Protoporphyrinogen oxidase

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protoporphyrinogen oxidase
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
PMC
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PMC	articles
PubMed	articles
NCBI	proteins

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)
End	161,178,013 bp
Gene location (Mouse)
Chr.	Chromosome 1 (mouse)
End	171,108,760 bp
RNA expression pattern
	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
	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
	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
	Wikidata
View/Edit Human	View/Edit Mouse

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

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.^[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]

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.
^ Taketani S, Inazawa J, Abe T, Furukawa T, Kohno H, Tokunaga R, et al. (October 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 (July 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".
^ Brzezowski P, Ksas B, Havaux M, Grimm B, Chazaux M, Peltier G, et al. (2019-05-03). "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. pp. 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. pp. 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. pp. 1733–1751. doi:10.1016/B978-0-12-374367-1.00081-1. ISBN 9780123743671.

External links

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

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

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000062729 – Ensembl, May 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. (October 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 (July 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".

[8] Brzezowski P, Ksas B, Havaux M, Grimm B, Chazaux M, Peltier G, et al. (2019-05-03). "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.

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

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

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

[5]

Protoporphyrinogen oxidase

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