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Protein

Cytosolic non-specific dipeptidase

Gene

CNDP2

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

Functioni

Hydrolyzes a variety of dipeptides including L-carnosine but has a strong preference for Cys-Gly (PubMed:19346245). Acts as a functional tumor suppressor in gastric cancer via activation of the mitogen-activated protein kinase (MAPK) pathway. An elevated level of CNDP2 activates the p38 and JNK MAPK pathways to induce cell apoptosis, and a lower level of CNDP2 activates the ERK MAPK pathway to promote cell proliferation (PubMed:24395568). Isoform 2 may play a role as tumor suppressor in hepatocellular carcinoma (HCC) cells (PubMed:17121880). Catalyzes the production of N-lactoyl-amino acids from lactate and amino acids by reverse proteolysis (PubMed:25964343).4 Publications

Miscellaneous

The reverse proteolysis is not negligible in vivo as long as the substrates are present in considerable concentrations, such as upon physical exercice. N-lac-Phe plasma levels are increased in patients with PKU with increased plasma Phe levels. N-lactoyl-amino acids are present in many tissues.1 Publication

Catalytic activityi

Hydrolysis of dipeptides, preferentially hydrophobic dipeptides including prolyl amino acids.1 Publication

Cofactori

Mn2+By similarityNote: Binds 2 manganese ions per subunit.By similarity

Enzyme regulationi

Inhibited by p-hydroxymercurybenzoate. The inhibitory concentration 50% (IC50) is 13 µM. Inhibited by bestatin. The inhibitory concentration 50% (IC50) is 7 nM at pH 9.5.1 Publication

Kineticsi

  1. KM=1.04 mM for Ser-Gln (at pH 7.5 and in the presence of 0.1 mM manganese ions)2 Publications
  2. KM=0.6 mM for Cys-Gly (at pH 8.0 and in the presence of 50 µM manganese ions)2 Publications
  3. KM=15 mM for carnosine (at pH 9.5 and in the presence of 0.1 mM manganese ions)2 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi99Manganese 2By similarity1
    Active sitei101By similarity1
    Metal bindingi132Manganese 1By similarity1
    Metal bindingi132Manganese 2By similarity1
    Active sitei166Proton acceptorBy similarity1
    Metal bindingi167Manganese 1By similarity1
    Metal bindingi195Manganese 2By similarity1
    Binding sitei195Substrate; via carbonyl oxygenBy similarity1
    Binding sitei228Substrate; shared with homodimeric partnerBy similarity1
    Sitei228Important for catalytic activityBy similarity1
    Binding sitei330Substrate; shared with homodimeric partnerBy similarity1
    Binding sitei343SubstrateBy similarity1
    Binding sitei417Substrate; via amide nitrogen and carbonyl oxygenBy similarity1
    Metal bindingi445Manganese 1By similarity1
    Binding sitei445SubstrateBy similarity1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionCarboxypeptidase, Hydrolase, Metalloprotease, Protease
    LigandManganese, Metal-binding

    Enzyme and pathway databases

    BRENDAi3.4.13.18 2681
    ReactomeiR-HSA-174403 Glutathione synthesis and recycling
    SABIO-RKiQ96KP4

    Protein family/group databases

    MEROPSiM20.005

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Cytosolic non-specific dipeptidase (EC:3.4.13.18)
    Alternative name(s):
    CNDP dipeptidase 2
    Carnosine dipeptidase II1 Publication
    Epididymis secretory protein Li 13Imported
    Glutamate carboxypeptidase-like protein 1
    Peptidase A
    Gene namesi
    Name:CNDP2
    Synonyms:CN2, CPGL, HEL-S-13Imported, PEPA
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 18

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000133313.14
    HGNCiHGNC:24437 CNDP2
    MIMi169800 gene
    neXtProtiNX_Q96KP4

    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

    Cytoplasm

    Pathology & Biotechi

    Organism-specific databases

    DisGeNETi55748
    OpenTargetsiENSG00000133313
    PharmGKBiPA134975242

    Polymorphism and mutation databases

    BioMutaiCNDP2
    DMDMi23396498

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Initiator methionineiRemovedCombined sources1 Publication
    ChainiPRO_00001852722 – 475Cytosolic non-specific dipeptidaseAdd BLAST474

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei2N-acetylalanineCombined sources1 Publication1
    Modified residuei9N6-acetyllysineCombined sources1
    Modified residuei58PhosphoserineBy similarity1
    Modified residuei299PhosphoserineCombined sources1

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    EPDiQ96KP4
    PaxDbiQ96KP4
    PeptideAtlasiQ96KP4
    PRIDEiQ96KP4

    2D gel databases

    OGPiQ96KP4

    PTM databases

    iPTMnetiQ96KP4
    PhosphoSitePlusiQ96KP4

    Expressioni

    Tissue specificityi

    Isoform 1 is ubiquitously expressed with higher levels in kidney and liver (at protein level). Expressed in peripheral blood leukocytes (PubMed:12473676). Isoform 2 is expressed in fetal tissues, it is only expressed in adult liver and placental tissues. Down-regulated in gastric cancer tissues (at protein level) (PubMed:24395568).3 Publications

    Gene expression databases

    BgeeiENSG00000133313
    CleanExiHS_CNDP2
    ExpressionAtlasiQ96KP4 baseline and differential
    GenevisibleiQ96KP4 HS

    Organism-specific databases

    HPAiCAB026196
    HPA036898
    HPA036899

    Interactioni

    Subunit structurei

    Homodimer.1 Publication

    Protein-protein interaction databases

    BioGridi120866, 49 interactors
    IntActiQ96KP4, 5 interactors
    STRINGi9606.ENSP00000325548

    Structurei

    Secondary structure

    1475
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi5 – 13Combined sources9
    Helixi15 – 27Combined sources13
    Beta strandi31 – 33Combined sources3
    Helixi35 – 37Combined sources3
    Helixi38 – 54Combined sources17
    Beta strandi58 – 62Combined sources5
    Beta strandi66 – 68Combined sources3
    Beta strandi74 – 76Combined sources3
    Beta strandi80 – 85Combined sources6
    Beta strandi93 – 99Combined sources7
    Helixi107 – 109Combined sources3
    Beta strandi119 – 121Combined sources3
    Beta strandi124 – 127Combined sources4
    Turni128 – 133Combined sources6
    Helixi134 – 149Combined sources16
    Beta strandi155 – 164Combined sources10
    Helixi166 – 168Combined sources3
    Helixi173 – 180Combined sources8
    Turni181 – 184Combined sources4
    Beta strandi190 – 193Combined sources4
    Beta strandi199 – 203Combined sources5
    Beta strandi205 – 210Combined sources6
    Beta strandi212 – 221Combined sources10
    Helixi229 – 232Combined sources4
    Turni233 – 235Combined sources3
    Helixi239 – 247Combined sources9
    Beta strandi259 – 261Combined sources3
    Helixi284 – 289Combined sources6
    Turni290 – 292Combined sources3
    Helixi301 – 309Combined sources9
    Beta strandi313 – 322Combined sources10
    Beta strandi325 – 327Combined sources3
    Beta strandi334 – 344Combined sources11
    Helixi350 – 368Combined sources19
    Beta strandi372 – 382Combined sources11
    Helixi392 – 405Combined sources14
    Beta strandi410 – 416Combined sources7
    Helixi420 – 428Combined sources9
    Beta strandi430 – 434Combined sources5
    Beta strandi450 – 452Combined sources3
    Helixi453 – 471Combined sources19

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    4RUHX-ray2.25A/B1-475[»]
    ProteinModelPortaliQ96KP4
    SMRiQ96KP4
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni166 – 167Substrate bindingBy similarity2

    Sequence similaritiesi

    Belongs to the peptidase M20A family.Curated

    Phylogenomic databases

    eggNOGiKOG2276 Eukaryota
    COG0624 LUCA
    GeneTreeiENSGT00390000009682
    HOGENOMiHOG000216709
    HOVERGENiHBG051103
    InParanoidiQ96KP4
    KOiK08660
    OMAiHITIPGF
    OrthoDBiEOG091G05RU
    PhylomeDBiQ96KP4
    TreeFamiTF300633

    Family and domain databases

    CDDicd05676 M20_dipept_like_CNDP, 1 hit
    InterProiView protein in InterPro
    IPR001261 ArgE/DapE_CS
    IPR017153 CNDP/DUG1
    IPR002933 Peptidase_M20
    IPR011650 Peptidase_M20_dimer
    PfamiView protein in Pfam
    PF07687 M20_dimer, 1 hit
    PF01546 Peptidase_M20, 1 hit
    PIRSFiPIRSF037242 CNDP_dipeptidase, 1 hit
    PROSITEiView protein in PROSITE
    PS00759 ARGE_DAPE_CPG2_2, 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

    Isoform 1 (identifier: Q96KP4-1) [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
    MAALTTLFKY IDENQDRYIK KLAKWVAIQS VSAWPEKRGE IRRMMEVAAA
    60 70 80 90 100
    DVKQLGGSVE LVDIGKQKLP DGSEIPLPPI LLGRLGSDPQ KKTVCIYGHL
    110 120 130 140 150
    DVQPAALEDG WDSEPFTLVE RDGKLYGRGS TDDKGPVAGW INALEAYQKT
    160 170 180 190 200
    GQEIPVNVRF CLEGMEESGS EGLDELIFAR KDTFFKDVDY VCISDNYWLG
    210 220 230 240 250
    KKKPCITYGL RGICYFFIEV ECSNKDLHSG VYGGSVHEAM TDLILLMGSL
    260 270 280 290 300
    VDKRGNILIP GINEAVAAVT EEEHKLYDDI DFDIEEFAKD VGAQILLHSH
    310 320 330 340 350
    KKDILMHRWR YPSLSLHGIE GAFSGSGAKT VIPRKVVGKF SIRLVPNMTP
    360 370 380 390 400
    EVVGEQVTSY LTKKFAELRS PNEFKVYMGH GGKPWVSDFS HPHYLAGRRA
    410 420 430 440 450
    MKTVFGVEPD LTREGGSIPV TLTFQEATGK NVMLLPVGSA DDGAHSQNEK
    460 470
    LNRYNYIEGT KMLAAYLYEV SQLKD
    Length:475
    Mass (Da):52,878
    Last modified:September 19, 2002 - v2
    Checksum:i43FA0668B0587A39
    GO
    Isoform 2 (identifier: Q96KP4-2) [UniParc]FASTAAdd to basket
    Also known as: CPGL-B

    The sequence of this isoform differs from the canonical sequence as follows:
         69-152: Missing.

    Note: Lacks a part of the catalytic domain.Curated
    Show »
    Length:391
    Mass (Da):43,833
    Checksum:i07E5F4464C8FC179
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti128R → G in BAA91840 (PubMed:14702039).Curated1
    Sequence conflicti348M → T in BAG53426 (PubMed:14702039).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_057154126Y → H1 PublicationCorresponds to variant dbSNP:rs2278161Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_03820369 – 152Missing in isoform 2. 1 PublicationAdd BLAST84

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AX523938 Unassigned DNA Translation: CAD56843.1
    AJ347717 mRNA Translation: CAC69883.1
    AK001692 mRNA Translation: BAA91840.1
    AK097155 mRNA Translation: BAG53426.1
    AF258592 mRNA Translation: AAG23795.1
    EU794600 mRNA Translation: ACJ13654.1
    AC009704 Genomic DNA No translation available.
    CH471117 Genomic DNA Translation: EAW66551.1
    CH471117 Genomic DNA Translation: EAW66552.1
    CH471117 Genomic DNA Translation: EAW66554.1
    BC001375 mRNA Translation: AAH01375.1
    BC003176 mRNA Translation: AAH03176.1
    CCDSiCCDS12006.1 [Q96KP4-1]
    CCDS54190.1 [Q96KP4-2]
    RefSeqiNP_001161971.1, NM_001168499.1 [Q96KP4-2]
    NP_060705.2, NM_018235.2 [Q96KP4-1]
    XP_005266785.1, XM_005266728.2 [Q96KP4-1]
    XP_006722566.1, XM_006722503.2 [Q96KP4-1]
    XP_011524373.1, XM_011526071.2 [Q96KP4-1]
    XP_011524374.1, XM_011526072.2 [Q96KP4-1]
    UniGeneiHs.149185

    Genome annotation databases

    EnsembliENST00000324262; ENSP00000325548; ENSG00000133313 [Q96KP4-1]
    ENST00000324301; ENSP00000325756; ENSG00000133313 [Q96KP4-2]
    ENST00000579847; ENSP00000462311; ENSG00000133313 [Q96KP4-1]
    GeneIDi55748
    KEGGihsa:55748
    UCSCiuc002llm.3 human
    uc002lln.3 human [Q96KP4-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiCNDP2_HUMAN
    AccessioniPrimary (citable) accession number: Q96KP4
    Secondary accession number(s): B3KUG4
    , Q8WY59, Q9BQ94, Q9NVB4, V9HWE5
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 19, 2002
    Last sequence update: September 19, 2002
    Last modified: February 28, 2018
    This is version 149 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, Direct protein sequencing, Reference proteome
    UniProt is an ELIXIR core data resource
    Main funding by: National Institutes of Health