Protoporphyrinogen oxidase
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| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
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| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the PPOX gene.[5][6][7]
Protoporphyrinogen oxidase is responsible for the seventh step in biosynthesis of protoporphyrin IX. This porphyrin is the precursor to hemoglobin, the oxygen carrier in animals, and chlorophyll, the dye in plants. The enzyme catalyzes the dehydrogenation (removal of hydrogen atoms) of protoporphyrinogen IX (the product of the sixth step in the production of heme) to form protoporphyrin IX. One additional enzyme must modify protoporphyrin IX before it becomes heme. Inhibition of this enzyme is a strategy used in certain herbicides.
Gene
The PPOX gene is located on the long (q) arm of
chromosome 1 at position 22, from base pair
157,949,266 to base pair 157,954,082.
Function
This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. This protein is a flavoprotein associated with the outer surface of the inner mitochondrial membrane.[7]
Heme biosynthetic pathway
The following genes encode enzymes that catalyze the various steps in the heme
biosynthetic
pathway:
- ALAD: aminolevulinate, delta-, dehydratase
- ALAS1: aminolevulinate, delta-, synthase 1
- ALAS2: aminolevulinate, delta-, synthase 2 (sideroblastic/hypochromic anemia)
- CPOX: coproporphyrinogen oxidase
- FECH: ferrochelatase (protoporphyria)
- HMBS: hydroxymethylbilane synthase
- PPOX: protoporphyrinogen oxidase
- UROD: uroporphyrinogen decarboxylase
- UROS: uroporphyrinogen III synthase (congenital erythropoietic porphyria)
Clinical significance
South African families with variegate porphyria. Mutations in the PPOX gene reduce the activity of the enzyme made by the gene, allowing byproducts of heme production to build up in the body. This buildup, in combination with nongenetic factors (such as certain drugs, alcohol
and dieting), causes this type of porphyria.
Inhibitors as herbicides
Inhibition of protoporphyrinogen oxidase is a mechanism of action for several commercial herbicides including the nitrophenyl ethers acifluorfen and fomesafen and the pyrimidinediones butafenacil and saflufenacil. The visible symptoms of treatment are chlorosis and desiccation. The damage is caused by an accumulation of protoporphyrin IX in the plant cells by inhibiting protox within the tetrapyrrole biosynthesis pathway.[8] This is a potent photosensitizer which activates oxygen, leading to lipid peroxidation. Both light and oxygen are required for this process to kill the plant.[9][10][11]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000143224 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062729 – Ensembl, May 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.
- PMID 8575762.
- S2CID 40509390.
- ^ a b "Entrez Gene: PPOX protoporphyrinogen oxidase".
- PMID 31069268.
- ISBN 978-3-642-63674-5.
- ISBN 978-3-642-63674-5.
- ISBN 9780123743671.
Further reading
- Elder GH (1998). "Genetic defects in the porphyrias: types and significance". Clinics in Dermatology. 16 (2): 225–33. 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. PMID 12922165.
- Morgan RR, Errington R, Elder GH (January 2004). "Identification of sequences required for the import of human protoporphyrinogen oxidase to mitochondria". The Biochemical Journal. 377 (Pt 2): 281–7. PMID 14535846.
- Sassa S, Kappas A (February 2000). "Molecular aspects of the inherited porphyrias". Journal of Internal Medicine. 247 (2): 169–78. 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. PMID 7713909.
- Dailey TA, Meissner P, Dailey HA (January 1994). "Expression of a cloned protoporphyrinogen oxidase". The Journal of Biological Chemistry. 269 (2): 813–5. PMID 8288631.
- Dailey TA, Dailey HA, Meissner P, Prasad AR (December 1995). "Cloning, sequence, and expression of mouse protoporphyrinogen oxidase". Archives of Biochemistry and Biophysics. 324 (2): 379–84. PMID 8554330.
- Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG, et al. (May 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. S2CID 11911664.
- Dailey TA, Dailey HA (January 1996). "Human protoporphyrinogen oxidase: expression, purification, and characterization of the cloned enzyme". Protein Science. 5 (1): 98–105. PMID 8771201.
- Puy H, Robréau AM, Rosipal R, Nordmann Y, Deybach JC (September 1996). "Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene". Biochemical and Biophysical Research Communications. 226 (1): 226–30. PMID 8806618.
- Deybach JC, Puy H, Robréau AM, Lamoril J, Da Silva V, Grandchamp B, Nordmann Y (March 1996). "Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria". Human Molecular Genetics. 5 (3): 407–10. PMID 8852667.
- Lam H, Dragan L, Tsou HC, Merk H, Peacocke M, Goerz G, et al. (January 1997). "Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene". Human Genetics. 99 (1): 126–9. S2CID 32134586.
- Dailey HA, Dailey TA (February 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. S2CID 32988570.
- Roberts AG, Puy H, Dailey TA, Morgan RR, Whatley SD, Dailey HA, et al. (November 1998). "Molecular characterization of homozygous variegate porphyria". Human Molecular Genetics. 7 (12): 1921–5. PMID 9811936.
- Whatley SD, Puy H, Morgan RR, Robreau AM, Roberts AG, Nordmann Y, et al. (October 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. PMID 10486317.
- Suzuki Y, Ishihara D, Sasaki M, Nakagawa H, Hata H, Tsunoda T, et al. (March 2000). "Statistical analysis of the 5' untranslated region of human mRNA using "Oligo-Capped" cDNA libraries". Genomics. 64 (3): 286–97. 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. 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. 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. S2CID 41419729.
- Corrigall AV, Hift RJ, Davids LM, Hancock V, Meissner D, Kirsch RE, Meissner PN (May 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. 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.
External links
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Protoporphyrinogen oxidase
