Protoporphyrin IX

Last updated
Protoporphyrin IX
PPIXtransH.png
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.008.213 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 209-033-7
251232
KEGG
PubChem CID
UNII
  • 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- Yes check.svgY
    Key: KSFOVUSSGSKXFI-UJJXFSCMSA-N Yes check.svgY
  • 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
C34H34N4O4
Molar mass 562.658 g/mol
Density 1.27 g/cm3
Hazards
GHS labelling: [1]
GHS-pictogram-exclam.svg
Warning
H315, H319, H335
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).

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.

Contents

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

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

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-synthesis-from-protoporphyrinogen-IX.png

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 florescence from 5-ALA administration is used in fluorescent-guided surgery of glioblastoma. [19] [20]

See also

Related Research Articles

<span class="mw-page-title-main">Heme</span> Chemical coordination complex of an iron ion chelated to a porphyrin

Heme, or haem, is a ring-shaped iron-containing molecular component of hemoglobin, which is necessary to bind oxygen in the bloodstream. It is composed of four pyrrole rings with 2 vinyl and 2 propionic acid side chains. Heme is biosynthesized in both the bone marrow and the liver.

<span class="mw-page-title-main">Porphyrin</span> Heterocyclic organic compound with four modified pyrrole subunits

Porphyrins are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). In vertebrates, an essential member of the porphyrin group is heme, which is a component of hemoproteins, whose functions include carrying oxygen in the bloodstream. In plants, an essential porphyrin derivative is chlorophyll, which is involved in light harvesting and electron transfer in photosynthesis.

<span class="mw-page-title-main">Aminolevulinic acid</span> Endogenous non-proteinogenic amino acid

δ-Aminolevulinic acid, an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in plants.

Chlorophyll <i>a</i> Chemical compound

Chlorophyll a is a specific form of chlorophyll used in oxygenic photosynthesis. It absorbs most energy from wavelengths of violet-blue and orange-red light, and it is a poor absorber of green and near-green portions of the spectrum. Chlorophyll does not reflect light but chlorophyll-containing tissues appear green because green light is diffusively reflected by structures like cell walls. This photosynthetic pigment is essential for photosynthesis in eukaryotes, cyanobacteria and prochlorophytes because of its role as primary electron donor in the electron transport chain. Chlorophyll a also transfers resonance energy in the antenna complex, ending in the reaction center where specific chlorophylls P680 and P700 are located.

<span class="mw-page-title-main">Chromophore</span> A molecule that absorbs light

A chromophore is a molecule which absorbs light at a particular wavelength and emits color as a result. Chromophores are commonly referred to as colored molecules for this reason. The word is derived from Ancient Greek χρῶμᾰ (chroma) 'color', and -φόρος (phoros) 'carrier of'. Many molecules in nature are chromophores, including chlorophyll, the molecule responsible for the green colors of leaves. The color that is seen by our eyes is that of the light not absorbed by the reflecting object within a certain wavelength spectrum of visible light. The chromophore indicates a region in the molecule where the energy difference between two separate molecular orbitals falls within the range of the visible spectrum. Visible light that hits the chromophore can thus be absorbed by exciting an electron from its ground state into an excited state. In biological molecules that serve to capture or detect light energy, the chromophore is the moiety that causes a conformational change in the molecule when hit by light.

Tetrapyrroles are a class of chemical compounds that contain four pyrrole or pyrrole-like rings. The pyrrole/pyrrole derivatives are linked by, in either a linear or a cyclic fashion. Pyrroles are a five-atom ring with four carbon atoms and one nitrogen atom. Tetrapyrroles are common cofactors in biochemistry and their biosynthesis and degradation feature prominently in the chemistry of life.

Chlorophyll <i>b</i> Chemical compound

Chlorophyll b is a form of chlorophyll. Chlorophyll b helps in photosynthesis by absorbing light energy. It is more soluble than chlorophyll a in polar solvents because of its carbonyl group. Its color is green, and it primarily absorbs blue light.

<span class="mw-page-title-main">Protoporphyrinogen oxidase</span>

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

<span class="mw-page-title-main">Porphine</span> Chemical compound

Porphine or porphin is an organic compound of empirical formula C20H14N4. It is heterocyclic and aromatic. The molecule is a flat macrocycle, consisting of four pyrrole-like rings joined by four methine bridges, which makes it the simplest of the tetrapyrroles.

<span class="mw-page-title-main">Ferrochelatase</span>

Protoporphyrin ferrochelatase (EC 4.98.1.1, formerly EC 4.99.1.1, or ferrochelatase; systematic name protoheme ferro-lyase (protoporphyrin-forming)) is an enzyme encoded by the FECH gene in humans. Ferrochelatase catalyses the eighth and terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme B. It catalyses the reaction:

<span class="mw-page-title-main">Coproporphyrinogen III</span> Chemical compound

Coproporphyrinogen III is a metabolic intermediate in the biosynthesis of many compounds that are critical for living organisms, such as hemoglobin and chlorophyll. It is a colorless solid.

<span class="mw-page-title-main">Uroporphyrinogen III</span> Chemical compound

Uroporphyrinogen III is a tetrapyrrole, the first macrocyclic intermediate in the biosynthesis of heme, chlorophyll, vitamin B12, and siroheme. It is a colorless compound, like other porphyrinogens.

<span class="mw-page-title-main">Protoporphyrinogen IX</span> Chemical compound

Protoporphyrinogen IX is an organic chemical compound which is produced along the synthesis of porphyrins, a class of critical biochemicals that include hemoglobin and chlorophyll. It is a direct precursor of protoporphyrin IX.

<span class="mw-page-title-main">Bilin (biochemistry)</span> Class of chemical compound

Bilins, bilanes or bile pigments are biological pigments formed in many organisms as a metabolic product of certain porphyrins. Bilin was named as a bile pigment of mammals, but can also be found in lower vertebrates, invertebrates, as well as red algae, green plants and cyanobacteria. Bilins can range in color from red, orange, yellow or brown to blue or green.

<span class="mw-page-title-main">Hemin</span> Class of compounds; (chloro)porphyrinato iron(III) complexes

Hemin is an iron-containing porphyrin with chlorine that can be formed from a heme group, such as heme B found in the hemoglobin of human blood.

<span class="mw-page-title-main">Porphyrinogen</span>

In biochemistry, a porphyrinogen is a member of a class of naturally occurring compounds with a tetrapyrrole core, a macrocycle of four pyrrole rings connected by four methylene bridges. They can be viewed as derived from the parent compound hexahydroporphine by the substitution of various functional groups for hydrogen atoms in the outermost (20-carbon) ring.

<span class="mw-page-title-main">Chlorophyllide</span> Chemical compound

Chlorophyllide a and Chlorophyllide b are the biosynthetic precursors of chlorophyll a and chlorophyll b respectively. Their propionic acid groups are converted to phytyl esters by the enzyme chlorophyll synthase in the final step of the pathway. Thus the main interest in these chemical compounds has been in the study of chlorophyll biosynthesis in plants, algae and cyanobacteria. Chlorophyllide a is also an intermediate in the biosynthesis of bacteriochlorophylls.

<span class="mw-page-title-main">Chelatase</span> Class of enzymes

In biochemistry, chelatases are enzymes that catalyze the insertion ("metalation") of naturally occurring tetrapyrroles. Many tetrapyrrole-based cofactors exist in nature including hemes, chlorophylls, and vitamin B12. These metallo cofactors are derived by the reaction of metal cations with tetrapyrroles, which are not ligands per se, but the conjugate acids thereof. In the case of ferrochelatases, the reaction that chelatases catalyze is:

<span class="mw-page-title-main">Hexahydroporphine</span> Chemical compound

Hexahydroporphine is an organic chemical compound with formula C20H20N4. The molecule consists of four pyrrole rings connected by methylene bridges −CH2− into a larger (non-aromatic) macrocycle ring, which makes it one of the simplest tetrapyrroles, and the simplest "true" one. As indicated by the name, it may be viewed as derived from porphine by the addition of six hydrogen atoms: four on the methine bridges, and two on the nitrogen atoms.

<span class="mw-page-title-main">Transition metal porphyrin complexes</span>

Transition metal porphyrin complexes are a family of coordination complexes of the conjugate base of porphyrins. Iron porphyrin complexes occur widely in Nature, which has stimulated extensive studies on related synthetic complexes. The metal-porphyrin interaction is a strong one such that metalloporphyrins are thermally robust. They are catalysts and exhibit rich optical properties, although these complexes remain mainly of academic interest.

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. 1 2 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. 1 2 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. 1 2 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.{{cite book}}: |journal= ignored (help)
  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.
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