ID HEM4_HUMAN Reviewed; 265 AA. AC P10746; B2RC13; D3DRF7; Q9H2T1; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1989, sequence version 1. DT 27-MAR-2024, entry version 209. DE RecName: Full=Uroporphyrinogen-III synthase; DE Short=UROIIIS; DE Short=UROS; DE EC=4.2.1.75; DE AltName: Full=Hydroxymethylbilane hydrolyase [cyclizing]; DE AltName: Full=Uroporphyrinogen-III cosynthase; GN Name=UROS; 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. RX PubMed=3174619; DOI=10.1073/pnas.85.19.7049; RA Tsai S.-F., Bishop D.F., Desnick R.J.; RT "Human uroporphyrinogen III synthase: molecular cloning, nucleotide RT sequence, and expression of a full-length cDNA."; RL Proc. Natl. Acad. Sci. U.S.A. 85:7049-7053(1988). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Liver; RX PubMed=11112350; DOI=10.1006/geno.2000.6373; RA Aizencang G., Solis C., Bishop D.F., Warner C., Desnick R.J.; RT "Human uroporphyrinogen-III synthase: genomic organization, alternative RT promoters, and erythroid-specific expression."; RL Genomics 70:223-231(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Cerebellum; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; 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 [7] RP REVIEW ON VARIANTS. RX PubMed=8829650; RX DOI=10.1002/(sici)1098-1004(1996)7:3<187::aid-humu1>3.0.co;2-8; RA Xu W., Astrin K.H., Desnick R.J.; RT "Molecular basis of congenital erythropoietic porphyria: mutations in the RT human uroporphyrinogen III synthase gene."; RL Hum. Mutat. 7:187-192(1996). RN [8] RP STRUCTURE BY NMR, FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=18004775; DOI=10.1002/prot.21755; RA Cunha L., Kuti M., Bishop D.F., Mezei M., Zeng L., Zhou M.M., Desnick R.J.; RT "Human uroporphyrinogen III synthase: NMR-based mapping of the active RT site."; RL Proteins 71:855-873(2008). RN [9] RP X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY, RP SUBUNIT, MUTAGENESIS OF SER-63; ARG-65; THR-103; GLU-127; TYR-168; SER-197; RP LYS-220; THR-227 AND THR-228, AND CHARACTERIZATION OF VARIANT CEP ALA-62. RX PubMed=11689424; DOI=10.1093/emboj/20.21.5832; RA Mathews M.A., Schubert H.L., Whitby F.G., Alexander K.J., Schadick K., RA Bergonia H.A., Phillips J.D., Hill C.P.; RT "Crystal structure of human uroporphyrinogen III synthase."; RL EMBO J. 20:5832-5839(2001). RN [10] RP VARIANTS CEP LEU-53 AND ARG-73. RX PubMed=2331520; RA Deybach J.-C., de Verneuil H., Boulechfar S., Grandchamp B., Nordmann Y.; RT "Point mutations in the uroporphyrinogen III synthase gene in congenital RT erythropoietic porphyria (Gunther's disease)."; RL Blood 75:1763-1765(1990). RN [11] RP VARIANTS CEP PHE-4; ARG-73 AND MET-228. RX PubMed=1733834; DOI=10.1007/bf00197267; RA Boulechfar S., da Silva V., Deybach J.-C., Nordmann Y., Grandchamp B., RA de Verneuil H.; RT "Heterogeneity of mutations in the uroporphyrinogen III synthase gene in RT congenital erythropoietic porphyria."; RL Hum. Genet. 88:320-324(1992). RN [12] RP VARIANTS CEP ALA-62; VAL-66; ARG-73 AND MET-228, AND CHARACTERIZATION OF RP VARIANTS CEP ALA-62; VAL-66; ARG-73 AND MET-228. RX PubMed=1737856; DOI=10.1172/jci115637; RA Warner C.A., Yoo H.-W., Roberts A.G., Desnick R.J.; RT "Congenital erythropoietic porphyria: identification and expression of RT exonic mutations in the uroporphyrinogen III synthase gene."; RL J. Clin. Invest. 89:693-700(1992). RN [13] RP VARIANTS CEP CYS-19; PHE-82; ALA-99; VAL-104 AND SER-225. RX PubMed=7860775; DOI=10.1172/jci117742; RA Xu W., Warner C.A., Desnick R.J.; RT "Congenital erythropoietic porphyria: identification and expression of 10 RT mutations in the uroporphyrinogen III synthase gene."; RL J. Clin. Invest. 95:905-912(1995). RN [14] RP VARIANT CEP PRO-212. RX PubMed=8655129; DOI=10.1007/bf02281859; RA Tanigawa K., Bensidhoum M., Takamura N., Namba H., Yamashita S., RA de Verneuil H., Ged C.; RT "A novel point mutation in congenital erythropoietic porphyria in two RT members of Japanese family."; RL Hum. Genet. 97:557-560(1996). RN [15] RP VARIANT CEP PHE-3, AND CHARACTERIZATION OF VARIANT CEP PHE-3. RX PubMed=9188670; RX DOI=10.1002/(sici)1096-8628(19970613)70:3<299::aid-ajmg16>3.0.co;2-g; RA Takamura N., Hombrados I., Tanigawa K., Namba H., Nagayama Y., RA de Verneuil H., Yamashita S.; RT "Novel point mutation in the uroporphyrinogen III synthase gene causes RT congenital erythropoietic porphyria of a Japanese family."; RL Am. J. Med. Genet. 70:299-302(1997). RN [16] RP VARIANT CEP ARG-188. RX PubMed=9834209; RA Tezcan I., Xu W., Gurgey A., Tuncer M., Cetin M., Oener C., Yetgin S., RA Ersoy F., Aizencang G., Astrin K.H., Desnick R.J.; RT "Congenital erythropoietic porphyria successfully treated by allogeneic RT bone marrow transplantation."; RL Blood 92:4053-4058(1998). RN [17] RP VARIANT CEP ARG-73. RX PubMed=9803266; DOI=10.1046/j.1469-1809.1998.6230225.x; RA Frank J., Wang X., Lam H.M., Aita V.M., Jugert F.K., Goerz G., Merk H.F., RA Poh-Fitzpatrick M.B., Christiano A.M.; RT "C73R is a hotspot mutation in the uroporphyrinogen III synthase gene in RT congenital erythropoietic porphyria."; RL Ann. Hum. Genet. 62:225-230(1998). RN [18] RP VARIANT CEP THR-129, AND CHARACTERIZATION OF VARIANT CEP THR-129. RX PubMed=11121156; DOI=10.1046/j.1523-1747.2000.0202a.x; RA Rogounovitch T., Takamura N., Hombrados I., Morel C., Tanaka T., RA Kameyoshi Y., Shimizu-Yoshida Y., de Verneuil H., Yamashita S.; RT "Congenital erythropoietic porphyria: a novel homozygous mutation in a RT Japanese patient."; RL J. Invest. Dermatol. 115:1156-1156(2000). RN [19] RP VARIANTS CEP THR-69; ARG-73; TRP-188; 210-GLU-LEU-211 DELINS RP HIS-ILE-GLN-SER-GLN-ALA-GLN-SER-GLN-ALA-GLN-ASP-ASN; SER-219 AND MET-228, RP AND CHARACTERIZATION OF VARIANTS CEP THR-69; TRP-188 AND SER-219. RX PubMed=12060141; DOI=10.1046/j.1365-2141.2002.03558.x; RA Shady A.A., Colby B.R., Cunha L.F., Astrin K.H., Bishop D.F., Desnick R.J.; RT "Congenital erythropoietic porphyria: identification and expression of RT eight novel mutations in the uroporphyrinogen III synthase gene."; RL Br. J. Haematol. 117:980-987(2002). RN [20] RP VARIANT CEP PRO-47, AND CHARACTERIZATION OF VARIANT CEP PRO-47. RX PubMed=15304101; DOI=10.1111/j.0022-202x.2004.23401.x; RA Ged C., Megarbane H., Chouery E., Lalanne M., Megarbane A., de Verneuil H.; RT "Congenital erythropoietic porphyria: report of a novel mutation with RT absence of clinical manifestations in a homozygous mutant sibling."; RL J. Invest. Dermatol. 123:589-591(2004). RN [21] RP VARIANT CEP GLN-248. RX PubMed=21653323; DOI=10.1182/blood-2011-03-342873; RA To-Figueras J., Ducamp S., Clayton J., Badenas C., Delaby C., Ged C., RA Lyoumi S., Gouya L., de Verneuil H., Beaumont C., Ferreira G.C., RA Deybach J.C., Herrero C., Puy H.; RT "ALAS2 acts as a modifier gene in patients with congenital erythropoietic RT porphyria."; RL Blood 118:1443-1451(2011). RN [22] RP VARIANT CEP PRO-237. RX PubMed=22350154; DOI=10.1007/s11033-012-1497-z; RA Moghbeli M., Maleknejad M., Arabi A., Abbaszadegan M.R.; RT "Mutational analysis of uroporphyrinogen III cosynthase gene in Iranian RT families with congenital erythropoietic porphyria."; RL Mol. Biol. Rep. 39:6731-6735(2012). CC -!- FUNCTION: Catalyzes cyclization of the linear tetrapyrrole, CC hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the CC branch point for the various sub-pathways leading to the wide diversity CC of porphyrins (PubMed:11689424, PubMed:18004775). Porphyrins act as CC cofactors for a multitude of enzymes that perform a variety of CC processes within the cell such as methionine synthesis (vitamin B12) or CC oxygen transport (heme). {ECO:0000269|PubMed:11689424, CC ECO:0000269|PubMed:18004775}. CC -!- CATALYTIC ACTIVITY: CC Reaction=hydroxymethylbilane = H2O + uroporphyrinogen III; CC Xref=Rhea:RHEA:18965, ChEBI:CHEBI:15377, ChEBI:CHEBI:57308, CC ChEBI:CHEBI:57845; EC=4.2.1.75; CC Evidence={ECO:0000269|PubMed:11689424, ECO:0000269|PubMed:18004775}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.15 uM for hydroxymethylbilane; CC pH dependence: CC Optimum pH is 8.2. {ECO:0000269|PubMed:18004775}; CC -!- PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX CC biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 3/4. CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:11689424}. CC -!- TISSUE SPECIFICITY: Ubiquitous. {ECO:0000269|PubMed:11112350}. CC -!- DISEASE: Congenital erythropoietic porphyria (CEP) [MIM:263700]: CC Porphyrias are inherited defects in the biosynthesis of heme, resulting CC in the accumulation and increased excretion of porphyrins or porphyrin CC precursors. They are classified as erythropoietic or hepatic, depending CC on whether the enzyme deficiency occurs in red blood cells or in the CC liver. The manifestations of CEP are heterogeneous, ranging from CC nonimmune hydrops fetalis due to severe hemolytic anemia in utero to CC milder, later onset forms, which have only skin lesions due to CC cutaneous photosensitivity in adult life. The deficiency in UROS CC activity results in the non-enzymatic conversion of hydroxymethylbilane CC (HMB) into the uroporphyrinogen-I isomer. {ECO:0000269|PubMed:11121156, CC ECO:0000269|PubMed:11689424, ECO:0000269|PubMed:12060141, CC ECO:0000269|PubMed:15304101, ECO:0000269|PubMed:1733834, CC ECO:0000269|PubMed:1737856, ECO:0000269|PubMed:21653323, CC ECO:0000269|PubMed:22350154, ECO:0000269|PubMed:2331520, CC ECO:0000269|PubMed:7860775, ECO:0000269|PubMed:8655129, CC ECO:0000269|PubMed:9188670, ECO:0000269|PubMed:9803266, CC ECO:0000269|PubMed:9834209}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the uroporphyrinogen-III synthase family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J03824; AAA60273.1; -; mRNA. DR EMBL; AF230665; AAG36795.1; -; mRNA. DR EMBL; AH010036; AAG36794.1; -; Genomic_DNA. DR EMBL; AK314896; BAG37410.1; -; mRNA. DR EMBL; AL360176; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471066; EAW49221.1; -; Genomic_DNA. DR EMBL; CH471066; EAW49222.1; -; Genomic_DNA. DR EMBL; BC002573; AAH02573.1; -; mRNA. DR CCDS; CCDS7648.1; -. DR PIR; A40483; A40483. DR RefSeq; NP_000366.1; NM_000375.2. DR PDB; 1JR2; X-ray; 1.84 A; A/B=1-265. DR PDBsum; 1JR2; -. DR AlphaFoldDB; P10746; -. DR BMRB; P10746; -. DR SMR; P10746; -. DR BioGRID; 113236; 20. DR IntAct; P10746; 7. DR STRING; 9606.ENSP00000357787; -. DR ChEMBL; CHEMBL4433; -. DR GlyGen; P10746; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P10746; -. DR PhosphoSitePlus; P10746; -. DR BioMuta; UROS; -. DR DMDM; 122849; -. DR EPD; P10746; -. DR jPOST; P10746; -. DR MassIVE; P10746; -. DR MaxQB; P10746; -. DR PaxDb; 9606-ENSP00000357787; -. DR PeptideAtlas; P10746; -. DR ProteomicsDB; 52644; -. DR Pumba; P10746; -. DR Antibodypedia; 32416; 108 antibodies from 22 providers. DR DNASU; 7390; -. DR Ensembl; ENST00000368786.5; ENSP00000357775.1; ENSG00000188690.15. DR Ensembl; ENST00000368797.10; ENSP00000357787.4; ENSG00000188690.15. DR GeneID; 7390; -. DR KEGG; hsa:7390; -. DR MANE-Select; ENST00000368797.10; ENSP00000357787.4; NM_000375.3; NP_000366.1. DR UCSC; uc001liw.5; human. DR AGR; HGNC:12592; -. DR CTD; 7390; -. DR DisGeNET; 7390; -. DR GeneCards; UROS; -. DR GeneReviews; UROS; -. DR HGNC; HGNC:12592; UROS. DR HPA; ENSG00000188690; Low tissue specificity. DR MalaCards; UROS; -. DR MIM; 263700; phenotype. DR MIM; 606938; gene. DR neXtProt; NX_P10746; -. DR OpenTargets; ENSG00000188690; -. DR Orphanet; 79277; Congenital erythropoietic porphyria. DR PharmGKB; PA37222; -. DR VEuPathDB; HostDB:ENSG00000188690; -. DR eggNOG; KOG4132; Eukaryota. DR GeneTree; ENSGT00390000009853; -. DR HOGENOM; CLU_051874_1_1_1; -. DR InParanoid; P10746; -. DR OMA; CDSMLRG; -. DR OrthoDB; 1472480at2759; -. DR PhylomeDB; P10746; -. DR TreeFam; TF324092; -. DR BioCyc; MetaCyc:HS07569-MONOMER; -. DR BRENDA; 4.2.1.75; 2681. DR PathwayCommons; P10746; -. DR Reactome; R-HSA-189451; Heme biosynthesis. DR SignaLink; P10746; -. DR UniPathway; UPA00251; UER00320. DR BioGRID-ORCS; 7390; 88 hits in 1158 CRISPR screens. DR EvolutionaryTrace; P10746; -. DR GenomeRNAi; 7390; -. DR Pharos; P10746; Tbio. DR PRO; PR:P10746; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; P10746; Protein. DR Bgee; ENSG00000188690; Expressed in nucleus accumbens and 192 other cell types or tissues. DR ExpressionAtlas; P10746; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB. DR GO; GO:0005542; F:folic acid binding; IEA:Ensembl. DR GO; GO:0004852; F:uroporphyrinogen-III synthase activity; IDA:UniProtKB. DR GO; GO:0071418; P:cellular response to amine stimulus; IEA:Ensembl. DR GO; GO:0071243; P:cellular response to arsenic-containing substance; IEA:Ensembl. DR GO; GO:0006784; P:heme A biosynthetic process; IEA:Ensembl. DR GO; GO:0006785; P:heme B biosynthetic process; IEA:Ensembl. DR GO; GO:0006783; P:heme biosynthetic process; IDA:UniProtKB. DR GO; GO:0048034; P:heme O biosynthetic process; IEA:Ensembl. DR GO; GO:0006782; P:protoporphyrinogen IX biosynthetic process; IEA:UniProtKB-UniPathway. DR GO; GO:0070541; P:response to platinum ion; IEA:Ensembl. DR GO; GO:0006780; P:uroporphyrinogen III biosynthetic process; IDA:UniProtKB. DR CDD; cd06578; HemD; 1. DR Gene3D; 3.40.50.10090; -; 2. DR InterPro; IPR036108; 4pyrrol_syn_uPrphyn_synt_sf. DR InterPro; IPR003754; 4pyrrol_synth_uPrphyn_synth. DR InterPro; IPR039793; UROS/Hem4. DR PANTHER; PTHR12390; UROPORPHYRINOGEN III SYNTHASE; 1. DR PANTHER; PTHR12390:SF0; UROPORPHYRINOGEN-III SYNTHASE; 1. DR Pfam; PF02602; HEM4; 1. DR SUPFAM; SSF69618; HemD-like; 1. DR Genevisible; P10746; HS. PE 1: Evidence at protein level; KW 3D-structure; Direct protein sequencing; Disease variant; KW Heme biosynthesis; Lyase; Porphyrin biosynthesis; Reference proteome. FT CHAIN 1..265 FT /note="Uroporphyrinogen-III synthase" FT /id="PRO_0000135251" FT VARIANT 3 FT /note="V -> F (in CEP; no residual activity; FT dbSNP:rs773301339)" FT /evidence="ECO:0000269|PubMed:9188670" FT /id="VAR_021615" FT VARIANT 4 FT /note="L -> F (in CEP; dbSNP:rs121908015)" FT /evidence="ECO:0000269|PubMed:1733834" FT /id="VAR_003674" FT VARIANT 19 FT /note="Y -> C (in CEP)" FT /evidence="ECO:0000269|PubMed:7860775" FT /id="VAR_003675" FT VARIANT 47 FT /note="S -> P (in CEP; severe cutaneous lesions; less than FT 3% wild-type activity; dbSNP:rs397515527)" FT /evidence="ECO:0000269|PubMed:15304101" FT /id="VAR_021616" FT VARIANT 53 FT /note="P -> L (in CEP; severe phenotype; no detectable FT activity; dbSNP:rs121908013)" FT /evidence="ECO:0000269|PubMed:2331520" FT /id="VAR_003676" FT VARIANT 62 FT /note="T -> A (in CEP; the effect on catalytic activity is FT controversial; dbSNP:rs28941775)" FT /evidence="ECO:0000269|PubMed:11689424, FT ECO:0000269|PubMed:1737856" FT /id="VAR_003677" FT VARIANT 66 FT /note="A -> V (in CEP; mild phenotype; strong decrease in FT enzymatic activity, when tested in vitro; may affect FT thermal stability; dbSNP:rs28941774)" FT /evidence="ECO:0000269|PubMed:1737856" FT /id="VAR_003678" FT VARIANT 69 FT /note="A -> T (in CEP; less than 2% wild-type activity)" FT /evidence="ECO:0000269|PubMed:12060141" FT /id="VAR_021617" FT VARIANT 73 FT /note="C -> R (in CEP; frequent mutation in Western FT countries; severe phenotype; loss of enzymatic activity, FT when tested in vitro; dbSNP:rs121908012)" FT /evidence="ECO:0000269|PubMed:12060141, FT ECO:0000269|PubMed:1733834, ECO:0000269|PubMed:1737856, FT ECO:0000269|PubMed:2331520, ECO:0000269|PubMed:9803266" FT /id="VAR_003679" FT VARIANT 82 FT /note="V -> F (in CEP; mild phenotype; high residual FT activity; dbSNP:rs121908016)" FT /evidence="ECO:0000269|PubMed:7860775" FT /id="VAR_003680" FT VARIANT 99 FT /note="V -> A (in CEP)" FT /evidence="ECO:0000269|PubMed:7860775" FT /id="VAR_003681" FT VARIANT 104 FT /note="A -> V (in CEP; residual activity; FT dbSNP:rs397515528)" FT /evidence="ECO:0000269|PubMed:7860775" FT /id="VAR_003682" FT VARIANT 124 FT /note="K -> R (in dbSNP:rs17153561)" FT /id="VAR_049345" FT VARIANT 129 FT /note="I -> T (in CEP; no residual activity)" FT /evidence="ECO:0000269|PubMed:11121156" FT /id="VAR_021618" FT VARIANT 171 FT /note="V -> G (in dbSNP:rs17173752)" FT /id="VAR_049346" FT VARIANT 188 FT /note="G -> R (in CEP; less than 5% wild-type activity; FT dbSNP:rs121908017)" FT /evidence="ECO:0000269|PubMed:9834209" FT /id="VAR_013558" FT VARIANT 188 FT /note="G -> W (in CEP; mild phenotype; less than 2% FT wild-type activity; dbSNP:rs121908017)" FT /evidence="ECO:0000269|PubMed:12060141" FT /id="VAR_021619" FT VARIANT 210..211 FT /note="EL -> HIQSQAQSQAQDN (in CEP)" FT /evidence="ECO:0000269|PubMed:12060141" FT /id="VAR_021620" FT VARIANT 212 FT /note="S -> P (in CEP; no residual activity; FT dbSNP:rs139388833)" FT /evidence="ECO:0000269|PubMed:8655129" FT /id="VAR_003683" FT VARIANT 219 FT /note="I -> S (in CEP; moderately-severe phenotype; less FT than 2% wild-type activity; dbSNP:rs767029901)" FT /evidence="ECO:0000269|PubMed:12060141" FT /id="VAR_021621" FT VARIANT 225 FT /note="G -> S (in CEP; dbSNP:rs121908020)" FT /evidence="ECO:0000269|PubMed:7860775" FT /id="VAR_003684" FT VARIANT 228 FT /note="T -> M (in CEP; loss of enzymatic activity, when FT tested in vitro; dbSNP:rs121908014)" FT /evidence="ECO:0000269|PubMed:12060141, FT ECO:0000269|PubMed:1733834, ECO:0000269|PubMed:1737856" FT /id="VAR_003685" FT VARIANT 237 FT /note="L -> P (in CEP; dbSNP:rs777433697)" FT /evidence="ECO:0000269|PubMed:22350154" FT /id="VAR_067318" FT VARIANT 248 FT /note="P -> Q (in CEP; dbSNP:rs121908021)" FT /evidence="ECO:0000269|PubMed:21653323" FT /id="VAR_066247" FT MUTAGEN 63 FT /note="S->A: Does not affect enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT MUTAGEN 65 FT /note="R->A: Slightly affects enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT MUTAGEN 103 FT /note="T->A: Slightly affects enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT MUTAGEN 127 FT /note="E->A: Does not affect enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT MUTAGEN 168 FT /note="Y->F: Impairs enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT MUTAGEN 197 FT /note="S->A: Does not affect enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT MUTAGEN 220 FT /note="K->A: Does not affect enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT MUTAGEN 227 FT /note="T->A: Does not affect enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT MUTAGEN 228 FT /note="T->A: Impairs enzymatic activity." FT /evidence="ECO:0000269|PubMed:11689424" FT STRAND 2..9 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 18..24 FT /evidence="ECO:0007829|PDB:1JR2" FT TURN 25..27 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 29..34 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 36..40 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 43..50 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 53..55 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 57..61 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 64..76 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 80..86 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 88..93 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 94..98 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 101..109 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 122..130 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 139..144 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 146..148 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 151..156 FT /evidence="ECO:0007829|PDB:1JR2" FT TURN 157..159 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 162..166 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 168..172 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 176..187 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 191..197 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 198..212 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 213..218 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 219..225 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 226..234 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 240..242 FT /evidence="ECO:0007829|PDB:1JR2" FT STRAND 244..247 FT /evidence="ECO:0007829|PDB:1JR2" FT HELIX 248..258 FT /evidence="ECO:0007829|PDB:1JR2" SQ SEQUENCE 265 AA; 28628 MW; CEF171401361F61E CRC64; MKVLLLKDAK EDDCGQDPYI RELGLYGLEA TLIPVLSFEF LSLPSFSEKL SHPEDYGGLI FTSPRAVEAA ELCLEQNNKT EVWERSLKEK WNAKSVYVVG NATASLVSKI GLDTEGETCG NAEKLAEYIC SRESSALPLL FPCGNLKREI LPKALKDKGI AMESITVYQT VAHPGIQGNL NSYYSQQGVP ASITFFSPSG LTYSLKHIQE LSGDNIDQIK FAAIGPTTAR ALAAQGLPVS CTAESPTPQA LATGIRKALQ PHGCC //