Biology:Protoporphyrinogen oxidase
 Generic protein structure example |
| protoporphyrinogen oxidase | |||||||||
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 Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow) | |||||||||
| Identifiers | |||||||||
| EC number | 1.3.3.4 | ||||||||
| CAS number | 53986-32-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the PPOX gene.[1][2][3]
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.[3]
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
Variegate porphyria is caused by mutations in the PPOX gene. More than 100 mutations that can cause variegate porphyria have been identified in the PPOX gene. One mutation, a substitution of the amino acid tryptophan for arginine at position 59 (also written as Arg59Trp or R59W), is found in about 95 percent of 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.[4] 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.[5][6][7]
See also
References
- ↑ "The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1". Genomics 29 (3): 698–703. October 1995. doi:10.1006/geno.1995.9949. PMID 8575762.
- ↑ "Mutations in the translation initiation codon of the protoporphyrinogen oxidase gene underlie variegate porphyria". Clinical and Experimental Dermatology 24 (4): 296–301. July 1999. doi:10.1046/j.1365-2230.1999.00484.x. PMID 10457135.
- ↑ 3.0 3.1 "Entrez Gene: PPOX protoporphyrinogen oxidase". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5498.
- ↑ "The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii". Communications Biology 2 (1): 159. 2019-05-03. doi:10.1038/s42003-019-0395-5. PMID 31069268.
- ↑ "Structure-Activity Relationships of Diphenyl Ethers and Other Oxygen-Bridged Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. 1999. pp. 141–161. doi:10.1007/978-3-642-58633-0_5. ISBN 978-3-642-63674-5.
- ↑ "Herbicidal Efficacy of Protoporphyrinogen Oxidase Inhibitors". Peroxidizing Herbicides. 1999. pp. 293–302. doi:10.1007/978-3-642-58633-0_11. ISBN 978-3-642-63674-5.
- ↑ "Protoporphyrinogen Oxidase-Inhibiting Herbicides". Hayes' Handbook of Pesticide Toxicology. 2010. pp. 1733–1751. doi:10.1016/B978-0-12-374367-1.00081-1. ISBN 9780123743671.
Further reading
- "Genetic defects in the porphyrias: types and significance". Clinics in Dermatology 16 (2): 225–33. 1998. doi:10.1016/S0738-081X(97)00202-2. PMID 9554235.
- "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. August 2003. doi:10.1016/s1570-9639(03)00186-9. PMID 12922165.
- "Identification of sequences required for the import of human protoporphyrinogen oxidase to mitochondria". The Biochemical Journal 377 (Pt 2): 281–7. January 2004. doi:10.1042/BJ20030978. PMID 14535846.
- "Molecular aspects of the inherited porphyrias". Journal of Internal Medicine 247 (2): 169–78. February 2000. doi:10.1046/j.1365-2796.2000.00618.x. PMID 10692079.
- "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. April 1995. doi:10.1074/jbc.270.14.8076. PMID 7713909.
- "Expression of a cloned protoporphyrinogen oxidase". The Journal of Biological Chemistry 269 (2): 813–5. January 1994. doi:10.1016/S0021-9258(17)42182-X. PMID 8288631.
- "Cloning, sequence, and expression of mouse protoporphyrinogen oxidase". Archives of Biochemistry and Biophysics 324 (2): 379–84. December 1995. doi:10.1006/abbi.1995.0051. PMID 8554330.
- "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. May 1996. doi:10.1038/ng0596-95. PMID 8673113.
- "Human protoporphyrinogen oxidase: expression, purification, and characterization of the cloned enzyme". Protein Science 5 (1): 98–105. January 1996. doi:10.1002/pro.5560050112. PMID 8771201.
- "Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene". Biochemical and Biophysical Research Communications 226 (1): 226–30. September 1996. doi:10.1006/bbrc.1996.1337. PMID 8806618.
- "Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria". Human Molecular Genetics 5 (3): 407–10. March 1996. doi:10.1093/hmg/5.3.407. PMID 8852667.
- "Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene". Human Genetics 99 (1): 126–9. January 1997. doi:10.1007/s004390050325. PMID 9003509.
- "Characteristics of human protoporphyrinogen oxidase in controls and variegate porphyrias". Cellular and Molecular Biology 43 (1): 67–73. February 1997. PMID 9074790.
- "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. August 1998. doi:10.1007/s004030050333. PMID 9763307.
- "Molecular characterization of homozygous variegate porphyria". Human Molecular Genetics 7 (12): 1921–5. November 1998. doi:10.1093/hmg/7.12.1921. PMID 9811936.
- "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. October 1999. doi:10.1086/302586. PMID 10486317.
- "Statistical analysis of the 5' untranslated region of human mRNA using "Oligo-Capped" cDNA libraries". Genomics 64 (3): 286–97. March 2000. doi:10.1006/geno.2000.6076. PMID 10756096.
- "Homozygous variegate porphyria in South Africa: genotypic analysis in two cases". Molecular Genetics and Metabolism 69 (4): 323–30. April 2000. doi:10.1006/mgme.2000.2975. PMID 10870850.
- "Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect". The Journal of Investigative Dermatology 116 (4): 610–3. April 2001. doi:10.1046/j.1523-1747.2001.01293.x. PMID 11286631.
- "Homozygous variegate porphyria: a compound heterozygote with novel mutations in the protoporphyrinogen oxidase gene". The British Journal of Dermatology 144 (4): 866–9. April 2001. doi:10.1046/j.1365-2133.2001.04147.x. PMID 11298551.
- "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. May 2001. doi:10.1006/mgme.2001.3163. PMID 11350188.
- "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. 2002. PMID 12017191.
External links
- PDBe-KB provides an overview of all the structure information available in the PDB for Human Protoporphyrinogen oxidase
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