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Protoporphyrin IX
Protoporphyrin IX
Protoporphyrin IX
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Protoporphyrin IX
Names
IUPAC name
7,12-Diethenyl-3,8,13,17-tetramethylporphyrin-2,18-dipropanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.008.213 Edit this at Wikidata
EC Number
  • 209-033-7
251232
KEGG
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- checkY
    Key: KSFOVUSSGSKXFI-UJJXFSCMSA-N checkY
  • 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]
GHS07: Exclamation mark
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.

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

[edit]

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

[edit]
  • When UV light is shone on the compound, it fluoresces with a bright red color.
  • It is the component of eggshells that gives them their characteristic brown color.[10]

Natural occurrence

[edit]

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

[edit]
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 synthesis from protoporphyrinogen-IX

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

[edit]

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

[edit]

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

Clinical Importance

[edit]

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

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Protoporphyrin IX

View on Grokipedia
from Grokipedia
Protoporphyrin IX (PPIX) is a naturally occurring , a cyclic compound that functions as the immediate precursor to in the biosynthetic pathway of heme, the iron-containing essential for oxygen transport in and various enzymatic functions in . With the molecular formula C₃₄H₃₄N₄O₄ and a molecular weight of 562.7 g/mol, PPIX features a macrocyclic composed of four rings linked by methine bridges, substituted with four methyl groups, two vinyl groups, and two side chains at the β-positions. This arrangement allows it to chelate metal ions, particularly iron, to form metalloporphyrins critical for biological processes. In biosynthesis, PPIX is produced in the mitochondria through the heme synthesis pathway, starting from and to form 5-aminolevulinic acid (ALA), which progresses through intermediates like porphobilinogen and uroporphyrinogen III, ultimately yielding protoporphyrinogen IX that is oxidized to PPIX by protoporphyrinogen oxidase. Its levels are tightly regulated by ferrochelatase, the that inserts iron to produce ; disruptions in this regulation lead to PPIX accumulation. Biologically, PPIX serves as a branch point in metabolism, directing toward in animals for oxygen binding, , and , or toward chlorophyll in and photosynthetic for light-harvesting. Medically, PPIX plays dual roles: its accumulation due to ferrochelatase deficiencies causes (EPP), resulting in severe , skin damage from upon light exposure, and potential hepatobiliary complications like gallstones or . Conversely, its photosensitizing properties—generating and other reactive species under light activation—make it valuable in (PDT), where administration of ALA induces PPIX buildup in target tissues for selective destruction of cancer cells or pathogens, with FDA approval for treating and investigational use for other conditions including certain cancers. Emerging applications also include fluorescence-based imaging, biosensing for metal ions and biomolecules, and synthetic catalysis using modified PPIX derivatives.

Structure and Nomenclature

Nomenclature

Protoporphyrin IX derives its name from the systematic classification of porphyrins developed by German chemist in the early 20th century, as part of his pioneering work on the structures of blood and plant pigments that earned him the 1930 . Fischer first isolated and characterized protoporphyrin from by removing the iron atom, establishing it as the core organic component of . The prefix "proto-" reflects the compound's role as the foundational or primitive member of the series with a specific substitution pattern, featuring four methyl groups, two vinyl groups, and two side chains arranged on the . The Roman numeral "IX" designates the particular isomeric configuration of these substituents, which identified as the ninth in a series of synthesized protoporphyrin isomers and the one predominant in natural biological systems, such as . In scientific literature, protoporphyrin IX is commonly abbreviated as PPIX or PpIX for brevity in discussions of its biochemical roles. Its full systematic IUPAC name is 7,12-diethenyl-3,8,13,17-tetramethylporphyrin-2,18-dipropanoic acid, which precisely describes the positions of the ethenyl (vinyl), methyl, and propanoic acid substituents on the ring.

Molecular Structure

Protoporphyrin IX is a derivative characterized by a core , consisting of four rings linked together at their α-positions by four methine bridges (-CH=), forming a fully conjugated 18 π-electron aromatic system. This planar ring structure, with atoms at positions 21, 22, 23, and 24 coordinating a central cavity, provides the foundational architecture for its biological roles as a precursor. The molecule's overall planarity, except for slight out-of-plane bending of the N-H bonds, facilitates extensive delocalization of electrons across the . The specific substituents define its unique identity: four methyl groups (-CH₃) are attached at the β-positions 3, 8, 13, and 17; two vinyl groups (-CH=CH₂) are located at positions 7 and 12; and two side chains (-CH₂CH₂COOH) are positioned at 2 and 18. The molecular formula of protoporphyrin IX is C34H34N4O4C_{34}H_{34}N_4O_4, reflecting these groups integrated into the scaffold. This arrangement results in an asymmetric structure, corresponding to the IX as established by Hans synthesis and , where the sequential order of substituents around the ring—propionate-methyl on rings A and D, and vinyl-methyl on rings B and C—distinguishes it from other possible stereoisomers. The extended conjugated π-system inherent to the core enables protoporphyrin IX to exhibit strong , with emission typically in the red region of the upon excitation. In standard depictions, the molecule is illustrated as a flat, symmetric-looking ring in 2D projections, with numbered positions (1 through 20 for the perimeter carbons) clearly marking the locations of the methyl, vinyl, and substituents to highlight the IX-specific asymmetry.

Physical and Chemical Properties

Physical Properties

Protoporphyrin IX appears as a dark to crystalline solid. The molecular weight of protoporphyrin IX is 562.66 g/mol, and its estimated is approximately 1.18 g/cm³. Protoporphyrin IX is insoluble in , with an estimated of approximately 0.1–0.2 mg/mL at 25°C, but it dissolves readily in organic solvents such as , , , acetone, and DMSO; it also forms more soluble disodium or dipotassium salts in basic conditions. The compound decomposes at temperatures above 300°C without a distinct melting point. In terms of spectroscopic properties, protoporphyrin IX exhibits characteristic UV-Vis absorption with a strong Soret band at approximately 404–406 nm and weaker Q bands at around 505, 535, 575, and 605 nm; it displays strong red fluorescence under UV excitation, with a primary emission peak at about 635 nm.

Chemical Properties

Protoporphyrin IX exhibits weakly acidic properties primarily due to its two side chains, with pKa values approximately 4.9 and 5.0, enabling the formation of salts such as the disodium salt under basic conditions. At physiological , these carboxyl groups are largely deprotonated, conferring a net negative charge that influences and interactions with proteins. The compound is notably unstable when exposed to and oxygen, undergoing through the generation of (ROS) upon absorbing visible , which leads to oxidative breakdown of the ring. This results in over 50% degradation within two hours under ambient conditions in plasma, whereas storage in the dark under inert atmospheres maintains stability. In coordination chemistry, the four central atoms of the act as chelating sites, forming stable complexes with divalent metal ions such as Fe²⁺ and Mg²⁺ through axial and equatorial bonding, which enhances the rigidity and electronic properties of the structure. These interactions are driven by the lone pairs on the nitrogens coordinating to the metal center, resulting in high formation constants for the metalloporphyrins.

Biosynthesis

Pathway in Animals and Microbes

The biosynthesis of protoporphyrin IX (PPIX) in animals occurs primarily through the heme biosynthetic pathway, a conserved process spanning mitochondrial and cytosolic compartments that ultimately yields PPIX as the immediate precursor to heme. This pathway begins in the mitochondria with the condensation of glycine and succinyl-CoA to form δ-aminolevulinic acid (ALA), catalyzed by ALA synthase (ALAS), which requires pyridoxal 5'-phosphate (PLP) as a cofactor; the reaction is represented as: Succinyl-CoA+Glycine+H2O→ALAS, PLP5-Aminolevulinic acid (ALA)+CoA+CO2\text{Succinyl-CoA} + \text{Glycine} + \text{H}_2\text{O} \xrightarrow{\text{ALAS, PLP}} \text{5-Aminolevulinic acid (ALA)} + \text{CoA} + \text{CO}_2
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