Protoporphyrinogen oxidase explained

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.

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

• Porphyrin

Further reading

• Elder GH . Genetic defects in the porphyrias: types and significance . Clinics in Dermatology . 16 . 2 . 225–33 . 1998 . 9554235 . 10.1016/S0738-081X(97)00202-2 .
• Maneli MH, Corrigall AV, Klump HH, Davids LM, Kirsch RE, Meissner PN . 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 . 12922165 . 10.1016/s1570-9639(03)00186-9 .
• Morgan RR, Errington R, Elder GH . Identification of sequences required for the import of human protoporphyrinogen oxidase to mitochondria . The Biochemical Journal . 377 . Pt 2 . 281–7 . January 2004 . 14535846 . 1223874 . 10.1042/BJ20030978 .
• Sassa S, Kappas A . Molecular aspects of the inherited porphyrias . Journal of Internal Medicine . 247 . 2 . 169–78 . February 2000 . 10692079 . 10.1046/j.1365-2796.2000.00618.x . 36820694 . free .
• Nishimura K, Taketani S, Inokuchi H . 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 . 7713909 . 10.1074/jbc.270.14.8076 . free .
• Dailey TA, Meissner P, Dailey HA . Expression of a cloned protoporphyrinogen oxidase . The Journal of Biological Chemistry . 269 . 2 . 813–5 . January 1994 . 10.1016/S0021-9258(17)42182-X . 8288631 . free .
• Dailey TA, Dailey HA, Meissner P, Prasad AR . Cloning, sequence, and expression of mouse protoporphyrinogen oxidase . Archives of Biochemistry and Biophysics . 324 . 2 . 379–84 . December 1995 . 8554330 . 10.1006/abbi.1995.0051 .
• Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG, Meissner DM, Kirsch RE, Dailey HA . 6 . 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 . 8673113 . 10.1038/ng0596-95 . 11911664 .
• Dailey TA, Dailey HA . Human protoporphyrinogen oxidase: expression, purification, and characterization of the cloned enzyme . Protein Science . 5 . 1 . 98–105 . January 1996 . 8771201 . 2143237 . 10.1002/pro.5560050112 .
• Puy H, Robréau AM, Rosipal R, Nordmann Y, Deybach JC . Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene . Biochemical and Biophysical Research Communications . 226 . 1 . 226–30 . September 1996 . 8806618 . 10.1006/bbrc.1996.1337 .
• Deybach JC, Puy H, Robréau AM, Lamoril J, Da Silva V, Grandchamp B, Nordmann Y . Mutations in the protoporphyrinogen oxidase gene in patients with variegate porphyria . Human Molecular Genetics . 5 . 3 . 407–10 . March 1996 . 8852667 . 10.1093/hmg/5.3.407 . free .
• Lam H, Dragan L, Tsou HC, Merk H, Peacocke M, Goerz G, Sassa S, Poh-Fitzpatrick M, Bickers DR, Christiano AM . 6 . Molecular basis of variegate porphyria: a de novo insertion mutation in the protoporphyrinogen oxidase gene . Human Genetics . 99 . 1 . 126–9 . January 1997 . 9003509 . 10.1007/s004390050325 . 32134586 .
• Dailey HA, Dailey TA . Characteristics of human protoporphyrinogen oxidase in controls and variegate porphyrias . Cellular and Molecular Biology . 43 . 1 . 67–73 . February 1997 . 9074790 .
• Frank J, Poh-Fitzpatrick MB, King LE, Christiano AM . 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 . 9763307 . 10.1007/s004030050333 . 32988570 .
• Roberts AG, Puy H, Dailey TA, Morgan RR, Whatley SD, Dailey HA, Martasek P, Nordmann Y, Deybach JC, Elder GH . 6 . Molecular characterization of homozygous variegate porphyria . Human Molecular Genetics . 7 . 12 . 1921–5 . November 1998 . 9811936 . 10.1093/hmg/7.12.1921 . free .
• Whatley SD, Puy H, Morgan RR, Robreau AM, Roberts AG, Nordmann Y, Elder GH, Deybach JC . 6 . 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 . 10486317 . 1288269 . 10.1086/302586 .
• Suzuki Y, Ishihara D, Sasaki M, Nakagawa H, Hata H, Tsunoda T, Watanabe M, Komatsu T, Ota T, Isogai T, Suyama A, Sugano S . 6 . Statistical analysis of the 5' untranslated region of human mRNA using "Oligo-Capped" cDNA libraries . Genomics . 64 . 3 . 286–97 . March 2000 . 10756096 . 10.1006/geno.2000.6076 .
• Corrigall AV, Hift RJ, Davids LM, Hancock V, Meissner D, Kirsch RE, Meissner PN . Homozygous variegate porphyria in South Africa: genotypic analysis in two cases . Molecular Genetics and Metabolism . 69 . 4 . 323–30 . April 2000 . 10870850 . 10.1006/mgme.2000.2975 .
• Kauppinen R, Timonen K, von und zu Fraunberg M, Laitinen E, Ahola H, Tenhunen R, Taketani S, Mustajoki P . 6 . Homozygous variegate porphyria: 20 y follow-up and characterization of molecular defect . The Journal of Investigative Dermatology . 116 . 4 . 610–3 . April 2001 . 11286631 . 10.1046/j.1523-1747.2001.01293.x . free .
• Palmer RA, Elder GH, Barrett DF, Keohane SG . 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 . 11298551 . 10.1046/j.1365-2133.2001.04147.x . 41419729 .
• Corrigall AV, Hift RJ, Davids LM, Hancock V, Meissner D, Kirsch RE, Meissner PN . 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 . 11350188 . 10.1006/mgme.2001.3163 .
• Donnelly JG, Detombe S, Hindmarsh JT . 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 . 12017191 .

External links

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

Notes and References

1. Taketani S, Inazawa J, Abe T, Furukawa T, Kohno H, Tokunaga R, Nishimura K, Inokuchi H . 6 . The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1 . Genomics . 29 . 3 . 698–703 . October 1995 . 8575762 . 10.1006/geno.1995.9949 .
2. Frank J, McGrath JA, Poh-Fitzpatrick MB, Hawk JL, Christiano AM . Mutations in the translation initiation codon of the protoporphyrinogen oxidase gene underlie variegate porphyria . Clinical and Experimental Dermatology . 24 . 4 . 296–301 . July 1999 . 10457135 . 10.1046/j.1365-2230.1999.00484.x . 40509390 .
3. Web site: Entrez Gene: PPOX protoporphyrinogen oxidase.
4. Brzezowski P, Ksas B, Havaux M, Grimm B, Chazaux M, Peltier G, Johnson X, Alric J . 6 . The function of PROTOPORPHYRINOGEN IX OXIDASE in chlorophyll biosynthesis requires oxidised plastoquinone in Chlamydomonas reinhardtii . Communications Biology . 2 . 1 . 159 . 2019-05-03 . 31069268 . 6499784 . 10.1038/s42003-019-0395-5 .
5. Book: 10.1007/978-3-642-58633-0_5 . Structure-Activity Relationships of Diphenyl Ethers and Other Oxygen-Bridged Protoporphyrinogen Oxidase Inhibitors . Peroxidizing Herbicides . 1999 . Dayan FE, Reddy KN, Duke SO . 141–161 . 978-3-642-63674-5 .
6. Book: 10.1007/978-3-642-58633-0_11 . Herbicidal Efficacy of Protoporphyrinogen Oxidase Inhibitors . Peroxidizing Herbicides . 1999 . Nagano E . 293–302 . 978-3-642-63674-5 .
7. Book: 10.1016/B978-0-12-374367-1.00081-1 . Protoporphyrinogen Oxidase-Inhibiting Herbicides . Hayes' Handbook of Pesticide Toxicology . 2010 . Dayan FE, Duke SO . 1733–1751 . 9780123743671 .