Protoporphyrinogen oxidase

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
3NKS, 4IVM, 4IVO

Identifiers

Symbols

PPOX ; PPO; V290M; VP

External IDs

OMIM: 600923 MGI: 104968 HomoloGene: 262 GeneCards: PPOX Gene

EC number

1.3.3.4

Gene ontology
Molecular function	• oxygen-dependent protoporphyrinogen oxidase activity • flavin adenine dinucleotide binding
Cellular component	• mitochondrial intermembrane space • intrinsic component of mitochondrial inner membrane • integral component of mitochondrial inner membrane • mitochondrial membrane
Biological process	• porphyrin-containing compound metabolic process • porphyrin-containing compound biosynthetic process • protoporphyrinogen IX biosynthetic process • heme biosynthetic process • response to drug • small molecule metabolic process • oxidation-reduction process
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 1:
161.17 – 161.18 Mb

Chr 1:
171.28 – 171.28 Mb

PubMed search

protoporphyrinogen oxidase

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

Identifiers

Databases

PDB structures

AmiGO / EGO

Search
PMC	articles
PubMed	articles
NCBI	proteins

Protoporphyrinogen oxidase 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.

References

↑ Taketani S, Inazawa J, Abe T, Furukawa T, Kohno H, Tokunaga R, Nishimura K, Inokuchi H (Oct 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 (Jul 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.
1 2 "Entrez Gene: PPOX protoporphyrinogen oxidase".

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 (Aug 2003). "Kinetic and physical characterisation of recombinant wild-type and mutant human protoporphyrinogen oxidases". Biochimica et Biophysica Acta 1650 (1-2): 10–21. doi:10.1016/s1570-9639(03)00186-9. PMID 12922165.
Morgan RR, Errington R, Elder GH (Jan 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 (Feb 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.
Nishimura K, Taketani S, Inokuchi H (Apr 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 (Jan 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 (Dec 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, Meissner DM, Kirsch RE, Dailey HA (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.
Dailey TA, Dailey HA (Jan 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 (Sep 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 (Mar 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, Sassa S, Poh-Fitzpatrick M, Bickers DR, Christiano AM (Jan 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.
Dailey HA, Dailey TA (Feb 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 (Aug 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.
Roberts AG, Puy H, Dailey TA, Morgan RR, Whatley SD, Dailey HA, Martasek P, Nordmann Y, Deybach JC, Elder GH (Nov 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, Elder GH, Deybach JC (Oct 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, Watanabe M, Komatsu T, Ota T, Isogai T, Suyama A, Sugano S (Mar 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 (Apr 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, Taketani S, Mustajoki P (Apr 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 (Apr 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.
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.

Protein: cell membrane proteins (other than Cell surface receptor, enzymes, and cytoskeleton)

Arrestin	SAG ARRB1 ARRB2 ARR3

Membrane-spanning 4A	MS4A1 MS4A2 MS4A3 MS4A4A MS4A4E MS4A5 MS4A6A MS4A6E MS4A7 MS4A8B MS4A9 MS4A10 MS4A12 MS4A13 MS4A14 MS4A15 MS4A18

Myelin	Myelin basic protein PMP2 Myelin proteolipid protein PLP1 Myelin oligodendrocyte glycoprotein Myelin-associated glycoprotein Myelin protein zero

Pulmonary surfactant	Pulmonary surfactant-associated protein B Pulmonary surfactant-associated protein C

Tetraspanin	TSPAN1 TSPAN2 TSPAN3 TSPAN4 TSPAN5 TSPAN6 TSPAN7 TSPAN8 TSPAN9 TSPAN10 TSPAN11 TSPAN12 TSPAN13 TSPAN14 TSPAN15 TSPAN16 TSPAN17 TSPAN18 TSPAN19 TSPAN20 TSPAN21 TSPAN22 TSPAN23 TSPAN24 TSPAN25 TSPAN26 TSPAN27 TSPAN28 TSPAN29 TSPAN30 TSPAN31 TSPAN32 TSPAN33 TSPAN34

Other/ungrouped	Calnexin LDL-receptor-related protein-associated protein Neurofibromin 2 Presenilin PSEN1 PSEN2 HFE Phospholipid transfer proteins Dysferlin STRC OTOF

see also other cell membrane protein disorders

Enzymes involved in the metabolism of heme and porphyrin

Porphyrin biosynthesis

early mitochondrial:	Aminolevulinic acid synthase ALAS1 ALAS2

cytosolic:	Porphobilinogen synthase Porphobilinogen deaminase Uroporphyrinogen III synthase Uroporphyrinogen III decarboxylase

late mitochondrial:	Coproporphyrinogen III oxidase Protoporphyrinogen oxidase Ferrochelatase

Heme degradation
to bile

spleen:	Heme oxygenase Biliverdin reductase

liver:	glucuronosyltransferase UGT1A1

Oxidoreductases: CH–CH oxidoreductases (EC 1.3)

1.3.1: NAD/NADP acceptor	Enoyl-acyl carrier protein reductase/Enoyl ACP reductase 7-Dehydrocholesterol reductase Biliverdin reductase 2,4 Dienoyl-CoA reductase Dihydroxymethyloxo-tetrahydroquinoline dehydrogenase

1.3.3: Oxygen acceptor	Dihydroorotate dehydrogenase Coproporphyrinogen III oxidase Protoporphyrinogen oxidase Bilirubin oxidase Acyl-CoA oxidase Dihydrouracil oxidase Tetrahydroberberine oxidase Secologanin synthase Tryptophan alpha,beta-oxidase Pyrroloquinoline-quinone synthase L-galactonolactone oxidase

1.3.5: Quinone	Succinate dehydrogenase SDHA SDHB SDHC SDHD

1.3.99: Other acceptors	Fumarate reductase Butyryl-CoA dehydrogenase Acyl CoA dehydrogenase ACADSB ACADS 5α-reductase SRD5A1 SRD5A2 SRD5A3 Glutaryl-CoA dehydrogenase Isovaleryl coenzyme A dehydrogenase 3-oxo-5beta-steroid 4-dehydrogenase

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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