CPOX
| Koprogen-oksidaza | |
|---|---|
 Koproporfirinogen III-oksidaza iz Leishmania major | |
| Identifikatori | |
| Simbol | Coprogen_oxidas |
Mitohondrijska koproporfirinogen-III oksidaza (skraćeno kao CPOX) je enzim koji je kod ljudi kodiran gen om "CPOX" sa hromosoma 13.[4][5][6] Genetički defekt u enzimu kod životinja dovodi do smanjene proizvodnje hema. Medicinsko stanje povezano s ovim defektom enzima naziva se nasljedna koproporfirija.[7][8]
CPOX, šesti enzim biosintetskog puta hema, pretvara koproporfirinogen III u protoporfirinogen IX preko dva uzastopna koraka oksidativne dekarboksilacije.[9] Aktivnost enzima CPOX, koji se nalazi u mitohondrijskoj membrani, mjeri se u limfocitima.[10]
Funkcija
CPOX je enzim uključen u šesti korak [metabolizam|[metabolizma]] porfirin a koji katalizira oksidativnu dekarboksilaciju koproporfirinogena III u protoporfirinogen IX u putevima biosinteze hema i hlorofila.[5][11] Protein je homodimer koji sadrži dva interno vezana gvožđeva atoma po molekuli prirodnog proteina.[12] Enzim je aktivan u prisustvu molekulnog kisika koji deluje kao akceptor elektrona. Enzim je široko rasprostranjen jer je pronađen u različitim eukariotskim i prokariotskim izvorima.
Struktura
Gen
Ljudski CPOX je mitohondrijski enzim kodiran CPOX genom od 14 kb, koji sadrži sedam egzona smještenih na hromosomu 3, sekvenca q11.2.[6]
Protein
CPOX se eksprimira kao 40 kDa prekursor i sadrži amino terminalni signal ciljanja mitohondrija.[13] Nakon proteolitske obrade, protein je prisutan kao zreli homodimerni oblik s molekulskom masom od 37 kDa.[14]
Klinički značaj
Nasljedna koproporfirija (HCP) i harderoporfirija su dva fenotipski odvojena poremećaja koji se tiču parcijalnog nedostatka CPOX-a. U dominira HCP neurovisceralna simptomatologija. Dodatno, može biti povezano s bolovima u stomaku i/ili fotosenzitivnošću kože. U biohemijskim testovima zabilježena je hiperekskrecija koproporfirina III u urinu i fecesu.[15] HCP je autosomno dominantni nasljedni poremećaj, dok je harderoporfirija rijetka eritropoetska varijanta oblika HCP-a i nasljeđuje se autosomno recesivno. Klinički, karakterizira ga neonatusna hemolitska anemija. Kod pacijenata sa harderoporfirom, onekad je opisano i prisustvo kožnih lezija sa izraženim fekalnim izlučivanjem harderoporfirina.[16]
Do danas je opisano preko 50 CPOX mutacija koje uzrokuju HCP.[17] Većina ovih mutacija rezultira supstitucijom aminokiselinskih ostataka unutar strukturnog okvira CPOX-a.[18] U pogledu molekulske osnove HCP-a i harderoporfirije, mutacije CPOX-a kod pacijenata sa harderoporfirijom su demonstrirane u području egzona 6, gdje su također identificirane mutacije kod pacijenata sa HCP-om.[19] Kako bi samo pacijenti sa mutacijom u ovoj regiji (K404E) mogli razviti harderoporfiriju, ova mutacija je dovela do smanjenja drugog koraka reakcije dekarboksilacije tokom konverzije koproporfirinogena u protoporfirinogenu IX, što implicira da se aktivno mjesto enzima uključenog u drugi korak dekarboksilacije nalazi u egzonu 6.[17]
Interakcije
Pokazalo se da CPOX ima interakcije sa atipskim keto-izokoproporfirinom (KICP) kod ljudi sa izloženošću živi (Hg).[20]
Reference
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022742 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Lamoril J, Martasek P, Deybach JC, Da Silva V, Grandchamp B, Nordmann Y (februar 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. PMID 7757079.
- ^ a b Kohno H, Furukawa T, Yoshinaga T, Tokunaga R, Taketani S (oktobar 1993). "Coproporphyrinogen oxidase. Purification, molecular cloning, and induction of mRNA during erythroid differentiation". The Journal of Biological Chemistry. 268 (28): 21359–63. doi:10.1016/S0021-9258(19)36931-5. PMID 8407975.
- ^ a b "Entrez Gene: CPOX coproporphyrinogen oxidase".
- ^ "Hereditary coproporphyria". Genetic and Rare Diseases Information Center. National Institutes of Health. Arhivirano s originala, 7. 8. 2012. Pristupljeno 8. 8. 2011.
- ^ "CPOX". Genetics Home Reference. Pristupljeno 8. 8. 2011.
- ^ Sano S, Granick S (april 1961). "Mitochondrial coproporphyrinogen oxidase and protoporphyrin formation". The Journal of Biological Chemistry. 236 (4): 1173–80. doi:10.1016/S0021-9258(18)64262-0. PMID 13746277.
- ^ Guo R, Lim CK, Peters TJ (oktobar 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. PMID 3233772.
- ^ Madsen O, Sandal L, Sandal NN, Marcker KA (oktobar 1993). "A soybean coproporphyrinogen oxidase gene is highly expressed in root nodules". Plant Molecular Biology. 23 (1): 35–43. doi:10.1007/BF00021417. PMID 8219054. S2CID 23011457.
- ^ Camadro JM, Chambon H, Jolles J, Labbe P (maj 1986). "Purification and properties of coproporphyrinogen oxidase from the yeast Saccharomyces cerevisiae". European Journal of Biochemistry. 156 (3): 579–87. doi:10.1111/j.1432-1033.1986.tb09617.x. PMID 3516695.
- ^ 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. Bibcode:1994PNAS...91.3024M. doi:10.1073/pnas.91.8.3024. PMC 43507. PMID 8159699.
- ^ Martasek P, Nordmann Y, Grandchamp B (mart 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. PMID 8012360.
- ^ 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 (BBA) - Bioenergetics. 1183 (3): 547–9. doi:10.1016/0005-2728(94)90083-3. PMID 8286403.
- ^ Kim DH, Hino R, Adachi Y, Kobori A, Taketani S (decembar 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. PMID 24078084.
- ^ 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 (februar 2011). "Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R". Journal of Inherited Metabolic Disease. 34 (1): 225–31. doi:10.1007/s10545-010-9237-9. PMC 3091031. PMID 21103937.
- ^ Lee DS, Flachsová E, Bodnárová M, Demeler B, Martásek P, Raman CS (oktobar 2005). "Structural basis of hereditary coproporphyria". Proceedings of the National Academy of Sciences of the United States of America. 102 (40): 14232–7. Bibcode:2005PNAS..10214232L. doi:10.1073/pnas.0506557102. PMC 1224704. PMID 16176984.
- ^ 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 (oktobar 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. PMID 16159891.
- ^ Heyer NJ, Bittner AC, Echeverria D, Woods JS (februar 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. PMID 16214298.
Dopunska literatura
- Fujita H, Kondo M, Taketani S, Nomura N, Furuyama K, Akagi R, Nagai T, Terajima M, Galbraith RA, Sassa S (oktobar 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. PMID 7849704.
- Cacheux V, Martasek P, Fougerousse F, Delfau MH, Druart L, Tachdjian G, Grandchamp B (novembar 1994). "Localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12". Human Genetics. 94 (5): 557–9. doi:10.1007/BF00211026. PMID 7959694. S2CID 11997203.
- Delfau-Larue MH, Martasek P, Grandchamp B (august 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. PMID 7987309.
- Martasek P, Nordmann Y, Grandchamp B (mart 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. PMID 8012360.
- 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. PMID 8125298.
- 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. Bibcode:1994PNAS...91.3024M. doi:10.1073/pnas.91.8.3024. PMC 43507. PMID 8159699.
- Lamoril J, Deybach JC, Puy H, Grandchamp B, Nordmann Y (1997). "Three novel mutations in the coproporphyrinogen oxidase gene". Human Mutation. 9 (1): 78–80. doi:10.1002/(SICI)1098-1004(1997)9:1<78::AID-HUMU17>3.0.CO;2-M. PMID 8990017.
- Daimon M, Gojyou E, Sugawara M, Yamatani K, Tominaga M, Sasaki H (februar 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. PMID 9048920. S2CID 1813242.
- Schreiber WE, Zhang X, Senz J, Jamani A (1997). "Hereditary coproporphyria: exon screening by heteroduplex analysis detects three novel mutations in the coproporphyrinogen oxidase gene". Human Mutation. 10 (3): 196–200. doi:10.1002/(SICI)1098-1004(1997)10:3<196::AID-HUMU3>3.0.CO;2-H. PMID 9298818.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (oktobar 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.
- Lamoril J, Puy H, Gouya L, Rosipal R, Da Silva V, Grandchamp B, Foint T, Bader-Meunier B, Dommergues JP, Deybach JC, Nordmann Y (februar 1998). "Neonatal hemolytic anemia due to inherited harderoporphyria: clinical characteristics and molecular basis". Blood. 91 (4): 1453–7. doi:10.1182/blood.V91.4.1453. PMID 9454777.
- Susa S, Daimon M, Kondo H, Kondo M, Yamatani K, Sasaki H (novembar 1998). "Identification of a novel mutation of the CPO gene in a Japanese hereditary coproporphyria family". American Journal of Medical Genetics. 80 (3): 204–6. doi:10.1002/(SICI)1096-8628(19981116)80:3<204::AID-AJMG4>3.0.CO;2-G. PMID 9843038.
- Rosipal R, Lamoril J, Puy H, Da Silva V, Gouya L, De Rooij FW, Te Velde K, Nordmann Y, Martàsek P, Deybach JC (1999). "Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update". Human Mutation. 13 (1): 44–53. doi:10.1002/(SICI)1098-1004(1999)13:1<44::AID-HUMU5>3.0.CO;2-Q. PMID 9888388.
- Taketani S, Furukawa T, Furuyama K (mart 2001). "Expression of coproporphyrinogen oxidase and synthesis of hemoglobin in human erythroleukemia K562 cells". European Journal of Biochemistry. 268 (6): 1705–11. doi:10.1046/j.1432-1327.2001.02045.x. PMID 11248690.
- Lamoril J, Puy H, Whatley SD, Martin C, Woolf JR, Da Silva V, Deybach JC, Elder GH (maj 2001). "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. doi:10.1086/320118. PMC 1226094. PMID 11309681.
- Elkon H, Don J, Melamed E, Ziv I, Shirvan A, Offen D (juni 2002). "Mutant and wild-type alpha-synuclein interact with mitochondrial cytochrome C oxidase". Journal of Molecular Neuroscience. 18 (3): 229–38. doi:10.1385/JMN:18:3:229. PMID 12059041. S2CID 42265181.
- 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. PMID 12181641.
Vanjski linkovi
- Coproporphyrinogen III Oxidases na US National Library of Medicine Medical Subject Headings (MeSH)
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