HACL1_MOUSE
ID HACL1_MOUSE Reviewed; 581 AA.
AC Q9QXE0; Q543K1; Q9DAV1;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 02-MAY-2002, sequence version 2.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=2-hydroxyacyl-CoA lyase 1;
DE EC=4.1.2.63 {ECO:0000269|PubMed:28629946};
DE AltName: Full=2-hydroxyphytanoyl-CoA lyase;
DE Short=2-HPCL;
DE AltName: Full=Phytanoyl-CoA 2-hydroxylase 2;
GN Name=Hacl1; Synonyms=Hpcl, Phyh2;
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 [MRNA].
RX PubMed=11171065; DOI=10.1042/0264-6021:3530673;
RA Huyghe S., Casteels M., Janssen A., Meulders L., Mannaerts G.P.,
RA Declercq P.E., Van Veldhoven P.P., Baes M.;
RT "Prenatal and postnatal development of peroxisomal lipid-metabolizing
RT pathways in the mouse.";
RL Biochem. J. 353:673-680(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Liver, Placenta, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17208939; DOI=10.1074/mcp.m600218-mcp200;
RA Lee J., Xu Y., Chen Y., Sprung R., Kim S.C., Xie S., Zhao Y.;
RT "Mitochondrial phosphoproteome revealed by an improved IMAC method and
RT MS/MS/MS.";
RL Mol. Cell. Proteomics 6:669-676(2007).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Kidney, Liver, 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 [6]
RP SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-354; LYS-361 AND LYS-368, 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 [7]
RP DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=28629946; DOI=10.1016/j.bbalip.2017.06.004;
RA Mezzar S., De Schryver E., Asselberghs S., Meyhi E., Morvay P.L., Baes M.,
RA Van Veldhoven P.P.;
RT "Phytol-induced pathology in 2-hydroxyacyl-CoA lyase (HACL1) deficient
RT mice. Evidence for a second non-HACL1-related lyase.";
RL Biochim. Biophys. Acta 1862:972-990(2017).
RN [8]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=29027957; DOI=10.3390/molecules22101718;
RA Jenkins B., de Schryver E., Van Veldhoven P.P., Koulman A.;
RT "Peroxisomal 2-Hydroxyacyl-CoA Lyase Is Involved in Endogenous Biosynthesis
RT of Heptadecanoic Acid.";
RL Molecules 22:0-0(2017).
CC -!- FUNCTION: Peroxisomal 2-OH acyl-CoA lyase involved in the cleavage (C1
CC removal) reaction in the fatty acid alpha-oxydation in a thiamine
CC pyrophosphate (TPP)-dependent manner (By similarity). Involved in the
CC degradation of 3-methyl-branched fatty acids like phytanic acid and the
CC shortening of 2-hydroxy long-chain fatty acids (By similarity). Plays a
CC significant role in the biosynthesis of heptadecanal in the liver
CC (PubMed:29027957). {ECO:0000250|UniProtKB:Q9UJ83,
CC ECO:0000269|PubMed:29027957}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 2-hydroxy-3-methyl fatty acyl-CoA = a 2-methyl-branched
CC fatty aldehyde + formyl-CoA; Xref=Rhea:RHEA:25375, ChEBI:CHEBI:49188,
CC ChEBI:CHEBI:57376, ChEBI:CHEBI:58783; EC=4.1.2.63;
CC Evidence={ECO:0000250|UniProtKB:Q8CHM7};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25376;
CC Evidence={ECO:0000250|UniProtKB:Q8CHM7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an (R)-2-hydroxy-long-chain-fatty acyl-CoA = a long-chain
CC fatty aldehyde + formyl-CoA; Xref=Rhea:RHEA:67444, ChEBI:CHEBI:17176,
CC ChEBI:CHEBI:57376, ChEBI:CHEBI:170012; EC=4.1.2.63;
CC Evidence={ECO:0000250|UniProtKB:Q8CHM7};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67445;
CC Evidence={ECO:0000250|UniProtKB:Q8CHM7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-hydroxy-3-methylhexadecanoyl-CoA = 2-methylpentadecanal +
CC formyl-CoA; Xref=Rhea:RHEA:25379, ChEBI:CHEBI:49190,
CC ChEBI:CHEBI:57376, ChEBI:CHEBI:58784;
CC Evidence={ECO:0000250|UniProtKB:Q8CHM7};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25380;
CC Evidence={ECO:0000250|UniProtKB:Q8CHM7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-hydroxyoctadecanoyl-CoA = formyl-CoA + heptadecanal;
CC Xref=Rhea:RHEA:55196, ChEBI:CHEBI:57376, ChEBI:CHEBI:74116,
CC ChEBI:CHEBI:138631; Evidence={ECO:0000269|PubMed:28629946};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55197;
CC Evidence={ECO:0000250|UniProtKB:Q9UJ83};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-hydroxyphytanoyl-CoA = 2,6,10,14-tetramethylpentadecanal +
CC formyl-CoA; Xref=Rhea:RHEA:25355, ChEBI:CHEBI:49189,
CC ChEBI:CHEBI:57334, ChEBI:CHEBI:57376;
CC Evidence={ECO:0000250|UniProtKB:Q9UJ83};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25356;
CC Evidence={ECO:0000250|UniProtKB:Q9UJ83};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q8CHM7};
CC Note=Binds 1 Mg(2+) ion per subunit. {ECO:0000250|UniProtKB:Q8CHM7};
CC -!- COFACTOR:
CC Name=thiamine diphosphate; Xref=ChEBI:CHEBI:58937;
CC Evidence={ECO:0000250|UniProtKB:Q8CHM7};
CC Note=Binds 1 thiamine pyrophosphate per subunit.
CC {ECO:0000250|UniProtKB:Q8CHM7};
CC -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:Q8CHM7}.
CC -!- SUBCELLULAR LOCATION: Peroxisome {ECO:0000250|UniProtKB:Q9UJ83}.
CC -!- TISSUE SPECIFICITY: Predominanly expressed in liver.
CC {ECO:0000269|PubMed:28629946}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable and fertile and show no abnormal
CC phenotype (PubMed:28629946, PubMed:29027957). However, upon dietary
CC administration of phytol, phytanic acid accumulated in tissues, mainly
CC in liver and serum of deficient mice. As a consequence of phytanic acid
CC (or a metabolite) toxicity, deficent mice display a significant weight
CC loss, absence of abdominal white adipose tissue, enlarged and mottled
CC liver and reduced hepatic glycogen and triglyceride (PubMed:28629946).
CC The presence of an other lyase, probably HCL2, can partially compensate
CC for the lost of HCL1 (PubMed:28629946). {ECO:0000269|PubMed:28629946,
CC ECO:0000269|PubMed:29027957}.
CC -!- SIMILARITY: Belongs to the TPP enzyme family. {ECO:0000305}.
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DR EMBL; AJ132139; CAB65550.1; -; mRNA.
DR EMBL; AK005505; BAB24085.1; -; mRNA.
DR EMBL; AK041686; BAC31032.1; -; mRNA.
DR EMBL; AK050078; BAC34059.1; -; mRNA.
DR EMBL; BC021360; AAH21360.1; -; mRNA.
DR CCDS; CCDS26915.1; -.
DR RefSeq; NP_064359.2; NM_019975.3.
DR AlphaFoldDB; Q9QXE0; -.
DR SMR; Q9QXE0; -.
DR BioGRID; 208178; 14.
DR STRING; 10090.ENSMUSP00000022437; -.
DR iPTMnet; Q9QXE0; -.
DR PhosphoSitePlus; Q9QXE0; -.
DR SwissPalm; Q9QXE0; -.
DR EPD; Q9QXE0; -.
DR jPOST; Q9QXE0; -.
DR MaxQB; Q9QXE0; -.
DR PaxDb; Q9QXE0; -.
DR PRIDE; Q9QXE0; -.
DR ProteomicsDB; 269709; -.
DR DNASU; 56794; -.
DR Ensembl; ENSMUST00000022437; ENSMUSP00000022437; ENSMUSG00000021884.
DR Ensembl; ENSMUST00000156431; ENSMUSP00000114922; ENSMUSG00000021884.
DR GeneID; 56794; -.
DR KEGG; mmu:56794; -.
DR UCSC; uc007sxx.2; mouse.
DR CTD; 26061; -.
DR MGI; MGI:1929657; Hacl1.
DR VEuPathDB; HostDB:ENSMUSG00000021884; -.
DR eggNOG; KOG1185; Eukaryota.
DR GeneTree; ENSGT00940000156802; -.
DR InParanoid; Q9QXE0; -.
DR OMA; FQEWPQV; -.
DR OrthoDB; 330201at2759; -.
DR PhylomeDB; Q9QXE0; -.
DR TreeFam; TF105690; -.
DR BRENDA; 4.1.2.63; 3474.
DR Reactome; R-MMU-389599; Alpha-oxidation of phytanate.
DR Reactome; R-MMU-9033241; Peroxisomal protein import.
DR UniPathway; UPA00199; -.
DR BioGRID-ORCS; 56794; 0 hits in 71 CRISPR screens.
DR PRO; PR:Q9QXE0; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q9QXE0; protein.
DR Bgee; ENSMUSG00000021884; Expressed in liver and 80 other tissues.
DR ExpressionAtlas; Q9QXE0; baseline and differential.
DR Genevisible; Q9QXE0; MM.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005777; C:peroxisome; ISS:HGNC-UCL.
DR GO; GO:0106360; F:2-hydroxy-3-methylhexadecanoyl-CoA lyase activity; ISO:MGI.
DR GO; GO:0106376; F:2-hydroxyphytanoyl-CoA lyase activity; IEA:RHEA.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0016830; F:carbon-carbon lyase activity; IMP:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB.
DR GO; GO:0016829; F:lyase activity; IDA:MGI.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0030976; F:thiamine pyrophosphate binding; ISS:HGNC-UCL.
DR GO; GO:0001561; P:fatty acid alpha-oxidation; IMP:UniProtKB.
DR GO; GO:0006631; P:fatty acid metabolic process; ISO:MGI.
DR GO; GO:0006629; P:lipid metabolic process; IDA:MGI.
DR GO; GO:0097089; P:methyl-branched fatty acid metabolic process; ISS:UniProtKB.
DR GO; GO:1903512; P:phytanic acid metabolic process; ISS:UniProtKB.
DR GO; GO:0006625; P:protein targeting to peroxisome; ISS:UniProtKB.
DR InterPro; IPR029035; DHS-like_NAD/FAD-binding_dom.
DR InterPro; IPR045025; HACL1-like.
DR InterPro; IPR029061; THDP-binding.
DR InterPro; IPR012000; Thiamin_PyroP_enz_cen_dom.
DR InterPro; IPR012001; Thiamin_PyroP_enz_TPP-bd_dom.
DR InterPro; IPR011766; TPP_enzyme-bd_C.
DR PANTHER; PTHR43710; PTHR43710; 1.
DR Pfam; PF02775; TPP_enzyme_C; 1.
DR Pfam; PF00205; TPP_enzyme_M; 1.
DR Pfam; PF02776; TPP_enzyme_N; 1.
DR SUPFAM; SSF52467; SSF52467; 1.
DR SUPFAM; SSF52518; SSF52518; 2.
PE 1: Evidence at protein level;
KW Fatty acid metabolism; Lipid metabolism; Lyase; Magnesium; Metal-binding;
KW Peroxisome; Phosphoprotein; Reference proteome; Thiamine pyrophosphate.
FT CHAIN 1..581
FT /note="2-hydroxyacyl-CoA lyase 1"
FT /id="PRO_0000090817"
FT REGION 404..487
FT /note="Thiamine pyrophosphate binding"
FT /evidence="ECO:0000250|UniProtKB:P40149"
FT MOTIF 579..581
FT /note="Microbody targeting signal"
FT /evidence="ECO:0000250|UniProtKB:Q9UJ83"
FT BINDING 63
FT /ligand="thiamine diphosphate"
FT /ligand_id="ChEBI:CHEBI:58937"
FT /evidence="ECO:0000250|UniProtKB:P40149"
FT BINDING 458
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P40149"
FT BINDING 485
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P40149"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UJ83"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8CHM7"
FT MOD_RES 354
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 361
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 368
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT CONFLICT 252
FT /note="M -> I (in Ref. 1; CAB65550)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 581 AA; 63660 MW; 7CABBFC780A32A69 CRC64;
MPESNSAEGS DRSEEQVSGA KVIAQALKTQ DVEYMFGVVG IPVTEIALAA QELGIKYIGM
RNEQAACYAA SAVGYLTGRP GVCLVVSGPG LIHALGGMAN ANMNCWPLIV IGGSSERNQE
AMGAFQEFPQ VEACRLYTKF SARPSTIELI PFIIEKAVRS SIYGRPGACY IDIPADFVTL
QANVTSIKYK ECCMPPPVSM AETSAVCAAA SVLRDAKQPL LIIGKGAAYS HAEDSIRKLV
EQCSLPFLPT PMGKGVVPDN HPNCVGAARS RALQSADVIV LFGARLNWIL HFGLPPRYQA
DVKFIQIDIC AEELGNNVRP SVILLGDIDA VSKQLLEQFD KTPWQCPPDS QWWKTLREKM
KSNEAISKEL ASQKSLPMNY YTVFYHVQEQ LPRDSFIVSE GANTMDIGRT MLQNCLPRHR
LDAGSFGTMG VGLGFAIAAA LVAKDRSPGQ RVICVEGDSA FGFSGMEVET ICRYNLPIIL
LVVNNNGIYQ GFDADTWEKM LHFQEAATTV PPMCLLPNSH YEQVMTAFGG KGYFVRTPEE
LQHSLRQALQ DTSKPCLLNI MIEPQSTRKA QDFHWLTRSN M
