Protoporphyrin IX explained

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.[1]

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.[2] Fischer described iron-deprived heme becoming the "proto-" porphyrin, particularly in reference to Hugo Kammerer's porphyrin.[3] [4] In modern times, 'proto-' specifies a porphyrin species bearing methyl, vinyl, and carboxyethyl/propionate side groups.[5]

Fischer also generated the Roman numeral naming system which includes 15 protoporphyrin analogs, the naming system is not systematic however.[6] An alternative name for heme is iron protoporphyrin IX (iron PPIX). PPIX contains four methyl groups (M), two vinyl groups (V), and two propionic acid groups (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.

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.[7] The use of Greek letters in this context originates from the pioneering work of Georg Barkan in 1932.[8]

Properties

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, 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.[10]

Biosynthesis

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.[10] 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.[11] [12] [13]

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).[14] 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.[15] Other metalsnickel, tin, chromiumhave been investigated for their therapeutic value.[16]

Palepron is the disodium salt of protoporphyrin IX.[17]

History

Laidlaw may have first isolated PPIX in 1904.

Clinical Importance

Protoporphyrin IX florescence from 5-ALA administration is used in fluorescent-guided surgery of glioblastoma.[18] [19]

See also

Notes and References

  1. Crystal and Molecular Structure of the Free Base Porphyrin, Protoporphyrin IX Dimethyl Ester. Winslow S. Caughey . James A. Ibers. J. Am. Chem. Soc.. 1977. 99. 20. 6639–6645. 10.1021/ja00462a027. 19518.
  2. Vicente. Maria da G.H.. Smith. Kevin M.. 2014. Syntheses and Functionalizations of Porphyrin Macrocycles. Current Organic Synthesis. 11. 1. 3–28. 10.2174/15701794113106660083. 1570-1794. 4251786. 25484638.
  3. Web site: Fischer. Hans. 1930. On haemin and the relationships between haemin and chlorophyll . Nobel Prize.
  4. 1980-01-01. A short history of porphyrins and the porphyrias. International Journal of Biochemistry. en. 11. 3–4. 189–200. 10.1016/0020-711X(80)90219-0. 0020-711X. With. Torben K.. 6993245.
  5. Neves. Ana Carolina de Oliveira. Galván. Ismael. 2020. Models for human porphyrias: Have animals in the wild been overlooked?. BioEssays. en. 42. 12. 2000155. 10.1002/bies.202000155. 33155299. 226269267. 1521-1878.
  6. 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. 10.1111/j.1432-1033.1988.tb14453.x. 0014-2956. 3208761. free.
  7. Book: Berk. Paul D.. International Symposium on Chemistry and Physiology of Bile Pigments. Berlin. Nathaniel I.. 1977. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health. en.
  8. Barkan. Georg. Schales. Otto. 1938. A Hæmoglobin from Bile Pigment. Nature. en. 142. 3601. 836–837. 10.1038/142836b0. 1938Natur.142..836B. 4073510. 1476-4687.
  9. 10.1124/jpet.115.228130 . free . Protoporphyrin IX: The Good, the Bad, and the Ugly . 2016 . Sachar . M. . Anderson . K. E. . Ma . X. . Journal of Pharmacology and Experimental Therapeutics . 356 . 2 . 267–275 . 26588930 . 4727154 .
  10. Encyclopedia: Hemes in Biology. Paul R. Ortiz de Montellano. 2008. Wiley Encyclopedia of Chemical Biology. 1–10 . 10.1002/9780470048672.wecb221. John Wiley & Sons. 978-0-470-04867-2.
  11. A. R. Battersby . C. J. R. Fookes . G. W. J. Matcham . E. McDonald . Biosynthesis of the pigments of life: formation of the macrocycle . Nature . 285 . 17–21 . 1980 . 5759 . 10.1038/285017a0 . 6769048. 1980Natur.285...17B . 9070849 . free .
  12. F. J. Leeper . The biosynthesis of porphyrins, chlorophylls, and vitamin B12 . Natural Product Reports . 2. 19–47. 10.1039/NP9850200019. 1983. 1 . 3895052 .
  13. G. Layer . J. Reichelt . D. Jahn . D. W. Heinz. Structure and function of enzymes in heme biosynthesis . Protein Science . 19 . 1137–1161 . 2010 . 6 . 10.1002/pro.405. 2895239 . 20506125.
  14. Book: Chang, C. K.. DiNello, R. K.. Dolphin, D.. Inorganic Syntheses. Iron Porphines . 2007 . 20. 147–155. 10.1002/9780470132517.ch35. 978-0-470-13251-7.
  15. 10.1016/S0022-0728(02)00722-2. 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. 2002. Dias. Sı́Lvio L.P. Gushikem. Yoshitaka. Ribeiro. Emerson S.. Benvenutti. Edilson V.. Journal of Electroanalytical Chemistry. 523. 1–2. 64–69.
  16. 10.1203/00006450-199302000-00021. Selection of Metalloporphyrin Heme Oxygenase Inhibitors Based on Potency and Photoreactivity. 1993. Verman. Hendrik J.. Ekstrand. Bradley C.. Stevenson. David K. . Pediatric Research. 33. 2. 195–200. 8433895. 9223457. free.
  17. Web site: PubChem. Protoporphyrin disodium. 2021-04-15. pubchem.ncbi.nlm.nih.gov. en.
  18. 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 . en . 12 . 5 . 555 . 10.3390/brainsci12050555 . free . 2076-3425 . 9138621 . 35624942.
  19. 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 . en . 20 . 153303382110216 . 10.1177/15330338211021605 . 1533-0346 . 8255554 . 34212784.

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