AL1L2_MOUSE
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 03-AUG-2022, entry version 152.
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, 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=(6S)-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:57454, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; 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}.
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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; 3.
DR STRING; 10090.ENSMUSP00000020497; -.
DR iPTMnet; Q8K009; -.
DR PhosphoSitePlus; Q8K009; -.
DR SwissPalm; Q8K009; -.
DR jPOST; Q8K009; -.
DR MaxQB; Q8K009; -.
DR PaxDb; Q8K009; -.
DR PeptideAtlas; Q8K009; -.
DR PRIDE; Q8K009; -.
DR ProteomicsDB; 296161; -.
DR Antibodypedia; 30615; 101 antibodies from 22 providers.
DR DNASU; 216188; -.
DR Ensembl; ENSMUST00000020497; ENSMUSP00000020497; ENSMUSG00000020256.
DR GeneID; 216188; -.
DR KEGG; mmu:216188; -.
DR UCSC; uc007gkh.2; mouse.
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; 153834at2759; -.
DR PhylomeDB; Q8K009; -.
DR TreeFam; TF354242; -.
DR Reactome; R-MMU-196757; Metabolism of folate and pterines.
DR BioGRID-ORCS; 216188; 3 hits in 72 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 165 other tissues.
DR ExpressionAtlas; Q8K009; baseline and differential.
DR Genevisible; Q8K009; MM.
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:0016742; F:hydroxymethyl-, formyl- and related transferase activity; IEA:InterPro.
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 Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.10.25.10; -; 1.
DR Gene3D; 3.40.309.10; -; 1.
DR Gene3D; 3.40.605.10; -; 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 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; SSF47336; 1.
DR SUPFAM; SSF50486; SSF50486; 1.
DR SUPFAM; SSF53328; SSF53328; 1.
DR SUPFAM; SSF53720; SSF53720; 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.
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="(6S)-10-formyltetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57454"
FT /evidence="ECO:0000250|UniProtKB:O75891"
FT BINDING 164
FT /ligand="(6S)-10-formyltetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57454"
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
