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Protein

Citramalyl-CoA lyase, mitochondrial

Gene

CLYBL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Mitochondrial citramalyl-CoA lyase indirectly involved in the vitamin B12 metabolism (PubMed:29056341). Converts citramalyl-CoA into acetyl-CoA and pyruvate in the C5-dicarboxylate catabolism pathway (PubMed:29056341). The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, a vitamin B12-poisoning metabolite (PubMed:29056341). Also acts as a malate synthase in vitro, converting glyoxylate and acetyl-CoA to malate (PubMed:24334609, PubMed:29056341). Also acts as a beta-methylmalate synthase in vitro, by mediating conversion of glyoxylate and propionyl-CoA to beta-methylmalate (PubMed:24334609, PubMed:29056341). Also has very weak citramalate synthase activity in vitro (PubMed:24334609, PubMed:29056341).2 Publications

Caution

This organism lacks the other subunits that are necessary for ATP-independent citrate lyase activity. Even though this protein has clear similarity to citrate lyase beta subunit, it is expected to have a somewhat different enzyme activity.Curated

Catalytic activityi

Acetyl-CoA + H2O + glyoxylate = (S)-malate + CoA.2 Publications
Propionyl-CoA + H2O + glyoxylate = beta-methylmalate + CoA.2 Publications
(3S)-citramalyl-CoA = acetyl-CoA + pyruvate.1 Publication

Cofactori

Mg2+2 PublicationsNote: Binds 1 Mg2+ ion per subunit.1 Publication

Kineticsi

kcat is 0.12 sec(-1) for malate synthase reaction (PubMed:24334609). kcat is 0.09 sec(-1) for beta-methylmalate synthase reaction (PubMed:24334609). kcat is 0.135 sec(-1) for beta-methylmalate synthase reaction (PubMed:29056341). kcat is 0.146 sec(-1) for malate synthase reaction (PubMed:29056341). kcat is 0.08 sec(-1) for citramalate synthase reaction (PubMed:29056341). kcat is 14.1 sec(-1) for citramalyl-CoA lyase reaction (PubMed:29056341).2 Publications
  1. KM=3.6 mM for glyoxylate (with acetyl-CoA as cosubstrate)1 Publication
  2. KM=1.2 mM for glyoxylate (with propionyl-CoA as cosubstrate)1 Publication
  3. KM=28.7 µM for propionyl-CoA (for beta-methylmalate synthase)1 Publication
  4. KM=57.3 µM for acetyl-CoA (for malate synthase)1 Publication
  5. KM=25 µM for acetyl-CoA (for citramalate synthase)1 Publication
  6. KM=23 µM for (3S)-citramalyl-CoA (for citramalyl-CoA lyase)1 Publication
  7. KM=74 µM for acetyl-CoA1 Publication
  8. KM=23 µM for propionyl-CoA1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei50SubstrateCombined sources1 Publication1
    Binding sitei57SubstrateCombined sources1 Publication1
    Binding sitei61SubstrateCombined sources1 Publication1
    Binding sitei107SubstrateCombined sources1 Publication1
    Metal bindingi171MagnesiumCombined sources1 Publication1
    Metal bindingi206MagnesiumCombined sources1 Publication1
    Active sitei3201 Publication1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionLyase, Transferase
    LigandMagnesium, Metal-binding

    Enzyme and pathway databases

    BioCyciMetaCyc:HS04862-MONOMER
    BRENDAi4.1.3.6 2681

    Chemistry databases

    SwissLipidsiSLP:000001839

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Citramalyl-CoA lyase, mitochondrial1 Publication (EC:4.1.3.251 Publication)
    Alternative name(s):
    Beta-methylmalate synthase (EC:2.3.3.-2 Publications)
    Citrate lyase subunit beta-like proteinCurated
    Short name:
    Citrate lyase beta-likeCurated
    Malate synthase (EC:2.3.3.92 Publications)
    Gene namesi
    Name:CLYBLImported
    Synonyms:CLB
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 13

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000125246.15
    HGNCiHGNC:18355 CLYBL
    MIMi609686 gene
    neXtProtiNX_Q8N0X4

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Mitochondrion

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi320D → A or N: Abolishes citramalyl-CoA lyase activity. 1 Publication1

    Organism-specific databases

    DisGeNETi171425
    OpenTargetsiENSG00000125246
    PharmGKBiPA26622

    Polymorphism and mutation databases

    BioMutaiCLYBL
    DMDMi146286073

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 22MitochondrionSequence analysisAdd BLAST22
    ChainiPRO_000028638923 – 340Citramalyl-CoA lyase, mitochondrialAdd BLAST318

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei57N6-acetyllysineBy similarity1
    Modified residuei61N6-acetyllysineBy similarity1
    Modified residuei82N6-acetyllysine; alternateBy similarity1
    Modified residuei82N6-succinyllysine; alternateBy similarity1
    Modified residuei92N6-acetyllysine; alternateBy similarity1
    Modified residuei92N6-succinyllysine; alternateBy similarity1
    Modified residuei309N6-succinyllysineBy similarity1

    Keywords - PTMi

    Acetylation

    Proteomic databases

    EPDiQ8N0X4
    MaxQBiQ8N0X4
    PaxDbiQ8N0X4
    PeptideAtlasiQ8N0X4
    PRIDEiQ8N0X4
    ProteomicsDBi71483
    71484 [Q8N0X4-2]

    PTM databases

    iPTMnetiQ8N0X4
    PhosphoSitePlusiQ8N0X4

    Expressioni

    Gene expression databases

    BgeeiENSG00000125246 Expressed in 183 organ(s), highest expression level in liver
    CleanExiHS_CLYBL
    ExpressionAtlasiQ8N0X4 baseline and differential
    GenevisibleiQ8N0X4 HS

    Organism-specific databases

    HPAiHPA039959
    HPA040691

    Interactioni

    Subunit structurei

    Homotrimer.1 Publication

    Protein-protein interaction databases

    BioGridi128126, 3 interactors
    STRINGi9606.ENSP00000342991

    Structurei

    Secondary structure

    1340
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliQ8N0X4
    SMRiQ8N0X4
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni272 – 273Substrate bindingCombined sources1 Publication2

    Sequence similaritiesi

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiENOG410IGUQ Eukaryota
    COG2301 LUCA
    GeneTreeiENSGT00390000017163
    HOGENOMiHOG000242281
    HOVERGENiHBG059382
    InParanoidiQ8N0X4
    KOiK11390
    OMAiAWLFCPA
    OrthoDBiEOG091G0EXW
    PhylomeDBiQ8N0X4
    TreeFamiTF313596

    Family and domain databases

    InterProiView protein in InterPro
    IPR005000 Aldolase/citrate-lyase_domain
    IPR011206 Citrate_lyase_beta/mcl1/mcl2
    IPR015813 Pyrv/PenolPyrv_Kinase-like_dom
    PfamiView protein in Pfam
    PF03328 HpcH_HpaI, 1 hit
    PIRSFiPIRSF015582 Cit_lyase_B, 1 hit
    SUPFAMiSSF51621 SSF51621, 1 hit

    Sequences (2+)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    This entry has 2 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

    Isoform 1 (identifier: Q8N0X4-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide
            10         20         30         40         50
    MALRLLRRAA RGAAAAALLR LKASLAADIP RLGYSSSSHH KYIPRRAVLY
    60 70 80 90 100
    VPGNDEKKIK KIPSLNVDCA VLDCEDGVAA NKKNEARLRI VKTLEDIDLG
    110 120 130 140 150
    PTEKCVRVNS VSSGLAEEDL ETLLQSRVLP SSLMLPKVES PEEIQWFADK
    160 170 180 190 200
    FSFHLKGRKL EQPMNLIPFV ETAMGLLNFK AVCEETLKVG PQVGLFLDAV
    210 220 230 240 250
    VFGGEDFRAS IGATSSKETL DILYARQKIV VIAKAFGLQA IDLVYIDFRD
    260 270 280 290 300
    GAGLLRQSRE GAAMGFTGKQ VIHPNQIAVV QEQFSPSPEK IKWAEELIAA
    310 320 330 340
    FKEHQQLGKG AFTFQGSMID MPLLKQAQNT VTLATSIKEK
    Length:340
    Mass (Da):37,359
    Last modified:May 1, 2007 - v2
    Checksum:i0C99A5A4F09E03E2
    GO
    Isoform 2 (identifier: Q8N0X4-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         147-180: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:306
    Mass (Da):33,409
    Checksum:iEDFEA04BA12E1934
    GO

    Computationally mapped potential isoform sequencesi

    There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    Q5JVC2Q5JVC2_HUMAN
    Citramalyl-CoA lyase, mitochondrial
    CLYBL
    181Annotation score:
    Q5JVC1Q5JVC1_HUMAN
    Citramalyl-CoA lyase, mitochondrial
    CLYBL
    147Annotation score:
    Q5JVC0Q5JVC0_HUMAN
    Citramalyl-CoA lyase, mitochondrial
    CLYBL
    103Annotation score:
    Q5JVB9Q5JVB9_HUMAN
    Citramalyl-CoA lyase, mitochondrial
    CLYBL
    89Annotation score:

    Polymorphismi

    The protein is absent in 2.7% of the human population due to a loss-of-function polymorphism (rs41281112) that changes Arg-259 to a premature stop codon, leading to loss of the protein product (PubMed:23754956, PubMed:24334609). This polymorphism is associated with reduction of circulating vitamin B12 (PubMed:23754956, PubMed:24334609). The reduction of circulating vitamin B12 is caused by accumulation of citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate (PubMed:29056341). Itaconate acting as a vitamin B12-poisoning metabolite that inactivates the mitochondrial methylglutaconyl-CoA hydratase (AUH) enzyme (PubMed:29056341).3 Publications

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_03209928D → Y. Corresponds to variant dbSNP:rs17577293Ensembl.1
    Natural variantiVAR_032100128V → I. Corresponds to variant dbSNP:rs35680839Ensembl.1
    Natural variantiVAR_032101241I → V2 PublicationsCorresponds to variant dbSNP:rs3783185Ensembl.1
    Natural variantiVAR_073420259 – 340Missing Polymorphism; loss of the protein product; reduction of circulating vitamin B12. 2 PublicationsCorresponds to variant dbSNP:rs41281112Add BLAST82

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_034643147 – 180Missing in isoform 2. CuratedAdd BLAST34

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF428253 mRNA Translation: AAL84703.1
    AK095506 mRNA Translation: BAC04561.1
    AL137139 Genomic DNA No translation available.
    AL139035 Genomic DNA No translation available.
    BC034360 mRNA Translation: AAH34360.1
    CCDSiCCDS32002.1 [Q8N0X4-1]
    RefSeqiNP_996531.1, NM_206808.3 [Q8N0X4-1]
    XP_005254087.1, XM_005254030.2 [Q8N0X4-1]
    XP_005254088.1, XM_005254031.2 [Q8N0X4-2]
    XP_006719978.1, XM_006719915.3 [Q8N0X4-1]
    XP_011519353.1, XM_011521051.2 [Q8N0X4-1]
    XP_011519354.1, XM_011521052.2 [Q8N0X4-1]
    XP_016875891.1, XM_017020402.1 [Q8N0X4-2]
    UniGeneiHs.655642

    Genome annotation databases

    EnsembliENST00000339105; ENSP00000342991; ENSG00000125246 [Q8N0X4-1]
    ENST00000376354; ENSP00000365532; ENSG00000125246 [Q8N0X4-2]
    ENST00000376355; ENSP00000365533; ENSG00000125246 [Q8N0X4-1]
    GeneIDi171425
    KEGGihsa:171425
    UCSCiuc001vok.5 human [Q8N0X4-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF428253 mRNA Translation: AAL84703.1
    AK095506 mRNA Translation: BAC04561.1
    AL137139 Genomic DNA No translation available.
    AL139035 Genomic DNA No translation available.
    BC034360 mRNA Translation: AAH34360.1
    CCDSiCCDS32002.1 [Q8N0X4-1]
    RefSeqiNP_996531.1, NM_206808.3 [Q8N0X4-1]
    XP_005254087.1, XM_005254030.2 [Q8N0X4-1]
    XP_005254088.1, XM_005254031.2 [Q8N0X4-2]
    XP_006719978.1, XM_006719915.3 [Q8N0X4-1]
    XP_011519353.1, XM_011521051.2 [Q8N0X4-1]
    XP_011519354.1, XM_011521052.2 [Q8N0X4-1]
    XP_016875891.1, XM_017020402.1 [Q8N0X4-2]
    UniGeneiHs.655642

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5VXCX-ray1.87A30-340[»]
    5VXOX-ray2.27A/B/C30-340[»]
    5VXSX-ray2.95A/B/C/D/E/F30-340[»]
    ProteinModelPortaliQ8N0X4
    SMRiQ8N0X4
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi128126, 3 interactors
    STRINGi9606.ENSP00000342991

    Chemistry databases

    SwissLipidsiSLP:000001839

    PTM databases

    iPTMnetiQ8N0X4
    PhosphoSitePlusiQ8N0X4

    Polymorphism and mutation databases

    BioMutaiCLYBL
    DMDMi146286073

    Proteomic databases

    EPDiQ8N0X4
    MaxQBiQ8N0X4
    PaxDbiQ8N0X4
    PeptideAtlasiQ8N0X4
    PRIDEiQ8N0X4
    ProteomicsDBi71483
    71484 [Q8N0X4-2]

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000339105; ENSP00000342991; ENSG00000125246 [Q8N0X4-1]
    ENST00000376354; ENSP00000365532; ENSG00000125246 [Q8N0X4-2]
    ENST00000376355; ENSP00000365533; ENSG00000125246 [Q8N0X4-1]
    GeneIDi171425
    KEGGihsa:171425
    UCSCiuc001vok.5 human [Q8N0X4-1]

    Organism-specific databases

    CTDi171425
    DisGeNETi171425
    EuPathDBiHostDB:ENSG00000125246.15
    GeneCardsiCLYBL
    HGNCiHGNC:18355 CLYBL
    HPAiHPA039959
    HPA040691
    MIMi609686 gene
    neXtProtiNX_Q8N0X4
    OpenTargetsiENSG00000125246
    PharmGKBiPA26622
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiENOG410IGUQ Eukaryota
    COG2301 LUCA
    GeneTreeiENSGT00390000017163
    HOGENOMiHOG000242281
    HOVERGENiHBG059382
    InParanoidiQ8N0X4
    KOiK11390
    OMAiAWLFCPA
    OrthoDBiEOG091G0EXW
    PhylomeDBiQ8N0X4
    TreeFamiTF313596

    Enzyme and pathway databases

    BioCyciMetaCyc:HS04862-MONOMER
    BRENDAi4.1.3.6 2681

    Miscellaneous databases

    ChiTaRSiCLYBL human
    GenomeRNAii171425
    PROiPR:Q8N0X4
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000125246 Expressed in 183 organ(s), highest expression level in liver
    CleanExiHS_CLYBL
    ExpressionAtlasiQ8N0X4 baseline and differential
    GenevisibleiQ8N0X4 HS

    Family and domain databases

    InterProiView protein in InterPro
    IPR005000 Aldolase/citrate-lyase_domain
    IPR011206 Citrate_lyase_beta/mcl1/mcl2
    IPR015813 Pyrv/PenolPyrv_Kinase-like_dom
    PfamiView protein in Pfam
    PF03328 HpcH_HpaI, 1 hit
    PIRSFiPIRSF015582 Cit_lyase_B, 1 hit
    SUPFAMiSSF51621 SSF51621, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiCLYBL_HUMAN
    AccessioniPrimary (citable) accession number: Q8N0X4
    Secondary accession number(s): Q5W0F7, Q8TDH8
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 1, 2007
    Last sequence update: May 1, 2007
    Last modified: September 12, 2018
    This is version 131 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Human chromosome 13
      Human chromosome 13: entries, gene names and cross-references to MIM
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