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26  structures 3971  species 1  interaction 4381  sequences 24  architectures

Family: Coprogen_oxidas (PF01218)

Summary: Coproporphyrinogen III oxidase

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Coproporphyrinogen III oxidase Edit Wikipedia article

CPOX
Protein CPOX PDB 2aex.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CPOX, CPO, CPX, HCP, coproporphyrinogen oxidase
External IDs OMIM: 612732 MGI: 104841 HomoloGene: 76 GeneCards: CPOX
Gene location (Human)
Chromosome 3 (human)
Chr. Chromosome 3 (human)[1]
Chromosome 3 (human)
Genomic location for CPOX
Genomic location for CPOX
Band No data available Start 98,521,132 bp[1]
End 98,593,723 bp[1]
RNA expression pattern
PBB GE CPOX 204172 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000097

NM_007757

RefSeq (protein)

NP_000088

NP_031783

Location (UCSC) Chr 3: 98.52 – 98.59 Mb Chr 3: 58.67 – 58.68 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Coprogen_oxidas
PDB 1vju EBI.jpg
coproporphyrinogen iii oxidase from leishmania major
Identifiers
Symbol Coprogen_oxidas
Pfam PF01218
InterPro IPR001260
PROSITE PDOC00783

Coproporphyrinogen-III oxidase, mitochondrial (abbreviated as CPOX) is an enzyme that in humans is encoded by the CPOX gene.[5][6][7] A genetic defect in the enzyme results in a reduced production of heme in animals. The medical condition associated with this enzyme defect is called hereditary coproporphyria.[8][9]

CPOX, the sixth enzyme of the haem biosynthetic pathway, converts coproporphyrinogen III to protoporphyrinogen IX through two sequential steps of oxidative decarboxylation.[10] The activity of the CPOX enzyme, located in the mitochondrial membrane, is measured in lymphocytes.[11]

Function

CPOX is an enzyme involved in the sixth step of porphyrin metabolism it catalyses the oxidative decarboxylation of coproporphyrinogen III to proto-porphyrinogen IX in the haem and chlorophyll biosynthetic pathways.[6][12] The protein is a homodimer containing two internally bound iron atoms per molecule of native protein.[13] The enzyme is active in the presence of molecular oxygen that acts as an electron acceptor. The enzyme is widely distributed having been found in a variety of eukaryotic and prokaryotic sources.

Structure

Gene

Human CPOX is a mitochondrial enzyme encoded by a 14 kb CPOX gene containing seven exons located on chromosome 3 at q11.2.[7]

Protein

CPOX is expressed as a 40 kDa precursor and contains an amino terminal mitochondrial targeting signal.[14] After proteolytic processing, the protein is present as a mature form of a homodimer with a molecular mass of 37 kDa.[15]

Clinical significance

Hereditary coproporphyria (HCP) and harderoporphyria are two phenotypically separate disorders that concern partial deficiency of CPOX. Neurovisceral symptomatology predominates in HCP. Additionally, it may be associated with abdominal pain and/or skin photosensitivity. Hyper-excretion of coproporphyrin III in urine and faeces has been recorded in biochemical tests.[16] HCP is an autosomal dominant inherited disorder, whereas harderoporphyria is a rare erythropoietic variant form of HCP and is inherited in an autosomal recessive fashion. Clinically, it is characterized by neonatal haemolytic anaemia. Sometimes, the presence of skin lesions with marked faecal excretion of harderoporphyrin is also described in harderoporphyric patients.[17]

To date, over 50 CPOX mutations causing HCP have been described.[18] Most of these mutations result in substitution of amino acid residues within the structural framework of CPOX.[19] In terms of the molecular basis of HCP and harderoporphyria, mutations of CPOX in patients with harderoporphyria were demonstrated in the region of exon 6, where mutations in those with HCP were also identified.[20] As only patients with mutation in this region (K404E) would develop harderoporphyria, this mutation led to diminishment of the second step of the decarboxylation reaction during the conversion of coproporphyrinogen to protoporphyrinogen, implying that the active site of the enzyme involved in the second step of decarboxylation is located in exon 6.[18]

Interactions

CPOX has been shown to interact with the atypical keto-isocoproporphyrin (KICP) in human subjects with mercury (Hg) exposure.[21]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000080819 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022742 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ Lamoril J, Martasek P, Deybach JC, Da Silva V, Grandchamp B, Nordmann Y (February 1995). "A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria". Human Molecular Genetics. 4 (2): 275–8. PMID 7757079. doi:10.1093/hmg/4.2.275. 
  6. ^ a b Kohno H, Furukawa T, Yoshinaga T, Tokunaga R, Taketani S (October 1993). "Coproporphyrinogen oxidase. Purification, molecular cloning, and induction of mRNA during erythroid differentiation". The Journal of Biological Chemistry. 268 (28): 21359–63. PMID 8407975. 
  7. ^ a b "Entrez Gene: CPOX coproporphyrinogen oxidase". 
  8. ^ "Hereditary coproporphyria". Genetic and Rare Diseases Information Center. National Institutes of Health. Retrieved 8 August 2011. 
  9. ^ "CPOX". Genetics Home Reference. Retrieved 8 August 2011. 
  10. ^ Sano S, Granick S (April 1961). "Mitochondrial coproporphyrinogen oxidase and protoporphyrin formation". The Journal of Biological Chemistry. 236: 1173–80. PMID 13746277. 
  11. ^ Guo R, Lim CK, Peters TJ (October 1988). "Accurate and specific HPLC assay of coproporphyrinogen III oxidase activity in human peripheral leucocytes". Clinica Chimica Acta; International Journal of Clinical Chemistry. 177 (3): 245–52. PMID 3233772. doi:10.1016/0009-8981(88)90069-1. 
  12. ^ Madsen O, Sandal L, Sandal NN, Marcker KA (October 1993). "A soybean coproporphyrinogen oxidase gene is highly expressed in root nodules". Plant Molecular Biology. 23 (1): 35–43. PMID 8219054. doi:10.1007/BF00021417. 
  13. ^ Camadro JM, Chambon H, Jolles J, Labbe P (May 1986). "Purification and properties of coproporphyrinogen oxidase from the yeast Saccharomyces cerevisiae". European Journal of Biochemistry / FEBS. 156 (3): 579–87. PMID 3516695. doi:10.1111/j.1432-1033.1986.tb09617.x. 
  14. ^ Martasek P, Camadro JM, Delfau-Larue MH, Dumas JB, Montagne JJ, de Verneuil H, Labbe P, Grandchamp B (April 1994). "Molecular cloning, sequencing, and functional expression of a cDNA encoding human coproporphyrinogen oxidase". Proceedings of the National Academy of Sciences of the United States of America. 91 (8): 3024–8. PMC 43507Freely accessible. PMID 8159699. doi:10.1073/pnas.91.8.3024. 
  15. ^ Martasek P, Nordmann Y, Grandchamp B (March 1994). "Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms". Human Molecular Genetics. 3 (3): 477–80. PMID 8012360. doi:10.1093/hmg/3.3.477. 
  16. ^ Taketani S, Kohno H, Furukawa T, Yoshinaga T, Tokunaga R (Jan 1994). "Molecular cloning, sequencing and expression of cDNA encoding human coproporphyrinogen oxidase". Biochimica et Biophysica Acta. 1183 (3): 547–9. PMID 8286403. doi:10.1016/0005-2728(94)90083-3. 
  17. ^ Kim DH, Hino R, Adachi Y, Kobori A, Taketani S (December 2013). "The enzyme engineering of mutant homodimer and heterodimer of coproporphyinogen oxidase contributes to new insight into hereditary coproporphyria and harderoporphyria". Journal of Biochemistry. 154 (6): 551–9. PMID 24078084. doi:10.1093/jb/mvt086. 
  18. ^ a b Hasanoglu A, Balwani M, Kasapkara CS, Ezgü FS, Okur I, Tümer L, Cakmak A, Nazarenko I, Yu C, Clavero S, Bishop DF, Desnick RJ (February 2011). "Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R". Journal of Inherited Metabolic Disease. 34 (1): 225–31. PMC 3091031Freely accessible. PMID 21103937. doi:10.1007/s10545-010-9237-9. 
  19. ^ Lee DS, Flachsová E, Bodnárová M, Demeler B, Martásek P, Raman CS (October 2005). "Structural basis of hereditary coproporphyria". Proceedings of the National Academy of Sciences of the United States of America. 102 (40): 14232–7. PMC 1224704Freely accessible. PMID 16176984. doi:10.1073/pnas.0506557102. 
  20. ^ Schmitt C, Gouya L, Malonova E, Lamoril J, Camadro JM, Flamme M, Rose C, Lyoumi S, Da Silva V, Boileau C, Grandchamp B, Beaumont C, Deybach JC, Puy H (October 2005). "Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria". Human Molecular Genetics. 14 (20): 3089–98. PMID 16159891. doi:10.1093/hmg/ddi342. 
  21. ^ Heyer NJ, Bittner AC, Echeverria D, Woods JS (February 2006). "A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathway and porphyrin production". Toxicology Letters. 161 (2): 159–66. PMID 16214298. doi:10.1016/j.toxlet.2005.09.005. 

Further reading

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

External links

This article incorporates text from the public domain Pfam and InterPro IPR001260

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This tab holds annotation information from the InterPro database.

InterPro entry IPR001260

Coprogen oxidase (i.e. coproporphyrin III oxidase or coproporphyrinogenase) catalyses the oxidative decarboxylation of coproporphyrinogen III to proto-porhyrinogen IX in the haem and chlorophyll biosynthetic pathways [PUBMED:8407975, PUBMED:8219054]. The protein is a homodimer containing two internally bound iron atoms per molecule of native protein [PUBMED:3516695]. The enzyme is active in the presence of molecular oxygen that acts as an electron acceptor. The enzyme is widely distributed having been found in a variety of eukaryotic and prokaryotic sources.

Gene Ontology

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  Seed
(284)
Full
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Representative proteomes UniProt
(11466)
NCBI
(14921)
Meta
(2409)
RP15
(1029)
RP35
(2691)
RP55
(4194)
RP75
(5934)
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  Seed
(284)
Full
(4381)
Representative proteomes UniProt
(11466)
NCBI
(14921)
Meta
(2409)
RP15
(1029)
RP35
(2691)
RP55
(4194)
RP75
(5934)
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Seed source: Prosite
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Finn RD , Bateman A
Number in seed: 284
Number in full: 4381
Average length of the domain: 288.10 aa
Average identity of full alignment: 46 %
Average coverage of the sequence by the domain: 90.00 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 31.8 31.8
Trusted cut-off 31.9 32.6
Noise cut-off 31.2 31.7
Model length: 296
Family (HMM) version: 18
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Interactions

There is 1 interaction for this family. More...

Coprogen_oxidas

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Coprogen_oxidas domain has been found. There are 26 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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