Coproporphyrinogen-III oxidase, mitochondrial (abbreviated as CPOX) is an enzyme that in humans is encoded by the CPOXgene. 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 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.
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. 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.
^Lamoril J, Martasek P, Deybach JC, Da Silva V, Grandchamp B, Nordmann Y (Feb 1995). "A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria". Human Molecular Genetics. 4 (2): 275–8. doi:10.1093/hmg/4.2.275. PMID7757079.
^ abKohno H, Furukawa T, Yoshinaga T, Tokunaga R, Taketani S (Oct 1993). "Coproporphyrinogen oxidase. Purification, molecular cloning, and induction of mRNA during erythroid differentiation". The Journal of Biological Chemistry. 268 (28): 21359–63. PMID8407975.
^"CPOX". Genetics Home Reference. Retrieved 8 August 2011.
^Sano S, Granick S (Apr 1961). "Mitochondrial coproporphyrinogen oxidase and protoporphyrin formation". The Journal of Biological Chemistry. 236: 1173–80. PMID13746277.
^Guo R, Lim CK, Peters TJ (Oct 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. doi:10.1016/0009-8981(88)90069-1. PMID3233772.
^Madsen O, Sandal L, Sandal NN, Marcker KA (Oct 1993). "A soybean coproporphyrinogen oxidase gene is highly expressed in root nodules". Plant Molecular Biology. 23 (1): 35–43. doi:10.1007/BF00021417. PMID8219054.
^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. doi:10.1111/j.1432-1033.1986.tb09617.x. PMID3516695.
^Martasek P, Nordmann Y, Grandchamp B (Mar 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. doi:10.1093/hmg/3.3.477. PMID8012360.
^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. doi:10.1016/0005-2728(94)90083-3. PMID8286403.
^Kim DH, Hino R, Adachi Y, Kobori A, Taketani S (Dec 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. doi:10.1093/jb/mvt086. PMID24078084.
^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 (Oct 2005). "Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria". Human Molecular Genetics. 14 (20): 3089–98. doi:10.1093/hmg/ddi342. PMID16159891.
^Heyer NJ, Bittner AC, Echeverria D, Woods JS (Feb 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. doi:10.1016/j.toxlet.2005.09.005. PMID16214298.
Fujita H, Kondo M, Taketani S, Nomura N, Furuyama K, Akagi R, Nagai T, Terajima M, Galbraith RA, Sassa S (Oct 1994). "Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria". Human Molecular Genetics. 3 (10): 1807–10. doi:10.1093/hmg/3.10.1807. PMID7849704.
Cacheux V, Martasek P, Fougerousse F, Delfau MH, Druart L, Tachdjian G, Grandchamp B (Nov 1994). "Localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12". Human Genetics. 94 (5): 557–9. doi:10.1007/BF00211026. PMID7959694.
Delfau-Larue MH, Martasek P, Grandchamp B (Aug 1994). "Coproporphyrinogen oxidase: gene organization and description of a mutation leading to exon 6 skipping". Human Molecular Genetics. 3 (8): 1325–30. doi:10.1093/hmg/3.8.1325. PMID7987309.
Martasek P, Nordmann Y, Grandchamp B (Mar 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. doi:10.1093/hmg/3.3.477. PMID8012360.
Maruyama K, Sugano S (Jan 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. PMID8125298.
Daimon M, Gojyou E, Sugawara M, Yamatani K, Tominaga M, Sasaki H (Feb 1997). "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. doi:10.1007/s004390050338. PMID9048920.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 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. PMID9373149.
Lamoril J, Puy H, Gouya L, Rosipal R, Da Silva V, Grandchamp B, Foint T, Bader-Meunier B, Dommergues JP, Deybach JC, Nordmann Y (Feb 1998). "Neonatal hemolytic anemia due to inherited harderoporphyria: clinical characteristics and molecular basis". Blood. 91 (4): 1453–7. PMID9454777.
Taketani S, Furukawa T, Furuyama K (Mar 2001). "Expression of coproporphyrinogen oxidase and synthesis of hemoglobin in human erythroleukemia K562 cells". European Journal of Biochemistry / FEBS. 268 (6): 1705–11. doi:10.1046/j.1432-1327.2001.02045.x. PMID11248690.
Elkon H, Don J, Melamed E, Ziv I, Shirvan A, Offen D (Jun 2002). "Mutant and wild-type alpha-synuclein interact with mitochondrial cytochrome C oxidase". Journal of Molecular Neuroscience : MN. 18 (3): 229–38. doi:10.1385/JMN:18:3:229. PMID12059041.
Wiman A, Floderus Y, Harper P (2002). "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. doi:10.1007/s100380200059. PMID12181641.