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Protoporfirinogen-oksidaza
Protoporfirinogen-oksidaza
	Sinteza hema: neke reakcije dešavaju se u citoplazmi, a neke u mitohondrijama (žuto)
Identifikatori
Simbol	PPOX
CAS broj	53986-32-6

PPOX
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	3NKS, 4IVM, 4IVO
Identifikatori
Aliasi	PPOX
Vanjski ID-jevi	OMIM: 600923 MGI: 104968 HomoloGene: 262 GeneCards: PPOX
Lokacija gena (čovjek)
Hrom.	Hromosom 1 (čovjek)
Kraj	161,178,013 bp
Lokacija gena (miš)
Hrom.	Hromosom 1 (miš)
Kraj	171,108,760 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• flavin adenine dinucleotide binding; • oxidoreductase activity; • oxygen-dependent protoporphyrinogen oxidase activity;
Ćelijska komponenta	• mitochondrial inner membrane; • mitochondrial intermembrane space; • intrinsic component of mitochondrial inner membrane; • membrana; • mitohondrija; • integral component of mitochondrial inner membrane; • mitochondrial membranes;
Biološki proces	• heme biosynthetic process; • protoporphyrinogen IX metabolic process; • protoporphyrinogen IX biosynthetic process; • porphyrin-containing compound biosynthetic process;
	Izvori:Amigo / QuickGO
Ortolozi
	5498
	19044
	ENSG00000143224
	ENSMUSG00000062729
	P50336
	P51175
NM_000309; NM_001122764; NM_001350128; NM_001350129; NM_001350130;
	NM_001350131; NM_001365398; NM_001365399; NM_001365400; NM_001365401
	NM_008911
NP_000300; NP_001116236; NP_001337057; NP_001337058; NP_001337059;
	NP_001337060
	NP_032937
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Protoporfirinogen-oksidaza ili protoks jest enzim koji je kod ljudi kodiran genom PPOX sa hromosoma 1.^[5]^[6]^[7]

Protoporfirinogen-oksidaza odgovorna je za sedmi korak u biosintezi protoporfirina IX. Ovaj porfirin je prekursor hemoglobina, nositelja kisika kod životinja i hlorofila, u biljkama. Enzim katalizira dehidrogenaciju (uklanjanje vodikovih atoma) protoporfirinogena IX (proizvod šestog koraka u proizvodnji hema), da bi se formirao protoporfirin IX. Jedan dodatni enzim mora modificirati protoporfirin IX, prije nego što postane hem. Inhibicija ovog enzima je strategija koja se koristi u određenim herbicidima.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 477 aminokiselina, a molekulska težina 50.765 Da.^[8]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MGRTVVVLGG	GISGLAASYH	LSRAPCPPKV	VLVESSERLG	GWIRSVRGPN
GAIFELGPRG	IRPAGALGAR	TLLLVSELGL	DSEVLPVRGD	HPAAQNRFLY
VGGALHALPT	GLRGLLRPSP	PFSKPLFWAG	LRELTKPRGK	EPDETVHSFA
QRRLGPEVAS	LAMDSLCRGV	FAGNSRELSI	RSCFPSLFQA	EQTHRSILLG
LLLGAGRTPQ	PDSALIRQAL	AERWSQWSLR	GGLEMLPQAL	ETHLTSRGVS
VLRGQPVCGL	SLQAEGRWKV	SLRDSSLEAD	HVISAIPASV	LSELLPAEAA
PLARALSAIT	AVSVAVVNLQ	YQGAHLPVQG	FGHLVPSSED	PGVLGIVYDS
VAFPEQDGSP	PGLRVTVMLG	GSWLQTLEAS	GCVLSQELFQ	QRAQEAAATQ
LGLKEMPSHC	LVHLHKNCIP	QYTLGHWQKL	ESARQFLTAH	RLPLTLAGAS
YEGVAVNDCI	ESGRQAAVSV	LGTEPNS

Gen

Gen PPOX nalazi se na dugom (q) kraku hromosoma 1, na poziciji 22, od bazmog pata 157,949.266 do baznog para 157,954.082.

Funkcija

Ovaj gen kodira pretposljednji enzim biosinteze hema, koji katalizuje 6-elektronsku oksidaciju protoporfirinogena IX da bi se formirao protoporfirin IX. Ovaj protein je flavoprotein, povezan sa vanjskom površinom unutrašnje mitohondrijalne membrane.^[7]

Biosintetski put hema

Sljedeći geni kodiraju enzime koji kataliziraju različite korake na biosintetskom putu hema:

ALAD: aminolevulinat, delta-, dehidrataza
ALAS1: aminolevulinat, delta-, sintaza 1
ALAS2: aminolevulinat, delta-, sintaza 2 (sideroblastna/hipohromna anemija)
CPOX: koproporfirinogen oksidaza
FECH: ferokelataza (protoporfirija)
HMBS: hidroksimetilbilan sintaza
PPOX: protoporfirinogen oksidaza
UROD: uroporfirinogen dekarboksilaza
UROS: uroporfirinogen III sintaza (kongenitalna eritropoetska porfirija)

Klinički značaj

Varijegatna porfirija ili šarolika porfirija, uzrokovana je mutacijama u genu PPOX. U PPOX genu identificirano je više od 100 mutacija koje mogu uzrokovati ovu porfiriju. Jedna od mutacija, zamjena aminokiseline triptofana za arginin na poziciji 59 (takođe pisano kao Arg59Trp ili R59W), pronađena je u oko 95 posto južnoafričkih porodica sa šarolikom porfirijom. Mutacije u PPOX genu smanjuju aktivnost enzima kojeg proizvodi gen, omogućavajući nusproizvodima da se nagomilaju u tijelu. Ovo nakupljanje, u kombinaciji s negenetskim faktorima (kao što su određeni lijekovi, alkohol i dijeta), uzrokuje ovaj tip porfirije.

Inhibitori kao herbicidi

Inhibicija protoporfirinogen-oksidaze je mehanizam djelovanja nekoliko komercijalnih herbicida uključujući nitrofenilne etere acifluorfen, fomesafen, pirimidindione butafenacil i saflufenacil. Vidljivi simptomi liječenja su hloroza i isušivanje. Oštećenje je uzrokovano akumulacijom protoporfirina IX u biljnim ćelijama, inhibicijom protoksa unutar puta biosinteze tetrapirola.^[9] Ovo je snažan fotosenzibilizator koji aktivira kisik, što dovodi do lipidne peroksidacije. I svjetlost i kisik su potrebni da bi ovaj proces ubio biljku.^[10]^[11]^[12]

Također pogledajte

Porfirin

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000143224 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000062729 - 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.
^ Taketani S, Inazawa J, Abe T, Furukawa T, Kohno H, Tokunaga R, et al. (oktobar 1995). "The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1". Genomics. 29 (3): 698–703. doi:10.1006/geno.1995.9949. PMID 8575762.
^ Frank J, McGrath JA, Poh-Fitzpatrick MB, Hawk JL, Christiano AM (juli 1999). "Mutations in the translation initiation codon of the protoporphyrinogen oxidase gene underlie variegate porphyria". Clinical and Experimental Dermatology. 24 (4): 296–301. doi:10.1046/j.1365-2230.1999.00484.x. PMID 10457135. S2CID 40509390.
^ ^a ^b "Entrez Gene: PPOX protoporphyrinogen oxidase".
^ "UniProt, P50336" (jezik: engleski). Pristupljeno 16. 12. 2021.
^ Brzezowski P, Ksas B, Havaux M, Grimm B, Chazaux M, Peltier G, et al. (3. 5. 2019). "The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii". Communications Biology. 2 (1): 159. doi:10.1038/s42003-019-0395-5. PMC 6499784. PMID 31069268.
^ Dayan FE, Reddy KN, Duke SO (1999). "Structure-Activity Relationships of Diphenyl Ethers and Other Oxygen-Bridged Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. str. 141–161. doi:10.1007/978-3-642-58633-0_5. ISBN 978-3-642-63674-5.
^ Nagano E (1999). "Herbicidal Efficacy of Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. str. 293–302. doi:10.1007/978-3-642-58633-0_11. ISBN 978-3-642-63674-5.
^ Dayan FE, Duke SO (2010). "Protoporphyrinogen Oxidase-Inhibiting Herbicides". Hayes' Handbook of Pesticide Toxicology. str. 1733–1751. doi:10.1016/B978-0-12-374367-1.00081-1. ISBN 9780123743671.

Dopunska literatura

Elder GH (1998). "Genetic defects in the porphyrias: types and significance". Clinics in Dermatology. 16 (2): 225–33. doi:10.1016/S0738-081X(97)00202-2. PMID 9554235.
Maneli MH, Corrigall AV, Klump HH, Davids LM, Kirsch RE, Meissner PN (august 2003). "Kinetic and physical characterisation of recombinant wild-type and mutant human protoporphyrinogen oxidases". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1650 (1–2): 10–21. doi:10.1016/s1570-9639(03)00186-9. PMID 12922165.
Morgan RR, Errington R, Elder GH (januar 2004). "Identification of sequences required for the import of human protoporphyrinogen oxidase to mitochondria". The Biochemical Journal. 377 (Pt 2): 281–7. doi:10.1042/BJ20030978. PMC 1223874. PMID 14535846.
Sassa S, Kappas A (februar 2000). "Molecular aspects of the inherited porphyrias". Journal of Internal Medicine. 247 (2): 169–78. doi:10.1046/j.1365-2796.2000.00618.x. PMID 10692079. S2CID 36820694.
Nishimura K, Taketani S, Inokuchi H (april 1995). "Cloning of a human cDNA for protoporphyrinogen oxidase by complementation in vivo of a hemG mutant of Escherichia coli". The Journal of Biological Chemistry. 270 (14): 8076–80. doi:10.1074/jbc.270.14.8076. PMID 7713909.
Dailey TA, Meissner P, Dailey HA (januar 1994). "Expression of a cloned protoporphyrinogen oxidase". The Journal of Biological Chemistry. 269 (2): 813–5. doi:10.1016/S0021-9258(17)42182-X. PMID 8288631.
Dailey TA, Dailey HA, Meissner P, Prasad AR (decembar 1995). "Cloning, sequence, and expression of mouse protoporphyrinogen oxidase". Archives of Biochemistry and Biophysics. 324 (2): 379–84. doi:10.1006/abbi.1995.0051. PMID 8554330.
Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG, et al. (maj 1996). "A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria". Nature Genetics. 13 (1): 95–7. doi:10.1038/ng0596-95. PMID 8673113. S2CID 11911664.
Dailey TA, Dailey HA (januar 1996). "Human protoporphyrinogen oxidase: expression, purification, and characterization of the cloned enzyme". Protein Science. 5 (1): 98–105. doi:10.1002/pro.5560050112. PMC 2143237. PMID 8771201.
Puy H, Robréau AM, Rosipal R, Nordmann Y, Deybach JC (septembar 1996). "Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene". Biochemical and Biophysical Research Communications. 226 (1): 226–30. doi:10.1006/bbrc.1996.1337. PMID 8806618.
Deybach JC, Puy H, Robréau AM, Lamoril J, Da Silva V, Grandchamp B, Nordmann Y (mart 1996). "Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria". Human Molecular Genetics. 5 (3): 407–10. doi:10.1093/hmg/5.3.407. PMID 8852667.
Lam H, Dragan L, Tsou HC, Merk H, Peacocke M, Goerz G, et al. (januar 1997). "Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene". Human Genetics. 99 (1): 126–9. doi:10.1007/s004390050325. PMID 9003509. S2CID 32134586.
Dailey HA, Dailey TA (februar 1997). "Characteristics of human protoporphyrinogen oxidase in controls and variegate porphyrias". Cellular and Molecular Biology. 43 (1): 67–73. PMID 9074790.
Frank J, Poh-Fitzpatrick MB, King LE, Christiano AM (august 1998). "The genetic basis of "Scarsdale Gourmet Diet" variegate porphyria: a missense mutation in the protoporphyrinogen oxidase gene". Archives of Dermatological Research. 290 (8): 441–5. doi:10.1007/s004030050333. PMID 9763307. S2CID 32988570.
Roberts AG, Puy H, Dailey TA, Morgan RR, Whatley SD, Dailey HA, et al. (novembar 1998). "Molecular characterization of homozygous variegate porphyria". Human Molecular Genetics. 7 (12): 1921–5. doi:10.1093/hmg/7.12.1921. PMID 9811936.
Whatley SD, Puy H, Morgan RR, Robreau AM, Roberts AG, Nordmann Y, et al. (oktobar 1999). "Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation". American Journal of Human Genetics. 65 (4): 984–94. doi:10.1086/302586. PMC 1288269. PMID 10486317.
Suzuki Y, Ishihara D, Sasaki M, Nakagawa H, Hata H, Tsunoda T, et al. (mart 2000). "Statistical analysis of the 5' untranslated region of human mRNA using "Oligo-Capped" cDNA libraries". Genomics. 64 (3): 286–97. doi:10.1006/geno.2000.6076. PMID 10756096.
Corrigall AV, Hift RJ, Davids LM, Hancock V, Meissner D, Kirsch RE, Meissner PN (april 2000). "Homozygous variegate porphyria in South Africa: genotypic analysis in two cases". Molecular Genetics and Metabolism. 69 (4): 323–30. doi:10.1006/mgme.2000.2975. PMID 10870850.
Kauppinen R, Timonen K, von und zu Fraunberg M, Laitinen E, Ahola H, Tenhunen R, et al. (april 2001). "Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect". The Journal of Investigative Dermatology. 116 (4): 610–3. doi:10.1046/j.1523-1747.2001.01293.x. PMID 11286631.
Palmer RA, Elder GH, Barrett DF, Keohane SG (april 2001). "Homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene". The British Journal of Dermatology. 144 (4): 866–9. doi:10.1046/j.1365-2133.2001.04147.x. PMID 11298551. S2CID 41419729.
Corrigall AV, Hift RJ, Davids LM, Hancock V, Meissner D, Kirsch RE, Meissner PN (maj 2001). "Identification of the first variegate porphyria mutation in an indigenous black South African and further evidence for heterogeneity in variegate porphyria". Molecular Genetics and Metabolism. 73 (1): 91–6. doi:10.1006/mgme.2001.3163. PMID 11350188.
Donnelly JG, Detombe S, Hindmarsh JT (2002). "Single-strand conformational polymorphism and denaturing gradient gel electrophoresis in screening for variegate porphyria: identification of two new mutations". Annals of Clinical and Laboratory Science. 32 (2): 107–13. PMID 12017191.

Vansjski linkovi

PDBe-KB provides an overview of all the structure information available in the PDB for Human Protoporphyrinogen oxidase

Portal Biologija

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000143224 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000062729 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid8575762-5] Taketani S, Inazawa J, Abe T, Furukawa T, Kohno H, Tokunaga R, et al. (oktobar 1995). "The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1". Genomics. 29 (3): 698–703. doi:10.1006/geno.1995.9949. PMID 8575762.

[pmid10457135-6] Frank J, McGrath JA, Poh-Fitzpatrick MB, Hawk JL, Christiano AM (juli 1999). "Mutations in the translation initiation codon of the protoporphyrinogen oxidase gene underlie variegate porphyria". Clinical and Experimental Dermatology. 24 (4): 296–301. doi:10.1046/j.1365-2230.1999.00484.x. PMID 10457135. S2CID 40509390.

[entrez-7] "Entrez Gene: PPOX protoporphyrinogen oxidase".

[UniProt-8] "UniProt, P50336" (jezik: engleski). Pristupljeno 16. 12. 2021.

[9] Brzezowski P, Ksas B, Havaux M, Grimm B, Chazaux M, Peltier G, et al. (3. 5. 2019). "The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii". Communications Biology. 2 (1): 159. doi:10.1038/s42003-019-0395-5. PMC 6499784. PMID 31069268.

[10] Dayan FE, Reddy KN, Duke SO (1999). "Structure-Activity Relationships of Diphenyl Ethers and Other Oxygen-Bridged Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. str. 141–161. doi:10.1007/978-3-642-58633-0_5. ISBN 978-3-642-63674-5.

[11] Nagano E (1999). "Herbicidal Efficacy of Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. str. 293–302. doi:10.1007/978-3-642-58633-0_11. ISBN 978-3-642-63674-5.

[12] Dayan FE, Duke SO (2010). "Protoporphyrinogen Oxidase-Inhibiting Herbicides". Hayes' Handbook of Pesticide Toxicology. str. 1733–1751. doi:10.1016/B978-0-12-374367-1.00081-1. ISBN 9780123743671.

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