AL1L1_MOUSE
ID AL1L1_MOUSE Reviewed; 902 AA.
AC Q8R0Y6;
DT 25-OCT-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Cytosolic 10-formyltetrahydrofolate dehydrogenase {ECO:0000305|PubMed:31624291};
DE Short=10-FTHFDH;
DE Short=FDH;
DE EC=1.5.1.6 {ECO:0000269|PubMed:31624291};
DE AltName: Full=Aldehyde dehydrogenase family 1 member L1 {ECO:0000303|PubMed:31624291};
GN Name=Aldh1l1 {ECO:0000312|MGI:MGI:1340024}; Synonyms=Fthfd;
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 MRNA].
RC STRAIN=FVB/N; TISSUE=Liver;
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 [2]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Kidney, Liver, Lung, Pancreas, Spleen,
RC and Testis;
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-38 AND LYS-767, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
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, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=31624291; DOI=10.1038/s41598-019-51397-1;
RA Krupenko N.I., Sharma J., Pediaditakis P., Fekry B., Helke K.L., Du X.,
RA Sumner S., Krupenko S.A.;
RT "Cytosolic 10-formyltetrahydrofolate dehydrogenase regulates glycine
RT metabolism in mouse liver.";
RL Sci. Rep. 9:14937-14937(2019).
CC -!- FUNCTION: Cytosolic 10-formyltetrahydrofolate dehydrogenase that
CC catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate
CC to tetrahydrofolate and carbon dioxide (PubMed:31624291). May also have
CC an NADP(+)-dependent aldehyde dehydrogenase activity towards
CC formaldehyde, acetaldehyde, propionaldehyde, and benzaldehyde (By
CC similarity). {ECO:0000250|UniProtKB:P28037,
CC ECO:0000269|PubMed:31624291}.
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:31624291};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10181;
CC Evidence={ECO:0000269|PubMed:31624291};
CC -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:P28037}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P28037}.
CC -!- TISSUE SPECIFICITY: Highly expressed in liver (at protein level)
CC (PubMed:31624291). Also expressed in pancreas, brain and lung (at
CC protein level) (PubMed:31624291). {ECO:0000269|PubMed:31624291}.
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:P28037}.
CC -!- PTM: Phosphopantetheinylation at Ser-354 by AASDHPPT is required for
CC the formyltetrahydrofolate dehydrogenase activity.
CC {ECO:0000250|UniProtKB:P28037}.
CC -!- DISRUPTION PHENOTYPE: Homozygous knockout mice are viable, fertile,
CC develop normally and do not display overt phenotype (PubMed:31624291).
CC However, they have metabolic signs of folate deficiency like the
CC accumulation of formiminoglutamate (PubMed:31624291). Mice show reduced
CC hepatic folate pools with a strong accumulation of (6S)-10-
CC formyltetrahydrofolate and a significant drop in tetrahydrofolate
CC levels (PubMed:31624291). This is associated with a strong decrease of
CC glycine levels as well as levels of several glycine conjugates
CC (PubMed:31624291). {ECO:0000269|PubMed:31624291}.
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; BC025939; AAH25939.1; -; mRNA.
DR EMBL; BC028817; AAH28817.1; -; mRNA.
DR EMBL; BC030722; AAH30722.1; -; mRNA.
DR EMBL; BC030723; AAH30723.1; -; mRNA.
DR EMBL; BC030727; AAH30727.1; -; mRNA.
DR EMBL; BC030730; AAH30730.1; -; mRNA.
DR CCDS; CCDS20361.1; -.
DR RefSeq; NP_081682.1; NM_027406.1.
DR RefSeq; XP_006505342.1; XM_006505279.3.
DR AlphaFoldDB; Q8R0Y6; -.
DR SMR; Q8R0Y6; -.
DR BioGRID; 223535; 2.
DR IntAct; Q8R0Y6; 3.
DR MINT; Q8R0Y6; -.
DR STRING; 10090.ENSMUSP00000114304; -.
DR iPTMnet; Q8R0Y6; -.
DR PhosphoSitePlus; Q8R0Y6; -.
DR SwissPalm; Q8R0Y6; -.
DR EPD; Q8R0Y6; -.
DR jPOST; Q8R0Y6; -.
DR MaxQB; Q8R0Y6; -.
DR PaxDb; Q8R0Y6; -.
DR PeptideAtlas; Q8R0Y6; -.
DR PRIDE; Q8R0Y6; -.
DR ProteomicsDB; 296091; -.
DR ABCD; Q8R0Y6; 1 sequenced antibody.
DR Antibodypedia; 33051; 528 antibodies from 37 providers.
DR DNASU; 107747; -.
DR Ensembl; ENSMUST00000032175; ENSMUSP00000032175; ENSMUSG00000030088.
DR Ensembl; ENSMUST00000130418; ENSMUSP00000114304; ENSMUSG00000030088.
DR GeneID; 107747; -.
DR KEGG; mmu:107747; -.
DR UCSC; uc009cxl.1; mouse.
DR CTD; 10840; -.
DR MGI; MGI:1340024; Aldh1l1.
DR VEuPathDB; HostDB:ENSMUSG00000030088; -.
DR eggNOG; KOG2452; Eukaryota.
DR GeneTree; ENSGT00940000160913; -.
DR HOGENOM; CLU_014974_0_0_1; -.
DR InParanoid; Q8R0Y6; -.
DR OMA; HMFVAQE; -.
DR OrthoDB; 153834at2759; -.
DR PhylomeDB; Q8R0Y6; -.
DR TreeFam; TF354242; -.
DR Reactome; R-MMU-196757; Metabolism of folate and pterines.
DR BioGRID-ORCS; 107747; 2 hits in 73 CRISPR screens.
DR ChiTaRS; Aldh1l1; mouse.
DR PRO; PR:Q8R0Y6; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; Q8R0Y6; protein.
DR Bgee; ENSMUSG00000030088; Expressed in left lobe of liver and 232 other tissues.
DR ExpressionAtlas; Q8R0Y6; baseline and differential.
DR Genevisible; Q8R0Y6; MM.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0004029; F:aldehyde dehydrogenase (NAD+) activity; IBA:GO_Central.
DR GO; GO:0033721; F:aldehyde dehydrogenase (NADP+) activity; ISO:MGI.
DR GO; GO:0004030; F:aldehyde dehydrogenase [NAD(P)+] activity; ISO:MGI.
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:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0009258; P:10-formyltetrahydrofolate catabolic process; IMP:UniProtKB.
DR GO; GO:0009058; P:biosynthetic process; IEA:InterPro.
DR GO; GO:0046655; P:folic acid metabolic process; ISO:MGI.
DR GO; GO:0006740; P:NADPH regeneration; ISS: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 Pfam; PF00171; Aldedh; 1.
DR Pfam; PF02911; Formyl_trans_C; 1.
DR Pfam; PF00551; Formyl_trans_N; 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.
PE 1: Evidence at protein level;
KW Acetylation; Cytoplasm; NADP; One-carbon metabolism; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Reference proteome.
FT CHAIN 1..902
FT /note="Cytosolic 10-formyltetrahydrofolate dehydrogenase"
FT /id="PRO_0000199420"
FT DOMAIN 318..395
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..310
FT /note="Hydrolase domain"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT REGION 417..902
FT /note="Aldehyde dehydrogenase domain"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT ACT_SITE 106
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT ACT_SITE 673
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT ACT_SITE 707
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT BINDING 88..90
FT /ligand="(6S)-10-formyltetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57454"
FT /evidence="ECO:0000250|UniProtKB:O75891"
FT BINDING 142
FT /ligand="(6S)-10-formyltetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57454"
FT /evidence="ECO:0000250|UniProtKB:O75891"
FT BINDING 571..573
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT BINDING 597..600
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT BINDING 630..635
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT BINDING 650..651
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT BINDING 673..674
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT BINDING 757
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT BINDING 804..806
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT SITE 142
FT /note="Essential for catalytic activity"
FT /evidence="ECO:0000250|UniProtKB:P28037"
FT MOD_RES 9
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O75891"
FT MOD_RES 38
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 354
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000250|UniProtKB:P28037,
FT ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 629
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O75891"
FT MOD_RES 631
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O75891"
FT MOD_RES 660
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8K009"
FT MOD_RES 767
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 825
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O75891"
FT MOD_RES 882
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q3SY69"
SQ SEQUENCE 902 AA; 98709 MW; 9B5526A7FB41909E CRC64;
MKIAVIGQSL FGQEVYCQLR KEGHEVVGVF TIPDKDGKAD PLGLEAEKDG VPVFKFPRWR
ARGQALPEVV AKYQALGAEL NVLPFCSQFI PMEVINAPRH GSIIYHPSLL PRHRGASAIN
WTLIHGDKKG GFTIFWADDG LDTGDLLLQK ECDVLPDDTV STLYNRFLFP EGIKGMVQAV
RLIAEGTAPR RPQPEEGATY EGIQKKETAM INWDQPAEAI HNWIRGNDKV PGAWTEACGQ
KLTFFNSTLN TSGLVAQGEA LPIPGAHRPG LVTKAGLILF GNDDRMLLVK NIQLEDGKMM
PASQFFKGSA SSALELTEEE LATAEAVRSS WMRILPNVPE VEDSTDFFKS GAASVDVVRL
VEEVKELCDG LELENEDVYM ATTFGDFIQL LVRKLRGEDG ESECVINYVE KAVKKLTLQM
PYQLFIGGEF VDAEGAKTYS TINPTDGSVI CQVSLAQVSD VDKAVAAAKE AFENGLWGKI
NARDRGRLLY RLADLMEQHQ EELATIEALD AGAVYTLALK THVGMSIQTF RYFAGWCDKI
QGATIPINQA RPNRNLTLTK KEPVGVCGIV IPWNYPLMML SWKTAACLAA GNTVVIKPAQ
VTPLTALKFA ELTLKAGIPK GVVNILPGSG SLVGQRLSDH PDVRKIGFTG STEVGKHIMK
SCALSNVKKV SLELGGKSPL IIFADCDLNK AVQMGMSSVF FNKGENCIAA GRLFVEDSIH
DQFVQKVVEE VGKMKIGNPL DRDTNHGPQN HEAHLRKLVE YCQRGVKEGA TLVCGGNQVP
RPGFFFQPTV FTDVEDHMYI AKEESFGPIM IISRFADGDV DAVLSRANAT EFGLASGVFT
RDINKALYVS DKLQAGTVFV NTYNKTDVAA PFGGFKQSGF GKDLGEAALN EYLRIKTVTF
EY
