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Protein

Uroporphyrinogen-III synthase

Gene

UROS

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins. Porphyrins act as cofactors for a multitude of enzymes that perform a variety of processes within the cell such as methionine synthesis (vitamin B12) or oxygen transport (heme).

Catalytic activityi

Hydroxymethylbilane = uroporphyrinogen III + H2O.1 Publication

Pathwayi: protoporphyrin-IX biosynthesis

This protein is involved in step 3 of the subpathway that synthesizes coproporphyrinogen-III from 5-aminolevulinate.
Proteins known to be involved in the 4 steps of the subpathway in this organism are:
  1. Delta-aminolevulinic acid dehydratase (ALAD)
  2. Porphobilinogen deaminase (HMBS)
  3. Uroporphyrinogen-III synthase (UROS)
  4. Uroporphyrinogen decarboxylase (UROD), Uroporphyrinogen decarboxylase (UROD)
This subpathway is part of the pathway protoporphyrin-IX biosynthesis, which is itself part of Porphyrin-containing compound metabolism.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes coproporphyrinogen-III from 5-aminolevulinate, the pathway protoporphyrin-IX biosynthesis and in Porphyrin-containing compound metabolism.

GO - Molecular functioni

  • cofactor binding Source: Ensembl
  • uroporphyrinogen-III synthase activity Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Lyase

Keywords - Biological processi

Heme biosynthesis, Porphyrin biosynthesis

Enzyme and pathway databases

BioCyciMetaCyc:HS07569-MONOMER.
ZFISH:HS07569-MONOMER.
BRENDAi4.2.1.75. 2681.
ReactomeiR-HSA-189451. Heme biosynthesis.
UniPathwayiUPA00251; UER00320.

Names & Taxonomyi

Protein namesi
Recommended name:
Uroporphyrinogen-III synthase (EC:4.2.1.75)
Short name:
UROIIIS
Short name:
UROS
Alternative name(s):
Hydroxymethylbilane hydrolyase [cyclizing]
Uroporphyrinogen-III cosynthase
Gene namesi
Name:UROS
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:12592. UROS.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: UniProtKB
  • mitochondrion Source: UniProtKB
Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

Congenital erythropoietic porphyria (CEP)13 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionPorphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. The manifestations of CEP are heterogeneous, ranging from nonimmune hydrops fetalis due to severe hemolytic anemia in utero to milder, later onset forms, which have only skin lesions due to cutaneous photosensitivity in adult life. The deficiency in UROS activity results in the non-enzymatic conversion of hydroxymethylbilane (HMB) into the uroporphyrinogen-I isomer.
See also OMIM:263700
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0216153V → F in CEP; no residual activity. 1 PublicationCorresponds to variant rs773301339dbSNPEnsembl.1
Natural variantiVAR_0036744L → F in CEP. 1 PublicationCorresponds to variant rs121908015dbSNPEnsembl.1
Natural variantiVAR_00367519Y → C in CEP. 1 Publication1
Natural variantiVAR_02161647S → P in CEP; severe cutaneous lesions; less than 3% wild-type activity. 1 PublicationCorresponds to variant rs397515527dbSNPEnsembl.1
Natural variantiVAR_00367653P → L in CEP; severe phenotype; no detectable activity. 1 PublicationCorresponds to variant rs121908013dbSNPEnsembl.1
Natural variantiVAR_00367762T → A in CEP; does not affect enzymatic activity. 2 PublicationsCorresponds to variant rs28941775dbSNPEnsembl.1
Natural variantiVAR_00367866A → V in CEP; mild phenotype; residual activity. 1 PublicationCorresponds to variant rs28941774dbSNPEnsembl.1
Natural variantiVAR_02161769A → T in CEP; less than 2% wild-type activity. 1 Publication1
Natural variantiVAR_00367973C → R in CEP; frequent mutation in Western countries; severe phenotype; no detectable activity. 5 PublicationsCorresponds to variant rs121908012dbSNPEnsembl.1
Natural variantiVAR_00368082V → F in CEP; mild phenotype; high residual activity. 1 PublicationCorresponds to variant rs121908016dbSNPEnsembl.1
Natural variantiVAR_00368199V → A in CEP. 1 Publication1
Natural variantiVAR_003682104A → V in CEP; residual activity. 1 PublicationCorresponds to variant rs397515528dbSNPEnsembl.1
Natural variantiVAR_021618129I → T in CEP; no residual activity. 1 Publication1
Natural variantiVAR_013558188G → R in CEP; less than 5% wild-type activity. 1 PublicationCorresponds to variant rs121908017dbSNPEnsembl.1
Natural variantiVAR_021619188G → W in CEP; mild phenotype; less than 2% wild-type activity. 1 PublicationCorresponds to variant rs121908017dbSNPEnsembl.1
Natural variantiVAR_021620210 – 211EL → HIQSQAQSQAQDN in CEP. 1 Publication2
Natural variantiVAR_003683212S → P in CEP; no residual activity. 1 PublicationCorresponds to variant rs139388833dbSNPEnsembl.1
Natural variantiVAR_021621219I → S in CEP; moderately-severe phenotype; less than 2% wild-type activity. 1 PublicationCorresponds to variant rs767029901dbSNPEnsembl.1
Natural variantiVAR_003684225G → S in CEP. 1 PublicationCorresponds to variant rs121908020dbSNPEnsembl.1
Natural variantiVAR_003685228T → M in CEP; no detectable activity. 3 PublicationsCorresponds to variant rs121908014dbSNPEnsembl.1
Natural variantiVAR_067318237L → P in CEP. 1 PublicationCorresponds to variant rs777433697dbSNPEnsembl.1
Natural variantiVAR_066247248P → Q in CEP. 1 PublicationCorresponds to variant rs121908021dbSNPEnsembl.1

Severe congenital erythropoietic porphyria is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi63S → A: Does not affect enzymatic activity. 1 Publication1
Mutagenesisi65R → A: Slightly affects enzymatic activity. 1 Publication1
Mutagenesisi103T → A: Slightly affects enzymatic activity. 1 Publication1
Mutagenesisi127E → A: Does not affect enzymatic activity. 1 Publication1
Mutagenesisi168Y → F: Impairs enzymatic activity. 1 Publication1
Mutagenesisi197S → A: Does not affect enzymatic activity. 1 Publication1
Mutagenesisi220K → A: Does not affect enzymatic activity. 1 Publication1
Mutagenesisi227T → A: Does not affect enzymatic activity. 1 Publication1
Mutagenesisi228T → A: Impairs enzymatic activity. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi7390.
MalaCardsiUROS.
MIMi263700. phenotype.
OpenTargetsiENSG00000188690.
Orphaneti79277. Congenital erythropoietic porphyria.
PharmGKBiPA37222.

Chemistry databases

ChEMBLiCHEMBL4433.

Polymorphism and mutation databases

BioMutaiUROS.
DMDMi122849.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001352511 – 265Uroporphyrinogen-III synthaseAdd BLAST265

Proteomic databases

EPDiP10746.
MaxQBiP10746.
PaxDbiP10746.
PeptideAtlasiP10746.
PRIDEiP10746.

PTM databases

iPTMnetiP10746.
PhosphoSitePlusiP10746.

Expressioni

Tissue specificityi

Ubiquitous.1 Publication

Gene expression databases

BgeeiENSG00000188690.
CleanExiHS_UROS.
ExpressionAtlasiP10746. baseline and differential.
GenevisibleiP10746. HS.

Organism-specific databases

HPAiHPA044038.

Interactioni

Subunit structurei

Monomer.1 Publication

Protein-protein interaction databases

BioGridi113236. 11 interactors.
IntActiP10746. 2 interactors.
MINTiMINT-2863993.
STRINGi9606.ENSP00000357775.

Structurei

Secondary structure

1265
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi2 – 9Combined sources8
Helixi18 – 24Combined sources7
Turni25 – 27Combined sources3
Beta strandi29 – 34Combined sources6
Beta strandi36 – 40Combined sources5
Helixi43 – 50Combined sources8
Helixi53 – 55Combined sources3
Beta strandi57 – 61Combined sources5
Helixi64 – 76Combined sources13
Helixi80 – 86Combined sources7
Helixi88 – 93Combined sources6
Beta strandi94 – 98Combined sources5
Helixi101 – 109Combined sources9
Helixi122 – 130Combined sources9
Beta strandi139 – 144Combined sources6
Helixi146 – 148Combined sources3
Helixi151 – 156Combined sources6
Turni157 – 159Combined sources3
Beta strandi162 – 166Combined sources5
Beta strandi168 – 172Combined sources5
Helixi176 – 187Combined sources12
Beta strandi191 – 197Combined sources7
Helixi198 – 212Combined sources15
Helixi213 – 218Combined sources6
Beta strandi219 – 225Combined sources7
Helixi226 – 234Combined sources9
Beta strandi240 – 242Combined sources3
Beta strandi244 – 247Combined sources4
Helixi248 – 258Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1JR2X-ray1.84A/B1-265[»]
ProteinModelPortaliP10746.
SMRiP10746.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP10746.

Family & Domainsi

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG4132. Eukaryota.
COG1587. LUCA.
GeneTreeiENSGT00390000009853.
HOGENOMiHOG000007209.
HOVERGENiHBG000492.
InParanoidiP10746.
KOiK01719.
OMAiALQPHGC.
OrthoDBiEOG091G0F70.
PhylomeDBiP10746.
TreeFamiTF324092.

Family and domain databases

CDDicd06578. HemD. 1 hit.
InterProiIPR003754. 4pyrrol_synth_uPrphyn_synth.
[Graphical view]
PfamiPF02602. HEM4. 1 hit.
[Graphical view]
SUPFAMiSSF69618. SSF69618. 1 hit.

Sequencei

Sequence statusi: Complete.

P10746-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKVLLLKDAK EDDCGQDPYI RELGLYGLEA TLIPVLSFEF LSLPSFSEKL
60 70 80 90 100
SHPEDYGGLI FTSPRAVEAA ELCLEQNNKT EVWERSLKEK WNAKSVYVVG
110 120 130 140 150
NATASLVSKI GLDTEGETCG NAEKLAEYIC SRESSALPLL FPCGNLKREI
160 170 180 190 200
LPKALKDKGI AMESITVYQT VAHPGIQGNL NSYYSQQGVP ASITFFSPSG
210 220 230 240 250
LTYSLKHIQE LSGDNIDQIK FAAIGPTTAR ALAAQGLPVS CTAESPTPQA
260
LATGIRKALQ PHGCC
Length:265
Mass (Da):28,628
Last modified:July 1, 1989 - v1
Checksum:iCEF171401361F61E
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0216153V → F in CEP; no residual activity. 1 PublicationCorresponds to variant rs773301339dbSNPEnsembl.1
Natural variantiVAR_0036744L → F in CEP. 1 PublicationCorresponds to variant rs121908015dbSNPEnsembl.1
Natural variantiVAR_00367519Y → C in CEP. 1 Publication1
Natural variantiVAR_02161647S → P in CEP; severe cutaneous lesions; less than 3% wild-type activity. 1 PublicationCorresponds to variant rs397515527dbSNPEnsembl.1
Natural variantiVAR_00367653P → L in CEP; severe phenotype; no detectable activity. 1 PublicationCorresponds to variant rs121908013dbSNPEnsembl.1
Natural variantiVAR_00367762T → A in CEP; does not affect enzymatic activity. 2 PublicationsCorresponds to variant rs28941775dbSNPEnsembl.1
Natural variantiVAR_00367866A → V in CEP; mild phenotype; residual activity. 1 PublicationCorresponds to variant rs28941774dbSNPEnsembl.1
Natural variantiVAR_02161769A → T in CEP; less than 2% wild-type activity. 1 Publication1
Natural variantiVAR_00367973C → R in CEP; frequent mutation in Western countries; severe phenotype; no detectable activity. 5 PublicationsCorresponds to variant rs121908012dbSNPEnsembl.1
Natural variantiVAR_00368082V → F in CEP; mild phenotype; high residual activity. 1 PublicationCorresponds to variant rs121908016dbSNPEnsembl.1
Natural variantiVAR_00368199V → A in CEP. 1 Publication1
Natural variantiVAR_003682104A → V in CEP; residual activity. 1 PublicationCorresponds to variant rs397515528dbSNPEnsembl.1
Natural variantiVAR_049345124K → R.Corresponds to variant rs17153561dbSNPEnsembl.1
Natural variantiVAR_021618129I → T in CEP; no residual activity. 1 Publication1
Natural variantiVAR_049346171V → G.Corresponds to variant rs17173752dbSNPEnsembl.1
Natural variantiVAR_013558188G → R in CEP; less than 5% wild-type activity. 1 PublicationCorresponds to variant rs121908017dbSNPEnsembl.1
Natural variantiVAR_021619188G → W in CEP; mild phenotype; less than 2% wild-type activity. 1 PublicationCorresponds to variant rs121908017dbSNPEnsembl.1
Natural variantiVAR_021620210 – 211EL → HIQSQAQSQAQDN in CEP. 1 Publication2
Natural variantiVAR_003683212S → P in CEP; no residual activity. 1 PublicationCorresponds to variant rs139388833dbSNPEnsembl.1
Natural variantiVAR_021621219I → S in CEP; moderately-severe phenotype; less than 2% wild-type activity. 1 PublicationCorresponds to variant rs767029901dbSNPEnsembl.1
Natural variantiVAR_003684225G → S in CEP. 1 PublicationCorresponds to variant rs121908020dbSNPEnsembl.1
Natural variantiVAR_003685228T → M in CEP; no detectable activity. 3 PublicationsCorresponds to variant rs121908014dbSNPEnsembl.1
Natural variantiVAR_067318237L → P in CEP. 1 PublicationCorresponds to variant rs777433697dbSNPEnsembl.1
Natural variantiVAR_066247248P → Q in CEP. 1 PublicationCorresponds to variant rs121908021dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
J03824 mRNA. Translation: AAA60273.1.
AF230665 mRNA. Translation: AAG36795.1.
AH010036 Genomic DNA. Translation: AAG36794.1.
AK314896 mRNA. Translation: BAG37410.1.
AL360176 Genomic DNA. Translation: CAI12087.1.
CH471066 Genomic DNA. Translation: EAW49221.1.
CH471066 Genomic DNA. Translation: EAW49222.1.
BC002573 mRNA. Translation: AAH02573.1.
CCDSiCCDS7648.1.
PIRiA40483.
RefSeqiNP_000366.1. NM_000375.2.
UniGeneiHs.501376.
Hs.684451.

Genome annotation databases

EnsembliENST00000368786; ENSP00000357775; ENSG00000188690.
ENST00000368797; ENSP00000357787; ENSG00000188690.
GeneIDi7390.
KEGGihsa:7390.
UCSCiuc001liw.5. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
J03824 mRNA. Translation: AAA60273.1.
AF230665 mRNA. Translation: AAG36795.1.
AH010036 Genomic DNA. Translation: AAG36794.1.
AK314896 mRNA. Translation: BAG37410.1.
AL360176 Genomic DNA. Translation: CAI12087.1.
CH471066 Genomic DNA. Translation: EAW49221.1.
CH471066 Genomic DNA. Translation: EAW49222.1.
BC002573 mRNA. Translation: AAH02573.1.
CCDSiCCDS7648.1.
PIRiA40483.
RefSeqiNP_000366.1. NM_000375.2.
UniGeneiHs.501376.
Hs.684451.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1JR2X-ray1.84A/B1-265[»]
ProteinModelPortaliP10746.
SMRiP10746.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi113236. 11 interactors.
IntActiP10746. 2 interactors.
MINTiMINT-2863993.
STRINGi9606.ENSP00000357775.

Chemistry databases

ChEMBLiCHEMBL4433.

PTM databases

iPTMnetiP10746.
PhosphoSitePlusiP10746.

Polymorphism and mutation databases

BioMutaiUROS.
DMDMi122849.

Proteomic databases

EPDiP10746.
MaxQBiP10746.
PaxDbiP10746.
PeptideAtlasiP10746.
PRIDEiP10746.

Protocols and materials databases

DNASUi7390.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000368786; ENSP00000357775; ENSG00000188690.
ENST00000368797; ENSP00000357787; ENSG00000188690.
GeneIDi7390.
KEGGihsa:7390.
UCSCiuc001liw.5. human.

Organism-specific databases

CTDi7390.
DisGeNETi7390.
GeneCardsiUROS.
GeneReviewsiUROS.
HGNCiHGNC:12592. UROS.
HPAiHPA044038.
MalaCardsiUROS.
MIMi263700. phenotype.
606938. gene.
neXtProtiNX_P10746.
OpenTargetsiENSG00000188690.
Orphaneti79277. Congenital erythropoietic porphyria.
PharmGKBiPA37222.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG4132. Eukaryota.
COG1587. LUCA.
GeneTreeiENSGT00390000009853.
HOGENOMiHOG000007209.
HOVERGENiHBG000492.
InParanoidiP10746.
KOiK01719.
OMAiALQPHGC.
OrthoDBiEOG091G0F70.
PhylomeDBiP10746.
TreeFamiTF324092.

Enzyme and pathway databases

UniPathwayiUPA00251; UER00320.
BioCyciMetaCyc:HS07569-MONOMER.
ZFISH:HS07569-MONOMER.
BRENDAi4.2.1.75. 2681.
ReactomeiR-HSA-189451. Heme biosynthesis.

Miscellaneous databases

EvolutionaryTraceiP10746.
GenomeRNAii7390.
PROiP10746.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000188690.
CleanExiHS_UROS.
ExpressionAtlasiP10746. baseline and differential.
GenevisibleiP10746. HS.

Family and domain databases

CDDicd06578. HemD. 1 hit.
InterProiIPR003754. 4pyrrol_synth_uPrphyn_synth.
[Graphical view]
PfamiPF02602. HEM4. 1 hit.
[Graphical view]
SUPFAMiSSF69618. SSF69618. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiHEM4_HUMAN
AccessioniPrimary (citable) accession number: P10746
Secondary accession number(s): B2RC13, D3DRF7, Q9H2T1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 1, 1989
Last sequence update: July 1, 1989
Last modified: November 2, 2016
This is version 165 of the entry and version 1 of the sequence. [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

Caution

Variant Ala-62 was originally reported to result in no detectable enzyme activity (PubMed:1737856), as measured in recombinant crude lysate extracts. Further experiments with the purified enzyme have shown that this variant does not affect activity (PubMed:11689424).2 Publications

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  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. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.