Coproporphyrinogen III oxidase explained

Symbol:	Coprogen oxidase
Coprogen oxidase
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.^{[1] [2] [3]} 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.^{[4] [5]}

CPOX, the sixth enzyme of the haem biosynthetic pathway, converts coproporphyrinogen III to protoporphyrinogen IX through two sequential steps of oxidative decarboxylation.^[6] The activity of the CPOX enzyme, located in the mitochondrial membrane, is measured in lymphocytes.^[7]

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.^{[2] [8]} The protein is a homodimer containing two internally bound iron atoms per molecule of native protein.^[9] 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.^[3]

Protein

CPOX is expressed as a 40 kDa precursor and contains an amino terminal mitochondrial targeting signal.^[10] After proteolytic processing, the protein is present as a mature form of a homodimer with a molecular mass of 37 kDa.^[11]

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.^[12] 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.^[13]

To date, over 50 CPOX mutations causing HCP have been described.^[14] Most of these mutations result in substitution of amino acid residues within the structural framework of CPOX.^[15] At least 32 of these mutations are considered to be disease-causing mutations.^[16] 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.^[17] 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.^[14]

Interactions

CPOX has been shown to interact with the atypical keto-isocoproporphyrin (KICP) in human subjects with mercury (Hg) exposure.^[18]

Further reading

• Fujita H, Kondo M, Taketani S, Nomura N, Furuyama K, Akagi R, Nagai T, Terajima M, Galbraith RA, Sassa S . Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria . Human Molecular Genetics . 3 . 10 . 1807–10 . October 1994 . 7849704 . 10.1093/hmg/3.10.1807 .
• Cacheux V, Martasek P, Fougerousse F, Delfau MH, Druart L, Tachdjian G, Grandchamp B . Localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12 . Human Genetics . 94 . 5 . 557–9 . November 1994 . 7959694 . 10.1007/BF00211026 . 11997203 .
• Delfau-Larue MH, Martasek P, Grandchamp B . Coproporphyrinogen oxidase: gene organization and description of a mutation leading to exon 6 skipping . Human Molecular Genetics . 3 . 8 . 1325–30 . August 1994 . 7987309 . 10.1093/hmg/3.8.1325 .
• Martasek P, Nordmann Y, Grandchamp B . 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 . 8012360 . 10.1093/hmg/3.3.477 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Martasek P, Camadro JM, Delfau-Larue MH, Dumas JB, Montagne JJ, de Verneuil H, Labbe P, Grandchamp B . 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 . 8159699 . 43507 . 10.1073/pnas.91.8.3024 . 1994PNAS...91.3024M . free .
• Lamoril J, Deybach JC, Puy H, Grandchamp B, Nordmann Y . Three novel mutations in the coproporphyrinogen oxidase gene . Human Mutation . 9 . 1 . 78–80 . 1997 . 8990017 . 10.1002/(SICI)1098-1004(1997)9:1<78::AID-HUMU17>3.0.CO;2-M . 45889945 . free .
• Daimon M, Gojyou E, Sugawara M, Yamatani K, Tominaga M, Sasaki H . 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 . 9048920 . 10.1007/s004390050338 . 1813242 .
• Schreiber WE, Zhang X, Senz J, Jamani A . Hereditary coproporphyria: exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene . Human Mutation . 10 . 3 . 196–200 . 1997 . 9298818 . 10.1002/(SICI)1098-1004(1997)10:3<196::AID-HUMU3>3.0.CO;2-H . 32065580 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Lamoril J, Puy H, Gouya L, Rosipal R, Da Silva V, Grandchamp B, Foint T, Bader-Meunier B, Dommergues JP, Deybach JC, Nordmann Y . Neonatal hemolytic anemia due to inherited harderoporphyria: clinical characteristics and molecular basis . Blood . 91 . 4 . 1453–7 . February 1998 . 9454777 . 10.1182/blood.V91.4.1453. free .
• Susa S, Daimon M, Kondo H, Kondo M, Yamatani K, Sasaki H . 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 . 9843038 . 10.1002/(SICI)1096-8628(19981116)80:3<204::AID-AJMG4>3.0.CO;2-G .
• Rosipal R, Lamoril J, Puy H, Da Silva V, Gouya L, De Rooij FW, Te Velde K, Nordmann Y, Martàsek P, Deybach JC . Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update . Human Mutation . 13 . 1 . 44–53 . 1999 . 9888388 . 10.1002/(SICI)1098-1004(1999)13:1<44::AID-HUMU5>3.0.CO;2-Q . 2705450 . free .
• Taketani S, Furukawa T, Furuyama K . Expression of coproporphyrinogen oxidase and synthesis of hemoglobin in human erythroleukemia K562 cells . European Journal of Biochemistry . 268 . 6 . 1705–11 . March 2001 . 11248690 . 10.1046/j.1432-1327.2001.02045.x . free .
• Lamoril J, Puy H, Whatley SD, Martin C, Woolf JR, Da Silva V, Deybach JC, Elder GH . 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 . 11309681 . 1226094 . 10.1086/320118 .
• Elkon H, Don J, Melamed E, Ziv I, Shirvan A, Offen D . Mutant and wild-type alpha-synuclein interact with mitochondrial cytochrome C oxidase . Journal of Molecular Neuroscience . 18 . 3 . 229–38 . June 2002 . 12059041 . 10.1385/JMN:18:3:229 . 42265181 .
• Wiman A, Floderus Y, Harper P . 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 . 12181641 . 10.1007/s100380200059 . free .

Notes and References

1. Lamoril J, Martasek P, Deybach JC, Da Silva V, Grandchamp B, Nordmann Y . A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria . Human Molecular Genetics . 4 . 2 . 275–8 . February 1995 . 7757079 . 10.1093/hmg/4.2.275 .
2. Kohno H, Furukawa T, Yoshinaga T, Tokunaga R, Taketani S . Coproporphyrinogen oxidase. Purification, molecular cloning, and induction of mRNA during erythroid differentiation . The Journal of Biological Chemistry . 268 . 28 . 21359–63 . October 1993 . 10.1016/S0021-9258(19)36931-5 . 8407975 . free .
3. Web site: Entrez Gene: CPOX coproporphyrinogen oxidase.
4. Web site: Hereditary coproporphyria. Genetic and Rare Diseases Information Center. National Institutes of Health. 8 August 2011. 7 August 2012. https://web.archive.org/web/20120807135631/http://rarediseases.info.nih.gov/GARD/Condition/6619/Coproporphyria.aspx. dead.
5. Web site: CPOX. Genetics Home Reference. 8 August 2011.
6. Sano S, Granick S . Mitochondrial coproporphyrinogen oxidase and protoporphyrin formation . The Journal of Biological Chemistry . 236 . 1173–80 . April 1961 . 4 . 10.1016/S0021-9258(18)64262-0 . 13746277 . free .
7. Guo R, Lim CK, Peters TJ . 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 . October 1988 . 3233772 . 10.1016/0009-8981(88)90069-1.
8. Madsen O, Sandal L, Sandal NN, Marcker KA . A soybean coproporphyrinogen oxidase gene is highly expressed in root nodules . Plant Molecular Biology . 23 . 1 . 35–43 . October 1993 . 8219054 . 10.1007/BF00021417 . 23011457 .
9. Camadro JM, Chambon H, Jolles J, Labbe P . Purification and properties of coproporphyrinogen oxidase from the yeast Saccharomyces cerevisiae . European Journal of Biochemistry . 156 . 3 . 579–87 . May 1986 . 3516695 . 10.1111/j.1432-1033.1986.tb09617.x . free .
10. Martasek P, Camadro JM, Delfau-Larue MH, Dumas JB, Montagne JJ, de Verneuil H, Labbe P, Grandchamp B . 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 . 8159699 . 10.1073/pnas.91.8.3024 . 43507. 1994PNAS...91.3024M . free .
11. Martasek P, Nordmann Y, Grandchamp B . 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 . 8012360 . 10.1093/hmg/3.3.477.
12. Taketani S, Kohno H, Furukawa T, Yoshinaga T, Tokunaga R . Molecular cloning, sequencing and expression of cDNA encoding human coproporphyrinogen oxidase . Biochimica et Biophysica Acta (BBA) - Bioenergetics . 1183 . 3 . 547–9 . Jan 1994 . 8286403 . 10.1016/0005-2728(94)90083-3.
13. Kim DH, Hino R, Adachi Y, Kobori A, Taketani S . 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 . December 2013 . 24078084 . 10.1093/jb/mvt086 .
14. Hasanoglu A, Balwani M, Kasapkara CS, Ezgü FS, Okur I, Tümer L, Cakmak A, Nazarenko I, Yu C, Clavero S, Bishop DF, Desnick RJ . Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R . Journal of Inherited Metabolic Disease . 34 . 1 . 225–31 . February 2011 . 21103937 . 10.1007/s10545-010-9237-9 . 3091031.
15. Lee DS, Flachsová E, Bodnárová M, Demeler B, Martásek P, Raman CS . Structural basis of hereditary coproporphyria . Proceedings of the National Academy of Sciences of the United States of America . 102 . 40 . 14232–7 . October 2005 . 16176984 . 10.1073/pnas.0506557102 . 1224704. 2005PNAS..10214232L . free .
16. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4. 2019NatSR...918577S .
17. 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 . Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria . Human Molecular Genetics . 14 . 20 . 3089–98 . October 2005 . 16159891 . 10.1093/hmg/ddi342 . free .
18. Heyer NJ, Bittner AC, Echeverria D, Woods JS . 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 . February 2006 . 16214298 . 10.1016/j.toxlet.2005.09.005 .