Protoporphyrin IX

Protoporphyrin IX

Identifiers
CAS Number	553-12-8^Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:15430^Y
ChEMBL	ChEMBL267548^Y
ChemSpider	10469486^Y
ECHA InfoCard	100.008.213
EC Number	209-033-7
Gmelin Reference	251232
KEGG	C02191
PubChem CID	4971
UNII	C2K325S808^Y
CompTox Dashboard (EPA)	DTXSID4048353
InChI InChI=1S/C34H34N4O4/c1-7-21-17(3)25-13-26-19(5)23(9-11-33(39)40)31(37-26)16-32-24(10-12-34(41)42)20(6)28(38-32)15-30-22(8-2)18(4)27(36-30)14-29(21)35-25/h7-8,13-16,35,38H,1-2,9-12H2,3-6H3,(H,39,40)(H,41,42)/b25-13-,26-13-,27-14-,28-15-,29-14-,30-15-,31-16-,32-16-^Y Key: KSFOVUSSGSKXFI-UJJXFSCMSA-N^Y
SMILES CC\1=C(/C/2=C/C3=N/C(=C\C4=C(C(=C(N4)/C=C\5/C(=C(C(=N5)/C=C1\N2)C=C)C)C=C)C)/C(=C3CCC(=O)O)C)CCC(=O)O
Properties
Chemical formula	C34H34N4O4
Molar mass	562.658 g/mol
Density	1.27 g/cm^3
Hazards
GHS labelling:[1]
Pictograms
Signal word	Warning
Hazard statements	H315, H319, H335
Precautionary statements	P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Protoporphyrin IX is an organic compound, classified as a porphyrin, that plays an important role in living organisms as a precursor to other critical compounds like heme (hemoglobin) and chlorophyll. It is a deeply colored solid that is not soluble in water. The name is often abbreviated as PPIX.

Protoporphyrin IX contains a porphine core, a tetrapyrrole macrocycle with a marked aromatic character. Protoporphyrin IX is essentially planar, except for the N-H bonds that are bent out of the plane of the rings, in opposite (trans) directions.^[2]

Nomenclature

The general term protoporphyrin refers to porphine derivatives that have the outer hydrogen atoms in the four pyrrole rings replaced by other functional groups. The prefix proto often means 'first' in science nomenclature (such as carbon protoxide), hence Hans Fischer is thought to have coined the name protoporphyrin as the first class of porphyrins.^[3] Fischer described iron-deprived heme becoming the "proto-" porphyrin, particularly in reference to Hugo Kammerer's porphyrin.^[4][5] In modern times, 'proto-' specifies a porphyrin species bearing methyl, vinyl, and carboxyethyl/propionate side groups.^[6]

Fischer also generated the Roman numeral naming system which includes 15 protoporphyrin analogs, the naming system is not systematic however.^[7] An alternative name for heme is iron protoporphyrin IX (iron PPIX). PPIX contains four methyl groups −CH₃ (M), two vinyl groups −CH=CH₂ (V), and two propionic acid groups −CH₂−CH₂−COOH (P). The suffix "IX" indicates that these chains occur in the circular order MV-MV-MP-PM around the outer cycle at the following respective positions: c2,c3-c7,c8-c12,c13-c17,c18.^[7]

The methine bridges of PPIX are named alpha (c5), beta (c10), gamma (c15), and delta (c20). In the context of heme, metabolic biotransformation by heme oxygenase results in the selective opening of the alpha-methine bridge to form biliverdin/bilirubin. In this case, the resulting bilin carries the suffix IXα which indicates the parent molecule was protoporphyrin IX cleaved at the alpha position. Non-enzymatic oxidation may result in the ring opening at other bridge positions.^[8] The use of Greek letters in this context originates from the pioneering work of Georg Barkan in 1932.^[9]

Properties

• When UV light is shone on the compound, it fluoresces with a bright red color.
• It Is also the component in egg shells that give them their characteristic brown color.^[10]

Natural occurrence

The compound is encountered in nature in the form of complexes where the two inner hydrogen atoms are replaced by a divalent metal cation. When complexed with an iron(II) (ferrous) cation Fe²⁺, the molecule is called heme. Hemes are prosthetic groups in some important proteins. These heme-containing proteins include hemoglobin, myoglobin, and cytochrome c. Complexes can also be formed with other metal ions, such as zinc.^[11]

Biosynthesis

Main article: Porphyrin § Synthesis

The compound is synthesized from acyclic precursors via a mono-pyrrole (porphobilinogen) then a tetrapyrrole (a porphyrinogen, specifically uroporphyrinogen III). This precursor is converted to protoporphyrinogen IX, which is oxidized to protoporphyrin IX.^[11] The last step is mediated by the enzyme protoporphyrinogen oxidase.

Protoporphyrin IX is an important precursor to biologically essential prosthetic groups such as heme, cytochrome c, and chlorophylls. As a result, a number of organisms are able to synthesize this tetrapyrrole from basic precursors such as glycine and succinyl-CoA, or glutamic acid. Despite the wide range of organisms that synthesize protoporphyrin IX, the process is largely conserved from bacteria to mammals with a few distinct exceptions in higher plants.^[12][13][14]

In the biosynthesis of those molecules, the metal cation is inserted into protoporphyrin IX by enzymes called chelatases. For example, ferrochelatase converts the compound into heme B (i.e. Fe-protoporphyrin IX or protoheme IX). In chlorophyll biosynthesis, the enzyme magnesium chelatase converts it into Mg-protoporphyrin IX.

Described metalloprotoporphyrin IX derivatives

Protoporphyrin IX reacts with iron salts in air to give the complex FeCl(PPIX).^[15] Heme coordinated with chlorine is known as hemin. Many metals other than Fe form Heme-like complexes when coordinated to PPIX. Of particular interest are cobalt derivatives because they also function as oxygen carriers.^[16] Other metals—nickel, tin, chromium—have been investigated for their therapeutic value.^[17]

Palepron is the disodium salt of protoporphyrin IX.^[18]

History

Laidlaw may have first isolated PPIX in 1904.^[5]

Clinical Importance

Protoporphyrin IX fluorescence from 5-ALA administration is used in fluorescent-guided surgery of glioblastoma.^[19][20]

See also

• Carbon monoxide-releasing molecules
• Heme oxygenase
• Biosynthesis of chlorophylls
• Biosynthesis of hemes

References

1. "protoporphyrin IX". pubchem.ncbi.nlm.nih.gov.
2. Winslow S. Caughey; James A. Ibers (1977). "Crystal and Molecular Structure of the Free Base Porphyrin, Protoporphyrin IX Dimethyl Ester". J. Am. Chem. Soc. 99 (20): 6639–6645. doi:10.1021/ja00462a027. PMID 19518.
3. Vicente, Maria da G.H.; Smith, Kevin M. (2014). "Syntheses and Functionalizations of Porphyrin Macrocycles". Current Organic Synthesis. 11 (1): 3–28. doi:10.2174/15701794113106660083. ISSN 1570-1794. PMC 4251786. PMID 25484638.
4. Fischer, Hans (1930). "On haemin and the relationships between haemin and chlorophyll" (PDF). Nobel Prize.
5. With, Torben K. (1980-01-01). "A short history of porphyrins and the porphyrias". International Journal of Biochemistry. 11 (3–4): 189–200. doi:10.1016/0020-711X(80)90219-0. ISSN 0020-711X. PMID 6993245.
6. Neves, Ana Carolina de Oliveira; Galván, Ismael (2020). "Models for human porphyrias: Have animals in the wild been overlooked?". BioEssays. 42 (12): 2000155. doi:10.1002/bies.202000155. ISSN 1521-1878. PMID 33155299. S2CID 226269267.
7. Moss, G. P. (1988-12-15). "Nomenclature of tetrapyrroles. Recommendations 1986 IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN)". European Journal of Biochemistry. 178 (2): 277–328. doi:10.1111/j.1432-1033.1988.tb14453.x. ISSN 0014-2956. PMID 3208761.
8. Berk, Paul D.; Berlin, Nathaniel I. (1977). International Symposium on Chemistry and Physiology of Bile Pigments. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health.
9. Barkan, Georg; Schales, Otto (1938). "A Hæmoglobin from Bile Pigment". Nature. 142 (3601): 836–837. Bibcode:1938Natur.142..836B. doi:10.1038/142836b0. ISSN 1476-4687. S2CID 4073510.
10. Sachar, M.; Anderson, K. E.; Ma, X. (2016). "Protoporphyrin IX: The Good, the Bad, and the Ugly". Journal of Pharmacology and Experimental Therapeutics. 356 (2): 267–275. doi:10.1124/jpet.115.228130. PMC 4727154. PMID 26588930.
11. Paul R. Ortiz de Montellano (2008). "Hemes in Biology". Wiley Encyclopedia of Chemical Biology. John Wiley & Sons. pp. 1–10. doi:10.1002/9780470048672.wecb221. ISBN 978-0-470-04867-2.
12. A. R. Battersby; C. J. R. Fookes; G. W. J. Matcham; E. McDonald (1980). "Biosynthesis of the pigments of life: formation of the macrocycle". Nature. 285 (5759): 17–21. Bibcode:1980Natur.285...17B. doi:10.1038/285017a0. PMID 6769048. S2CID 9070849.
13. F. J. Leeper (1983). "The biosynthesis of porphyrins, chlorophylls, and vitamin B12". Natural Product Reports. 2 (1): 19–47. doi:10.1039/NP9850200019. PMID 3895052.
14. G. Layer; J. Reichelt; D. Jahn; D. W. Heinz (2010). "Structure and function of enzymes in heme biosynthesis". Protein Science. 19 (6): 1137–1161. doi:10.1002/pro.405. PMC 2895239. PMID 20506125.
15. Chang, C. K.; DiNello, R. K.; Dolphin, D. (2007). "Iron Porphines". Inorganic Syntheses. Vol. 20. pp. 147–155. doi:10.1002/9780470132517.ch35. ISBN 978-0-470-13251-7.
16. Dias, Sı́Lvio L.P; Gushikem, Yoshitaka; Ribeiro, Emerson S.; Benvenutti, Edilson V. (2002). "Cobalt(II) hematoporphyrin IX and protoporphyrin IX complexes immobilized on highly dispersed titanium(IV) oxide on a cellulose microfiber surface: Electrochemical properties and dissolved oxygen reduction study". Journal of Electroanalytical Chemistry. 523 (1–2): 64–69. doi:10.1016/S0022-0728(02)00722-2.
17. Verman, Hendrik J.; Ekstrand, Bradley C.; Stevenson, David K. (1993). "Selection of Metalloporphyrin Heme Oxygenase Inhibitors Based on Potency and Photoreactivity". Pediatric Research. 33 (2): 195–200. doi:10.1203/00006450-199302000-00021. PMID 8433895. S2CID 9223457.
18. PubChem. "Protoporphyrin disodium". pubchem.ncbi.nlm.nih.gov. Retrieved 2021-04-15.
19. Zeppa, Pietro; De Marco, Raffaele; Monticelli, Matteo; Massara, Armando; Bianconi, Andrea; Di Perna, Giuseppe; Greco Crasto, Stefania; Cofano, Fabio; Melcarne, Antonio; Lanotte, Michele Maria; Garbossa, Diego (2022-04-26). "Fluorescence-Guided Surgery in Glioblastoma: 5-ALA, SF or Both? Differences between Fluorescent Dyes in 99 Consecutive Cases". Brain Sciences. 12 (5): 555. doi:10.3390/brainsci12050555. ISSN 2076-3425. PMC 9138621. PMID 35624942.
20. Palmieri, Giuseppe; Cofano, Fabio; Salvati, Luca Francesco; Monticelli, Matteo; Zeppa, Pietro; Perna, Giuseppe Di; Melcarne, Antonio; Altieri, Roberto; La Rocca, Giuseppe; Sabatino, Giovanni; Barbagallo, Giuseppe Maria; Tartara, Fulvio; Zenga, Francesco; Garbossa, Diego (2021-01-01). "Fluorescence-Guided Surgery for High-Grade Gliomas: State of the Art and New Perspectives". Technology in Cancer Research & Treatment. 20: 153303382110216. doi:10.1177/15330338211021605. ISSN 1533-0346. PMC 8255554. PMID 34212784.