Biology:Coproporphyrinogen III oxidase

Short description: Mammalian protein found in Homo sapiens

Generic protein structure example

Coprogen_oxidas
coproporphyrinogen iii oxidase from leishmania major
Identifiers
Symbol	Coprogen_oxidas
Pfam	PF01218
InterPro	IPR001260
PROSITE	PDOC00783
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Coproporphyrinogen-III oxidase, mitochondrial (abbreviated as CPOX) is an enzyme that in humans is encoded by the CPOX gene. 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.

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

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. The protein is a homodimer containing two internally bound iron atoms per molecule of native protein. 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.

Protein

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

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. 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.

To date, over 50 CPOX mutations causing HCP have been described. Most of these mutations result in substitution of amino acid residues within the structural framework of CPOX. At least 32 of these mutations are considered to be disease-causing mutations. 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. 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.

Interactions

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

Further reading

• "Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria". Human Molecular Genetics 3 (10): 1807–10. October 1994. doi:10.1093/hmg/3.10.1807. PMID 7849704. 
• "Localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12". Human Genetics 94 (5): 557–9. November 1994. doi:10.1007/BF00211026. PMID 7959694. 
• "Coproporphyrinogen oxidase: gene organization and description of a mutation leading to exon 6 skipping". Human Molecular Genetics 3 (8): 1325–30. August 1994. doi:10.1093/hmg/3.8.1325. PMID 7987309. 
• "Homozygous hereditary coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms". Human Molecular Genetics 3 (3): 477–80. March 1994. doi:10.1093/hmg/3.3.477. PMID 8012360. 
• "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. Jan 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
• "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. April 1994. doi:10.1073/pnas.91.8.3024. PMID 8159699. Bibcode: 1994PNAS...91.3024M. 
• "Three novel mutations in the coproporphyrinogen oxidase gene". Human Mutation 9 (1): 78–80. 1997. doi:10.1002/(SICI)1098-1004(1997)9:1<78::AID-HUMU17>3.0.CO;2-M. PMID 8990017. 
• "A novel missense mutation in exon 4 of the human coproporphyrinogen oxidase gene in two patients with hereditary coproporphyria". Human Genetics 99 (2): 199–201. February 1997. doi:10.1007/s004390050338. PMID 9048920. 
• "Hereditary coproporphyria: exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene". Human Mutation 10 (3): 196–200. 1997. doi:10.1002/(SICI)1098-1004(1997)10:3<196::AID-HUMU3>3.0.CO;2-H. PMID 9298818. 
• "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. October 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
• "Neonatal hemolytic anemia due to inherited harderoporphyria: clinical characteristics and molecular basis". Blood 91 (4): 1453–7. February 1998. doi:10.1182/blood.V91.4.1453. PMID 9454777. 
• "Identification of a novel mutation of the CPO gene in a Japanese hereditary coproporphyria family". American Journal of Medical Genetics 80 (3): 204–6. November 1998. doi:10.1002/(SICI)1096-8628(19981116)80:3<204::AID-AJMG4>3.0.CO;2-G. PMID 9843038. 
• "Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update". Human Mutation 13 (1): 44–53. 1999. doi:10.1002/(SICI)1098-1004(1999)13:1<44::AID-HUMU5>3.0.CO;2-Q. PMID 9888388. 
• "Expression of coproporphyrinogen oxidase and synthesis of hemoglobin in human erythroleukemia K562 cells". European Journal of Biochemistry 268 (6): 1705–11. March 2001. doi:10.1046/j.1432-1327.2001.02045.x. PMID 11248690. 
• "Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria". American Journal of Human Genetics 68 (5): 1130–8. May 2001. doi:10.1086/320118. PMID 11309681. 
• "Mutant and wild-type alpha-synuclein interact with mitochondrial cytochrome C oxidase". Journal of Molecular Neuroscience 18 (3): 229–38. June 2002. doi:10.1385/JMN:18:3:229. PMID 12059041. 
• "Two novel mutations and coexistence of the 991C>T and the 1339C>T mutation on a single allele in the coproporphyrinogen oxidase gene in Swedish patients with hereditary coproporphyria". Journal of Human Genetics 47 (8): 407–12. 2002. doi:10.1007/s100380200059. PMID 12181641. 

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

External links

• Coproporphyrinogen+III+Oxidases at the US National Library of Medicine Medical Subject Headings (MeSH)

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