS00373; GART; 1.
DR   PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
DR   Genevisible; Q8K009; MM.
PE   1: Evidence at protein level;
KW   Acetylation; Mitochondrion; NADP; One-carbon metabolism; Oxidoreductase;
KW   Phosphopantetheine; Phosphoprotein; Reference proteome; Transit peptide.
FT   CHAIN           1..923
FT                   /note="Mitochondrial 10-formyltetrahydrofolate
FT                   dehydrogenase"
FT                   /id="PRO_0000316002"
FT   TRANSIT         1..19
FT                   /note="Mitochondrion; not cleaved"
FT                   /evidence="ECO:0000250|UniProtKB:Q3SY69"
FT   DOMAIN          339..416
FT                   /note="Carrier"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          23..331
FT                   /note="Hydrolase domain"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   REGION          438..923
FT                   /note="Aldehyde dehydrogenase domain"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   ACT_SITE        128
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   ACT_SITE        694
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   ACT_SITE        728
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   BINDING         110..112
FT                   /ligand="(6R)-10-formyltetrahydrofolate"
FT                   /ligand_id="ChEBI:CHEBI:195366"
FT                   /evidence="ECO:0000250|UniProtKB:O75891"
FT   BINDING         164
FT                   /ligand="(6R)-10-formyltetrahydrofolate"
FT                   /ligand_id="ChEBI:CHEBI:195366"
FT                   /evidence="ECO:0000250|UniProtKB:O75891"
FT   BINDING         592..594
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   BINDING         618..621
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   BINDING         651..656
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   BINDING         671..672
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   BINDING         694..695
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   BINDING         778
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   BINDING         825..827
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   SITE            164
FT                   /note="Essential for catalytic activity"
FT                   /evidence="ECO:0000250|UniProtKB:P28037"
FT   MOD_RES         31
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O75891"
FT   MOD_RES         60
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8R0Y6"
FT   MOD_RES         375
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000250|UniProtKB:Q3SY69,
FT                   ECO:0000255|PROSITE-ProRule:PRU00258"
FT   MOD_RES         650
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O75891"
FT   MOD_RES         681
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0007744|PubMed:23806337"
FT   MOD_RES         903
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q3SY69"
FT   CONFLICT        476
FT                   /note="Y -> H (in Ref. 2; AAH34531)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   923 AA;  101590 MW;  57CB83C38FAFB0D2 CRC64;
     MLWRGSQALR HFSTSRVYFK NKLKLALIGQ SLFGQEVYSQ LLKEGHRVVG VFTVPDKDGK
     ADPLALAAEK DGTPVFKFPR WRLKGKTIKE VAEAYQSVGA ELNVLPFCTQ FIPMDVIDSP
     KHGSIIYHPS LLPRHRGASA INWTLIMGDK KAGFSVFWAD DGLDTGPILL QRSCDVKPND
     TVDSLYNRFL FPEGIKAMVE AVQLIADGKA PRTPQPEEGA TYEGIQKKEN AEVSWDQPAE
     GLHNWIRGHD KVPGAWAEIN GQMVTFYGSS LLTSSVPSGE PLDIRGAKKP GLVTKNGLVL
     FGNDGKALMV RNLQFEDGKM IPASQYFSAG ETSVVELTAE ELKVAETIKV IWARILSNTP
     VIEDSTDFFK SGASSMDVVR LVEEIRQSCG GLQLQNEDVY MATKFGDFIQ KVVRRLRGED
     EEAEMVVDYV SKEVNGMTVK IPYQCFINGQ FVDAEDGETY ATVNPTDGTT ICRVSYASLA
     DVDRAVAAAK DAFENGEWGR MNARDRGRLM YRLADLMEEN QEELATIEAL DSGAVYTLAL
     KTHIGMSVQT FRYFAGWCDK IQGSTIPINQ ARPNYNLTFT KKEPLGACAI IIPWNYPLMM
     LAWKSAACLA AGNTLVLKPA QVTPLTALKF AELTVKAGFP KGVINIIPGS GGVAGQRLSQ
     HPDIRKLGFT GSTSVGKQIM KSCAVSNLKK VSLELGGKSP LIIFSDCDLE KAVRMGMGAV
     FFNKGENCIA AGRLFVEEAI HDEFVTRVVE EIKKMKIGDP LDRSTDHGPQ NHRAHLEKLL
     QYCETGVQEG ATLVYGGRQV QRPGFFMEPT VFTGVEDHMY LAKEESFGPI MVISKFQNGD
     IDGVLQRANN TEYGLASGVF TRDINKAMYV SDKLEAGTVF INTYNKTDVA APFGGMKQSG
     FGKDLGEEAL NEYLKIKTVT LEY
//