ウロポルフィリノーゲン脱炭酸酵素 UROD
WordNet
- any of the enzymes that hydrolize the carboxyl group
Wikipedia preview
出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2014/05/01 04:28:27」(JST)
[Wiki en表示]
Uroporphyrinogen decarboxylase |
PDB rendering based on 1jph. |
Available structures |
PDB |
Ortholog search: PDBe, RCSB |
List of PDB id codes |
1JPH, 1JPI, 1JPK, 1R3Q, 1R3R, 1R3S, 1R3T, 1R3V, 1R3W, 1R3Y, 1URO, 2Q6Z, 2Q71, 3GVQ, 3GVR, 3GVV, 3GVW, 3GW0, 3GW3
|
|
|
Identifiers |
Symbols |
UROD ; PCT; UPD |
External IDs |
OMIM: 613521 MGI: 98916 HomoloGene: 320 ChEMBL: 1681619 GeneCards: UROD Gene |
EC number |
4.1.1.37 |
Gene ontology |
Molecular function |
• uroporphyrinogen decarboxylase activity
|
Cellular component |
• nucleus
• nucleolus
• cytoplasm
• cytosol
• microtubule cytoskeleton
|
Biological process |
• porphyrin-containing compound metabolic process
• protoporphyrinogen IX biosynthetic process
• heme biosynthetic process
• small molecule metabolic process
|
Sources: Amigo / QuickGO |
|
RNA expression pattern |
|
|
More reference expression data |
Orthologs |
Species |
Human |
Mouse |
|
Entrez |
7389 |
22275 |
|
Ensembl |
ENSG00000126088 |
ENSMUSG00000028684 |
|
UniProt |
P06132 |
P70697 |
|
RefSeq (mRNA) |
NM_000374 |
NM_009478 |
|
RefSeq (protein) |
NP_000365 |
NP_033504 |
|
Location (UCSC) |
Chr 1:
45.48 – 45.48 Mb |
Chr 4:
116.99 – 116.99 Mb |
|
PubMed search |
[1] |
[2] |
|
|
Uroporphyrinogen decarboxylase, also known as UROD, is an enzyme that in humans is encoded by the UROD gene.[1]
Contents
- 1 Function
- 2 Clinical significance
- 3 Mechanism
- 4 References
- 5 Further reading
Function
This gene encodes the fifth enzyme of the heme biosynthetic pathway. This enzyme is responsible for catalyzing the conversion of uroporphyrinogen to coproporphyrinogen through the removal of four carboxymethyl side chains.[1]
Uroporphyrinogen III decarboxylase (UroD) is a homodimeric enzyme (EC 4.1.1.37, PDB 1URO) that catalyzes the fifth step in heme biosynthesis: the elimination of carboxyl groups from the four acetate side chains of uroporphyrinogen III to yield coproporphyrinogen III.
Clinical significance
Mutations and deficiency in this enzyme are known to cause familial porphyria cutanea tarda and hepatoerythropoietic porphyria.[1]
Mechanism
At low substrate concentrations, the reaction is believed to follow an ordered route, with the sequential removal of CO2 from the D, A, B, and C rings, whereas at higher substrate/enzyme levels a random route seems to be operative. The enzyme functions as a dimer in solution, and both the enzymes from human and tobacco have been crystallized and solved at good resolutions.
The reaction catalyzed by UroD
UroD is regarded as an unusual decarboxylase, since it performs decarboxylations without the intervention of any cofactors, unlike the vast majority of decarboxylases. Its mechanism has recently been proposed to proceed through substrate protonation by an arginine residue.[2] A 2008 report demonstrated that the uncatalyzed rate for UroD's reaction is 10−19 s−1, so at pH 10 the rate acceleration of UroD relative to the uncatalyzed rate, catalytic proficiency, is the largest for any enzyme known, 6 x 1024 M−1.[3]
Proposed reaction mechanism of uroporphyrinogen III decarboxyklase
References
- ^ a b c "Entrez Gene: UROD uroporphyrinogen decarboxylase".
- ^ Silva PJ, Ramos MJ. Density-functional study of mechanisms for the cofactor-free decarboxylation performed by uroporphyrinogen III decarboxylase. J Phys Chem B 2005;109:18195-200. doi:10.1021/jp051792s.
- ^ Lewis CA, Wolfenden R (November 2008). "Uroporphyrinogen decarboxylation as a benchmark for the catalytic proficiency of enzymes". Proc. Natl. Acad. Sci. U.S.A. 105 (45): 17328–33. doi:10.1073/pnas.0809838105. PMC 2582308. PMID 18988736.
Further reading
- Elder GH, Lee GB, Tovey JA (1978). "Decreased activity of hepatic uroporphyrinogen decarboxylase in sporadic porphyria cutanea tarda.". N. Engl. J. Med. 299 (6): 274–8. doi:10.1056/NEJM197808102990603. PMID 661926.
- de Verneuil H, Bourgeois F, de Rooij F, et al. (1992). "Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria.". Hum. Genet. 89 (5): 548–52. PMID 1634232.
- Romana M, Grandchamp B, Dubart A, et al. (1991). "Identification of a new mutation responsible for hepatoerythropoietic porphyria.". Eur. J. Clin. Invest. 21 (2): 225–9. doi:10.1111/j.1365-2362.1991.tb01814.x. PMID 1905636.
- Garey JR, Harrison LM, Franklin KF, et al. (1990). "Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda.". J. Clin. Invest. 86 (5): 1416–22. doi:10.1172/JCI114856. PMC 296884. PMID 2243121.
- Garey JR, Hansen JL, Harrison LM, et al. (1989). "A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda.". Blood 73 (4): 892–5. PMID 2920211.
- Roméo PH, Raich N, Dubart A, et al. (1986). "Molecular cloning and nucleotide sequence of a complete human uroporphyrinogen decarboxylase cDNA.". J. Biol. Chem. 261 (21): 9825–31. PMID 3015909.
- Dubart A, Mattei MG, Raich N, et al. (1986). "Assignment of human uroporphyrinogen decarboxylase (URO-D) to the p34 band of chromosome 1.". Hum. Genet. 73 (3): 277–9. doi:10.1007/BF00401245. PMID 3460962.
- Romana M, Dubart A, Beaupain D, et al. (1987). "Structure of the gene for human uroporphyrinogen decarboxylase.". Nucleic Acids Res. 15 (18): 7343–56. doi:10.1093/nar/15.18.7343. PMC 306252. PMID 3658695.
- de Verneuil H, Grandchamp B, Beaumont C, et al. (1986). "Uroporphyrinogen decarboxylase structural mutant (Gly281----Glu) in a case of porphyria.". Science 234 (4777): 732–4. doi:10.1126/science.3775362. PMID 3775362.
- Roberts AG, Elder GH, De Salamanca RE, et al. (1995). "A mutation (G281E) of the human uroporphyrinogen decarboxylase gene causes both hepatoerythropoietic porphyria and overt familial porphyria cutanea tarda: biochemical and genetic studies on Spanish patients.". J. Invest. Dermatol. 104 (4): 500–2. doi:10.1111/1523-1747.ep12605953. PMID 7706766.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Meguro K, Fujita H, Ishida N, et al. (1994). "Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria". J. Invest. Dermatol. 102 (5): 681–5. doi:10.1111/1523-1747.ep12374134. PMID 8176248.
- Moran-Jimenez MJ, Ged C, Romana M, et al. (1996). "Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria". Am. J. Hum. Genet. 58 (4): 712–21. PMC 1914669. PMID 8644733.
- McManus JF, Begley CG, Sassa S, Ratnaike S (1996). "Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria". Blood 88 (9): 3589–600. PMID 8896428.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Whitby FG, Phillips JD, Kushner JP, Hill CP (1998). "Crystal structure of human uroporphyrinogen decarboxylase". EMBO J. 17 (9): 2463–71. doi:10.1093/emboj/17.9.2463. PMC 1170588. PMID 9564029.
- Mendez M, Sorkin L, Rossetti MV, et al. (1998). "Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles". Am. J. Hum. Genet. 63 (5): 1363–75. doi:10.1086/302119. PMC 1377546. PMID 9792863.
- Wang H, Long Q, Marty SD, et al. (1998). "A zebrafish model for hepatoerythropoietic porphyria". Nat. Genet. 20 (3): 239–43. doi:10.1038/3041. PMID 9806541.
- McManus JF, Begley CG, Sassa S, Ratnaike S (1999). "Three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda. Mutation in brief no. 237. Online". Hum. Mutat. 13 (5): 412. doi:10.1002/(SICI)1098-1004(1999)13:5<412::AID-HUMU13>3.0.CO;2-N. PMID 10338097.
- Christiansen L, Ged C, Hombrados I, et al. (1999). "Screening for mutations in the uroporphyrinogen decarboxylase gene using denaturing gradient gel electrophoresis. Identification and characterization of six novel mutations associated with familial PCT". Hum. Mutat. 14 (3): 222–32. doi:10.1002/(SICI)1098-1004(1999)14:3<222::AID-HUMU5>3.0.CO;2-V. PMID 10477430.
PDB gallery
|
|
|
1jph: Ile260Thr mutant of Human UroD, human uroporphyrinogen III decarboxylase
|
|
1jpi: Phe232Leu mutant of human UROD, human uroporphyrinogen III decarboxylase
|
|
1jpk: Gly156Asp mutant of Human UroD, human uroporphyrinogen III decarboxylase
|
|
1r3q: Uroporphyrinogen Decarboxylase in complex with coproporphyrinogen-I
|
|
1r3r: Uroporphyrinogen Decarboxylase with mutation D86N
|
|
1r3s: Uroporphyrinogen Decarboxylase single mutant D86G in complex with coproporphyrinogen-I
|
|
1r3t: Uroporphyrinogen Decarboxylase single mutant D86G in complex with coproporphyrinogen-III
|
|
1r3v: Uroporphyrinogen Decarboxylase single mutant D86E in complex with coproporphyrinogen-I
|
|
1r3w: Uroporphyrinogen Decarboxylase Y164F mutant in complex with coproporphyrinogen-III
|
|
1r3y: Uroporphyrinogen Decarboxylase in complex with coproporphyrinogen-III
|
|
1uro: UROPORPHYRINOGEN DECARBOXYLASE
|
|
|
|
Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)
- Metabolism: amino acid metabolism
- porphyrin/heme enzymes
|
|
Porphyrin biosynthesis |
early mitochondrial: |
- Aminolevulinic acid synthase
- Porphobilinogen synthase
|
|
cytosolic: |
- Porphobilinogen deaminase
- Uroporphyrinogen III synthase
- Uroporphyrinogen III decarboxylase
- Coproporphyrinogen III oxidase
|
|
late mitochondrial: |
- Protoporphyrinogen oxidase
- Ferrochelatase
|
|
|
Heme degradation
to bile |
spleen: |
- Heme oxygenase
- Biliverdin reductase
|
|
liver: |
|
|
|
|
mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
|
k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
|
m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
|
|
|
cell/phys (coag, heme, immu, gran), csfs
|
rbmg/mogr/tumr/hist, sysi/epon, btst
|
drug (B1/2/3+5+6), btst, trns
|
|
|
|
Carbon-carbon lyases (EC 4.1)
|
|
4.1.1: Carboxy-lyases |
- Pyruvate decarboxylase
- Oxaloacetate decarboxylase
- Acetoacetate decarboxylase
- Malonyl-CoA decarboxylase
- Glutamate decarboxylase
- Ornithine decarboxylase
- Lysine decarboxylase
- Phosphoribosylaminoimidazole carboxylase
- Histidine decarboxylase
- Uridine monophosphate synthetase/Orotidine 5'-phosphate decarboxylase
- Aromatic L-amino acid decarboxylase
- Phosphoenolpyruvate carboxylase
- Pyrophosphomevalonate decarboxylase
- Uroporphyrinogen III decarboxylase
- RuBisCO
- Phosphoenolpyruvate carboxykinase
- Adenosylmethionine decarboxylase
|
|
4.1.2: Aldehyde-lyases |
- Fructose-bisphosphate aldolase
- Aldolase A
- Aldolase B
- Aldolase C
- 2-hydroxyphytanoyl-CoA lyase
- Threonine aldolase
|
|
4.1.3: Oxo-acid-lyases |
- 3-hydroxy-3-methylglutaryl-CoA lyase
|
|
4.1.99: Other |
|
|
- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
|
|
|
|
UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
English Journal
- Porphyria cutanea tarda in a child following multi-agent chemotherapy.
- Lapresto L, Nyanda H, Knapp CF, Sopkovich J, Nelson CG.AbstractPorphyria cutanea tarda (PCT) is a blistering skin disorder that occurs most commonly in middle-aged individuals. It is caused by decreased uroporphyrinogen decarboxylase (UROD) activity, which results in elevated levels of uroporphyrinogen. Occurrence remains very rare in children with some sources quoting as few as 50 reports of childhood cases.1 The literature reports occasional cases of PCT onset with various drugs, including barbiturates, estrogens, griseofulvin, rifampicin, sulfonamides, imatinib, methotrexate, tamoxifen, and cyclophosphamide, however its incidence in childhood is uncommon.2-6 We present a case of new-onset PCT in an eight year-old following treatment of pre-B cell acute lymphoblastic leukemia with multi-agent chemotherapy.<BR /><BR /> <EM>J Drugs Dermatol.</EM> 2014;13(4):489-491.
- Journal of drugs in dermatology : JDD.J Drugs Dermatol.2014 Apr 1;13(4):489-91.
- Porphyria cutanea tarda (PCT) is a blistering skin disorder that occurs most commonly in middle-aged individuals. It is caused by decreased uroporphyrinogen decarboxylase (UROD) activity, which results in elevated levels of uroporphyrinogen. Occurrence remains very rare in children with some sources
- PMID 24719070
- Hepatitis C- and HIV-induced porphyria cutanea tarda.
- Quansah R, Cooper CJ, Said S, Bizet J, Paez D, Hernandez GT.Author information Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX, U.S.A.AbstractPatient: Male, 47 Final Diagnosis: Porphyria cutanea tarda Symptoms: Chills • cough dry • thumb swelling Medication: - Clinical Procedure: - Specialty: Metabolic Disorders and Diabetics.
- The American journal of case reports.Am J Case Rep.2014 Jan 21;15:35-40. doi: 10.12659/AJCR.889955. eCollection 2014.
- Patient: Male, 47 Final Diagnosis: Porphyria cutanea tarda Symptoms: Chills • cough dry • thumb swelling Medication: - Clinical Procedure: - Specialty: Metabolic Disorders and Diabetics.OBJECTIVE: Challenging differential diagnosis.BACKGROUND: Porphyria cutanea tarda (PCT) is the most common typ
- PMID 24470839
- A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase.
- Yip KW1, Zhang Z2, Sakemura-Nakatsugawa N1, Huang JW3, Vu NM2, Chiang YK3, Lin CL3, Kwan JY1, Yue S1, Jitkova Y1, To T1, Zahedi P1, Pai EF4, Schimmer AD5, Lovell JF6, Sessler JL2, Liu FF7.Author information 1Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada.2Department of Chemistry, Institute for Cellular and Molecular Biology, the University of Texas at Austin, Austin, Texas, United States of America.3Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsin-chu, Taiwan.4Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada ; Department of Biochemistry, University of Toronto, Ontario, Canada ; Department of Molecular Genetics; University of Toronto, Ontario, Canada.5Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.6Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, New York, United States of America.7Ontario Cancer Institute/Campbell Family Cancer Research Institute, University Health Network (UHN), Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada ; Department of Radiation Oncology, Princess Margaret Cancer Centre, UHN, Toronto, Ontario, Canada ; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.AbstractUroporphyrinogen decarboxylase (UROD) catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16), was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM), but did not affect porphobilinogen deaminase (at 62.5 µM), thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE) cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1). This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.
- PloS one.PLoS One.2014 Feb 25;9(2):e89889. doi: 10.1371/journal.pone.0089889. eCollection 2014.
- Uroporphyrinogen decarboxylase (UROD) catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton react
- PMID 24587102
Japanese Journal
- 色素関係 ウロポルフィリノーゲン脱炭酸酵素(UROD) (広範囲 血液・尿化学検査,免疫学的検査(第7版・1)その数値をどう読むか) -- (生化学的検査(1))
- Interaction of the Molecular Chaperone HtpG with Uroporphyrinogen Decarboxylase in the Cyanobacterium Synechococcus elongatus PCC 7942
- SAITO Masakazu,WATANABE Satoru,YOSHIKAWA Hirofumi,NAKAMOTO Hitoshi
- Bioscience, biotechnology, and biochemistry 72(5), 1394-1397, 2008-05-23
- … Uroporphyrinogen decarboxylase (HemE) is important due to its location at the first branch-point in tetrapyrrole biosynthesis. …
- NAID 10027528269
Related Links
- The official name of this gene is “uroporphyrinogen decarboxylase.” UROD is the gene's official symbol. The UROD gene is also known by other names, listed below. Read more about gene names and symbols on the About ...
- Human protein-coding gene UROD. Represented by 848 ESTs from 297 cDNA libraries. Corresponds to 2 reference sequences (different isoforms). [UniGene 140235 - Hs.78601] ... EST Profile: Approximate expression patterns ...
Related Pictures
★リンクテーブル★
[★]
- 英
- uroporphyrinogen decarboxylase, UROD
- 関
- ウロポルフィリノーゲンデカルボキシラーゼ
[★]
ウロポルフィリノーゲン脱炭酸酵素 uroporphyrinogen decarboxylase
[★]
- 同
- uroporphyrinogen decarboxylase
[★]
デカルボキシラーゼ、脱炭酸酵素
- 関
- carboxy-lyase
[★]
ウロ・ルフィリノーゲン
- 同
- uroporphyrinogens