PHS_HUMAN
ID PHS_HUMAN Reviewed; 104 AA.
AC P61457; P70519; P80095; Q9D930;
DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=Pterin-4-alpha-carbinolamine dehydratase;
DE Short=PHS;
DE EC=4.2.1.96 {ECO:0000250|UniProtKB:P61459};
DE AltName: Full=4-alpha-hydroxy-tetrahydropterin dehydratase;
DE AltName: Full=Dimerization cofactor of hepatocyte nuclear factor 1-alpha;
DE Short=DCoH;
DE Short=Dimerization cofactor of HNF1;
DE AltName: Full=Phenylalanine hydroxylase-stimulating protein;
DE AltName: Full=Pterin carbinolamine dehydratase;
DE Short=PCD;
GN Name=PCBD1; Synonyms=DCOH, PCBD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=1763325; DOI=10.1126/science.1763325;
RA Mendel D.B., Khavari P.A., Conley P.B., Graves M.K., Hansen L.P., Admon A.,
RA Crabtree G.R.;
RT "Characterization of a cofactor that regulates dimerization of a mammalian
RT homeodomain protein.";
RL Science 254:1762-1767(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=7763270; DOI=10.1006/bbrc.1995.1751;
RA Thoeny B., Neuheiser F., Blau N., Heizmann C.W.;
RT "Characterization of the human PCBD gene encoding the bifunctional protein
RT pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor for the
RT transcription factor HNF-1 alpha.";
RL Biochem. Biophys. Res. Commun. 210:966-973(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10098606; DOI=10.1089/104454999315466;
RA Lei X.D., Kaufman S.;
RT "Characterization of expression of the gene for human pterin carbinolamine
RT dehydratase/dimerization cofactor of HNF1.";
RL DNA Cell Biol. 18:243-252(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Muscle;
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 [5]
RP PROTEIN SEQUENCE OF 2-104, CLEAVAGE OF INITIATOR METHIONINE, AND
RP ACETYLATION AT ALA-2.
RC TISSUE=Liver;
RX PubMed=8444860; DOI=10.1016/s0021-9258(18)53471-2;
RA Hauer C.R., Rebrin I., Thoeny B., Neuheiser F., Curtius H.-C., Hunziker P.,
RA Blau N., Ghisla S., Heizmann C.W.;
RT "Phenylalanine hydroxylase-stimulating protein/pterin-4 alpha-carbinolamine
RT dehydratase from rat and human liver. Purification, characterization, and
RT complete amino acid sequence.";
RL J. Biol. Chem. 268:4828-4831(1993).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [8]
RP VARIANTS HPABH4D ARG-82 AND 87-GLU--THR-104 DEL.
RX PubMed=8352282;
RA Citron B.A., Kaufman S., Milstien S., Naylor E.W., Greene C.L., Davis M.D.;
RT "Mutation in the 4a-carbinolamine dehydratase gene leads to mild
RT hyperphenylalaninemia with defective cofactor metabolism.";
RL Am. J. Hum. Genet. 53:768-774(1993).
RN [9]
RP CHARACTERIZATION OF VARIANT HPABH4D ARG-82.
RX PubMed=8618906; DOI=10.1073/pnas.92.26.12384;
RA Johnen G., Kowlessur D., Citron B.A., Kaufman S.;
RT "Characterization of the wild-type form of 4a-carbinolamine dehydratase and
RT two naturally occurring mutants associated with hyperphenylalaninemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:12384-12388(1995).
RN [10]
RP VARIANTS HPABH4D ILE-79; 87-GLU--THR-104 DEL AND 98-GLN--THR-104 DEL.
RX PubMed=9585615; DOI=10.1086/301887;
RA Thoeny B., Neuheiser F., Kierat L., Blaskovics M., Arn P.H., Ferreira P.,
RA Rebrin I., Ayling J., Blau N.;
RT "Hyperphenylalaninemia with high levels of 7-biopterin is associated with
RT mutations in the PCBD gene encoding the bifunctional protein pterin-4a-
RT carbinolamine dehydratase and transcriptional coactivator (DCoH).";
RL Am. J. Hum. Genet. 62:1302-1311(1998).
RN [11]
RP VARIANTS HPABH4D 27-GLU--THR-104 DEL; GLN-88; LYS-97 AND 98-GLN--THR-104
RP DEL.
RX PubMed=9760199; DOI=10.1007/s004390050800;
RA Thoeny B., Neuheiser F., Kierat L., Rolland M.O., Guibaud P., Schlueter T.,
RA Germann R., Heidenreich R.A., Duran M., de Klerk J.B.C., Ayling J.E.,
RA Blau N.;
RT "Mutations in the pterin-4alpha-carbinolamine dehydratase (PCBD) gene cause
RT a benign form of hyperphenylalaninemia.";
RL Hum. Genet. 103:162-167(1998).
RN [12]
RP CHARACTERIZATION OF VARIANTS HPABH4D 27-GLU--THR-104 DEL; ILE-79; ARG-82;
RP 87-GLU--THR-104 DEL; GLN-88; LYS-97 AND 98-GLU--THR-104 DEL, FUNCTION,
RP INTERACTION WITH HNF1B, AND SUBCELLULAR LOCATION.
RX PubMed=24204001; DOI=10.1681/asn.2013040337;
RA Ferre S., de Baaij J.H., Ferreira P., Germann R., de Klerk J.B.,
RA Lavrijsen M., van Zeeland F., Venselaar H., Kluijtmans L.A.,
RA Hoenderop J.G., Bindels R.J.;
RT "Mutations in PCBD1 cause hypomagnesemia and renal magnesium wasting.";
RL J. Am. Soc. Nephrol. 25:574-586(2014).
CC -!- FUNCTION: Involved in tetrahydrobiopterin biosynthesis (By similarity).
CC Seems to both prevent the formation of 7-pterins and accelerate the
CC formation of quinonoid-BH2. Coactivator for HNF1A-dependent
CC transcription (By similarity). Regulates the dimerization of
CC homeodomain protein HNF1A and enhances its transcriptional activity (By
CC similarity). Also acts as a coactivator for HNF1B-dependent
CC transcription (PubMed:24204001). {ECO:0000250|UniProtKB:P61459,
CC ECO:0000269|PubMed:24204001}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin =
CC (6R)-L-erythro-6,7-dihydrobiopterin + H2O; Xref=Rhea:RHEA:11920,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15642, ChEBI:CHEBI:43120; EC=4.2.1.96;
CC Evidence={ECO:0000250|UniProtKB:P61459};
CC -!- SUBUNIT: Homotetramer and homodimer (By similarity). Heterotetramer
CC with HNF1A; formed by a dimer of dimers (By similarity). Interacts with
CC HNF1B (via HNF-p1 domain); the interaction increases HNF1B
CC transactivation activity (PubMed:24204001).
CC {ECO:0000250|UniProtKB:P61459, ECO:0000269|PubMed:24204001}.
CC -!- INTERACTION:
CC P61457; Q9UKV3: ACIN1; NbExp=2; IntAct=EBI-740475, EBI-396258;
CC P61457; P05067: APP; NbExp=2; IntAct=EBI-740475, EBI-77613;
CC P61457; P51116: FXR2; NbExp=6; IntAct=EBI-740475, EBI-740459;
CC P61457; Q9H8Y8: GORASP2; NbExp=6; IntAct=EBI-740475, EBI-739467;
CC P61457; P20823: HNF1A; NbExp=3; IntAct=EBI-740475, EBI-636034;
CC P61457; P35680: HNF1B; NbExp=7; IntAct=EBI-740475, EBI-2798841;
CC P61457; Q63ZY3: KANK2; NbExp=3; IntAct=EBI-740475, EBI-2556193;
CC P61457; Q8TBB1: LNX1; NbExp=7; IntAct=EBI-740475, EBI-739832;
CC P61457; Q96HA8: NTAQ1; NbExp=4; IntAct=EBI-740475, EBI-741158;
CC P61457; P61457: PCBD1; NbExp=8; IntAct=EBI-740475, EBI-740475;
CC P61457; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-740475, EBI-79165;
CC P61457; P25786: PSMA1; NbExp=3; IntAct=EBI-740475, EBI-359352;
CC P61457; O00560: SDCBP; NbExp=3; IntAct=EBI-740475, EBI-727004;
CC P61457; Q07654: TFF3; NbExp=6; IntAct=EBI-740475, EBI-10224676;
CC P61457; A0A0S2Z5X4: ZNF688; NbExp=3; IntAct=EBI-740475, EBI-16429014;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24204001}. Nucleus
CC {ECO:0000269|PubMed:24204001}. Note=Recruited to the nucleus through
CC the interaction with HNF1B. {ECO:0000269|PubMed:24204001}.
CC -!- DISEASE: Hyperphenylalaninemia, BH4-deficient, D (HPABH4D)
CC [MIM:264070]: An autosomal recessive disease characterized by
CC primapterinuria, a variant form of hyperphenylalaninemia defined by
CC increased excretion of 7-substituted pterins in the urine. Patients
CC with primapterinuria show an increased ratio of neopterin to biopterin
CC in the urine, excretion of subnormal levels of biopterins, and normal
CC levels of biogenic amines in cerebrospinal fluid. Neurologic signs are
CC mild, present in the neonatal period only, and include hypotonia,
CC delayed motor development and tremor. {ECO:0000269|PubMed:24204001,
CC ECO:0000269|PubMed:8352282, ECO:0000269|PubMed:8618906,
CC ECO:0000269|PubMed:9585615, ECO:0000269|PubMed:9760199}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the pterin-4-alpha-carbinolamine dehydratase
CC family. {ECO:0000305}.
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DR EMBL; M83742; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; L41560; AAA69662.1; -; Genomic_DNA.
DR EMBL; L41559; AAA69663.1; -; mRNA.
DR EMBL; AF082858; AAD25732.1; -; mRNA.
DR EMBL; BC006324; AAH06324.1; -; mRNA.
DR CCDS; CCDS31217.1; -.
DR PIR; A47010; A47010.
DR RefSeq; NP_000272.1; NM_000281.3.
DR RefSeq; NP_001276726.1; NM_001289797.1.
DR AlphaFoldDB; P61457; -.
DR SMR; P61457; -.
DR BioGRID; 111125; 88.
DR IntAct; P61457; 90.
DR MINT; P61457; -.
DR STRING; 9606.ENSP00000299299; -.
DR DrugBank; DB04400; L-erythro-7,8-dihydrobiopterin.
DR MoonDB; P61457; Curated.
DR iPTMnet; P61457; -.
DR PhosphoSitePlus; P61457; -.
DR BioMuta; PCBD1; -.
DR DMDM; 47606444; -.
DR UCD-2DPAGE; P61457; -.
DR EPD; P61457; -.
DR jPOST; P61457; -.
DR MassIVE; P61457; -.
DR MaxQB; P61457; -.
DR PaxDb; P61457; -.
DR PeptideAtlas; P61457; -.
DR PRIDE; P61457; -.
DR ProteomicsDB; 57301; -.
DR Antibodypedia; 29081; 236 antibodies from 28 providers.
DR DNASU; 5092; -.
DR Ensembl; ENST00000299299.4; ENSP00000299299.3; ENSG00000166228.9.
DR GeneID; 5092; -.
DR KEGG; hsa:5092; -.
DR MANE-Select; ENST00000299299.4; ENSP00000299299.3; NM_000281.4; NP_000272.1.
DR UCSC; uc001jrn.3; human.
DR CTD; 5092; -.
DR DisGeNET; 5092; -.
DR GeneCards; PCBD1; -.
DR HGNC; HGNC:8646; PCBD1.
DR HPA; ENSG00000166228; Tissue enhanced (liver).
DR MalaCards; PCBD1; -.
DR MIM; 126090; gene.
DR MIM; 264070; phenotype.
DR neXtProt; NX_P61457; -.
DR OpenTargets; ENSG00000166228; -.
DR Orphanet; 1578; Pterin-4 alpha-carbinolamine dehydratase deficiency.
DR PharmGKB; PA32985; -.
DR VEuPathDB; HostDB:ENSG00000166228; -.
DR eggNOG; KOG4073; Eukaryota.
DR GeneTree; ENSGT00390000007221; -.
DR HOGENOM; CLU_081974_3_2_1; -.
DR InParanoid; P61457; -.
DR OMA; FMTRVGL; -.
DR OrthoDB; 1588292at2759; -.
DR PhylomeDB; P61457; -.
DR TreeFam; TF300188; -.
DR BioCyc; MetaCyc:HS09360-MON; -.
DR PathwayCommons; P61457; -.
DR Reactome; R-HSA-8964208; Phenylalanine metabolism.
DR SignaLink; P61457; -.
DR SIGNOR; P61457; -.
DR BioGRID-ORCS; 5092; 15 hits in 1085 CRISPR screens.
DR ChiTaRS; PCBD1; human.
DR GeneWiki; PCBD1; -.
DR GenomeRNAi; 5092; -.
DR Pharos; P61457; Tbio.
DR PRO; PR:P61457; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; P61457; protein.
DR Bgee; ENSG00000166228; Expressed in right lobe of liver and 200 other tissues.
DR Genevisible; P61457; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0008124; F:4-alpha-hydroxytetrahydrobiopterin dehydratase activity; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004505; F:phenylalanine 4-monooxygenase activity; IEA:Ensembl.
DR GO; GO:0003713; F:transcription coactivator activity; TAS:ProtInc.
DR GO; GO:0006729; P:tetrahydrobiopterin biosynthetic process; IEA:UniProtKB-KW.
DR Gene3D; 3.30.1360.20; -; 1.
DR HAMAP; MF_00434; Pterin_4_alpha; 1.
DR InterPro; IPR036428; PCD_sf.
DR InterPro; IPR001533; Pterin_deHydtase.
DR PANTHER; PTHR12599; PTHR12599; 1.
DR Pfam; PF01329; Pterin_4a; 1.
DR SUPFAM; SSF55248; SSF55248; 1.
PE 1: Evidence at protein level;
KW Acetylation; Activator; Cytoplasm; Direct protein sequencing;
KW Disease variant; Lyase; Nucleus; Reference proteome;
KW Tetrahydrobiopterin biosynthesis; Transcription; Transcription regulation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:8444860"
FT CHAIN 2..104
FT /note="Pterin-4-alpha-carbinolamine dehydratase"
FT /id="PRO_0000063052"
FT BINDING 61..63
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 78..81
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000269|PubMed:8444860"
FT VARIANT 27..104
FT /note="Missing (in HPABH4D; when associated in cis with Q-
FT 88; reduced protein levels; loss of HNF1B interaction; loss
FT of HNF1B-coactivator activity; dbSNP:rs727505360)"
FT /evidence="ECO:0000269|PubMed:24204001,
FT ECO:0000269|PubMed:9760199"
FT /id="VAR_084829"
FT VARIANT 79
FT /note="T -> I (in HPABH4D; increased proteolytic
FT degradation; reduced interaction with HNF1B; loss of HNF1B-
FT coactivator activity; dbSNP:rs121913014)"
FT /evidence="ECO:0000269|PubMed:24204001,
FT ECO:0000269|PubMed:9585615"
FT /id="VAR_005527"
FT VARIANT 82
FT /note="C -> R (in HPABH4D; increased proteolytic
FT degradation; reduced dehydratase activity; no impact on
FT hydroxytetrahydrobiopterin-binding; reduced interaction
FT with HNF1B; partial impact on HNF1B-coactivator activity;
FT dbSNP:rs104894177)"
FT /evidence="ECO:0000269|PubMed:24204001,
FT ECO:0000269|PubMed:8352282, ECO:0000269|PubMed:8618906"
FT /id="VAR_005528"
FT VARIANT 87..104
FT /note="Missing (in HPABH4D; increased proteolytic
FT degradation; loss of HNF1B interaction; loss of HNF1B-
FT coactivator activity; dbSNP:rs104894172)"
FT /evidence="ECO:0000269|PubMed:24204001,
FT ECO:0000269|PubMed:8352282, ECO:0000269|PubMed:9585615"
FT /id="VAR_084830"
FT VARIANT 88
FT /note="R -> Q (in HPABH4D; when associated in cis with 27-
FT E--T-104 del; unknown pathological significance; no impact
FT on HNF1B interaction; no impact on HNF1B-coactivator
FT activity; dbSNP:rs115117837)"
FT /evidence="ECO:0000269|PubMed:24204001,
FT ECO:0000269|PubMed:9760199"
FT /id="VAR_005529"
FT VARIANT 97
FT /note="E -> K (in HPABH4D; increased proteolytic
FT degradation; loss of HNF1B interaction; loss of HNF1B-
FT coactivator activity; dbSNP:rs397518416)"
FT /evidence="ECO:0000269|PubMed:24204001,
FT ECO:0000269|PubMed:9760199"
FT /id="VAR_005530"
FT VARIANT 98..104
FT /note="Missing (in HPABH4D; increased proteolytic
FT degradation; loss of HNF1B interaction; loss of HNF1B-
FT coactivator activity; dbSNP:rs121913015)"
FT /evidence="ECO:0000269|PubMed:24204001,
FT ECO:0000269|PubMed:9585615"
FT /id="VAR_084831"
SQ SEQUENCE 104 AA; 12000 MW; 997DF8C2417FE5F5 CRC64;
MAGKAHRLSA EERDQLLPNL RAVGWNELEG RDAIFKQFHF KDFNRAFGFM TRVALQAEKL
DHHPEWFNVY NKVHITLSTH ECAGLSERDI NLASFIEQVA VSMT
