Protoporphyrinogen oxidase

PPOX
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3NKS, 4IVM, 4IVO
Identifiers
Aliases	PPOX, PPO, V290M, VP, protoporphyrinogen oxidase
External IDs	OMIM: 600923; MGI: 104968; HomoloGene: 262; GeneCards: PPOX; OMA:PPOX - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1q23.3 Start 161,166,056 bp End 161,178,013 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1|1 H3 Start 171,103,563 bp End 171,108,760 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube olfactory zone of nasal mucosa epithelium of bronchus right hemisphere of cerebellum bronchial epithelial cell left ovary anterior pituitary right ovary granulocyte canal of the cervix Top expressed in fetal liver hematopoietic progenitor cell granulocyte neural layer of retina tibiofemoral joint human fetus right kidney saccule yolk sac genital tubercle neural tube More reference expression data BioGPS More reference expression data
Gene ontology Molecular function flavin adenine dinucleotide binding oxidoreductase activity oxygen-dependent protoporphyrinogen oxidase activity Cellular component mitochondrial inner membrane mitochondrial intermembrane space intrinsic component of mitochondrial inner membrane membrane mitochondrion integral component of mitochondrial inner membrane mitochondrial membranes Biological process heme biosynthetic process protoporphyrinogen IX metabolic process protoporphyrinogen IX biosynthetic process porphyrin-containing compound biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5498 19044 Ensembl ENSG00000143224 ENSMUSG00000062729 UniProt P50336 P51175 RefSeq (mRNA) NM_000309 NM_001122764 NM_001350128 NM_001350129 NM_001350130 NM_001350131 NM_001365398 NM_001365399 NM_001365400 NM_001365401 NM_008911 RefSeq (protein) NP_000300 NP_001116236 NP_001337057 NP_001337058 NP_001337059 NP_001337060 NP_032937 Location (UCSC) Chr 1: 161.17 – 161.18 Mb Chr 1: 171.1 – 171.11 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

protoporphyrinogen oxidase
Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)
Identifiers
EC no.	1.3.3.4
CAS no.	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
Search PMC articles PubMed articles NCBI proteins

Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the PPOX gene.

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. 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.

See also

• Porphyrin

Further reading

• 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 (January 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 (February 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 (January 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 (December 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. (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. doi:10.1038/ng0596-95. PMID 8673113. 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. doi:10.1002/pro.5560050112. PMC 2143237. 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. doi:10.1006/bbrc.1996.1337. 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. doi:10.1093/hmg/5.3.407. 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. doi:10.1007/s004390050325. PMID 9003509. 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. doi:10.1007/s004030050333. PMID 9763307. 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. doi:10.1093/hmg/7.12.1921. 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. doi:10.1086/302586. PMC 1288269. 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. 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 (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. 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.

External links

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