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Protoporphyrin IX

Protoporphyrin IX (PPIX) is a naturally occurring porphyrin, a cyclic tetrapyrrole compound that functions as the immediate precursor to heme in the biosynthetic pathway of heme, the iron-containing prosthetic group essential for oxygen transport in hemoglobin and various enzymatic functions in cytochromes.^[1] With the molecular formula C₃₄H₃₄N₄O₄ and a molecular weight of 562.7 g/mol, PPIX features a macrocyclic structure composed of four pyrrole rings linked by methine bridges, substituted with four methyl groups, two vinyl groups, and two propionic acid side chains at the β-positions.^[1] This arrangement allows it to chelate metal ions, particularly iron, to form metalloporphyrins critical for biological processes.^[2] In biosynthesis, PPIX is produced in the mitochondria through the heme synthesis pathway, starting from glycine and succinyl-CoA 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.^[3] Its levels are tightly regulated by ferrochelatase, the enzyme that inserts iron to produce heme; disruptions in this regulation lead to PPIX accumulation.^[2] Biologically, PPIX serves as a branch point in tetrapyrrole metabolism, directing toward heme in animals for oxygen binding, electron transfer, and catalysis, or toward chlorophyll in plants and photosynthetic bacteria for light-harvesting.^[3] Medically, PPIX plays dual roles: its accumulation due to ferrochelatase deficiencies causes erythropoietic protoporphyria (EPP), resulting in severe photosensitivity, skin damage from reactive oxygen species upon light exposure, and potential hepatobiliary complications like gallstones or liver failure.^[2] Conversely, its photosensitizing properties—generating singlet oxygen and other reactive species under light activation—make it valuable in photodynamic therapy (PDT), where administration of ALA induces PPIX buildup in target tissues for selective destruction of cancer cells or pathogens, with FDA approval for treating actinic keratosis and investigational use for other conditions including certain cancers.^[2] Emerging applications also include fluorescence-based imaging, biosensing for metal ions and biomolecules, and synthetic catalysis using modified PPIX derivatives.^[3]

Structure and Nomenclature

Nomenclature

Protoporphyrin IX derives its name from the systematic classification of porphyrins developed by German chemist Hans Fischer in the early 20th century, as part of his pioneering work on the structures of blood and plant pigments that earned him the 1930 Nobel Prize in Chemistry. Fischer first isolated and characterized protoporphyrin from heme by removing the iron atom, establishing it as the core organic component of hemoglobin.^[4] The prefix "proto-" reflects the compound's role as the foundational or primitive member of the porphyrin series with a specific substitution pattern, featuring four methyl groups, two vinyl groups, and two propionic acid side chains arranged on the tetrapyrrole macrocycle. The Roman numeral "IX" designates the particular isomeric configuration of these substituents, which Fischer identified as the ninth in a series of synthesized protoporphyrin isomers and the one predominant in natural biological systems, such as heme biosynthesis.^[5]^[6] 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 porphyrin ring.^[1]

Molecular Structure

Protoporphyrin IX is a porphyrin derivative characterized by a core tetrapyrrole macrocycle, consisting of four pyrrole rings linked together at their α-positions by four methine bridges (-CH=), forming a fully conjugated 18 π-electron aromatic system.^[1] This planar ring structure, with nitrogen atoms at positions 21, 22, 23, and 24 coordinating a central cavity, provides the foundational architecture for its biological roles as a heme precursor.^[7] The molecule's overall planarity, except for slight out-of-plane bending of the N-H bonds, facilitates extensive delocalization of electrons across the macrocycle.^[1] 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 propionic acid side chains (-CH₂CH₂COOH) are positioned at 2 and 18.^[1] The molecular formula of protoporphyrin IX is C_{34}H_{34}N_4O_4, reflecting these groups integrated into the porphyrin scaffold.^[1] This arrangement results in an asymmetric structure, corresponding to the IX isomer as established by Hans Fischer's synthesis and nomenclature, 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.^[7] The extended conjugated π-system inherent to the porphyrin core enables protoporphyrin IX to exhibit strong fluorescence, with emission typically in the red region of the spectrum upon excitation.^[8] 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 propionic acid substituents to highlight the IX-specific asymmetry.^[1]

Physical and Chemical Properties

Physical Properties

Protoporphyrin IX appears as a dark purple to red crystalline solid.^[9]^[10] The molecular weight of protoporphyrin IX is 562.66 g/mol, and its estimated density is approximately 1.18 g/cm³.^[10]^[1] Protoporphyrin IX is insoluble in water, with an estimated solubility of approximately 0.1–0.2 mg/mL at 25°C, but it dissolves readily in organic solvents such as chloroform, methanol, pyridine, acetone, and DMSO; it also forms more soluble disodium or dipotassium salts in basic conditions.^[1]^[9]^[10] The compound decomposes at temperatures above 300°C without a distinct melting point.^[10] 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.^[11]^[12]

Chemical Properties

Protoporphyrin IX exhibits weakly acidic properties primarily due to its two propionic acid side chains, with pKa values approximately 4.9 and 5.0, enabling the formation of salts such as the disodium salt under basic conditions.^[13] At physiological pH, these carboxyl groups are largely deprotonated, conferring a net negative charge that influences solubility and interactions with proteins.^[14] The compound is notably unstable when exposed to light and oxygen, undergoing photodegradation through the generation of reactive oxygen species (ROS) upon absorbing visible light, which leads to oxidative breakdown of the porphyrin ring.^[15] This photosensitivity results in over 50% degradation within two hours under ambient light conditions in plasma, whereas storage in the dark under inert atmospheres maintains stability.^[16] In coordination chemistry, the four central nitrogen atoms of the porphyrin macrocycle 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.^[17] These interactions are driven by the lone pairs on the nitrogens coordinating to the metal center, resulting in high formation constants for the metalloporphyrins.^[18]

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:

\text{Succinyl-CoA} + \text{Glycine} + \text{H}_2\text{O} \xrightarrow{\text{ALAS, PLP}} \text{5-Aminolevulinic acid (ALA)} + \text{CoA} + \text{CO}_2

This step is rate-limiting and commits precursors to the pathway.^[19] In the cytosol, two molecules of ALA are condensed to form porphobilinogen (PBG) by ALA dehydratase (ALAD), a zinc-dependent enzyme. Four PBG units are then polymerized into hydroxymethylbilane (HMB) by hydroxymethylbilane synthase (also known as porphobilinogen deaminase), followed by cyclization and rearrangement to uroporphyrinogen III via uroporphyrinogen III synthase, which inverts the D-ring to produce the asymmetric isomer required for further steps. Uroporphyrinogen III is decarboxylated stepwise by uroporphyrinogen decarboxylase to coproporphyrinogen III, removing four acetate groups to yield four methyl propionate side chains.^[19] The pathway returns to the mitochondria for the final stages: coproporphyrinogen III is oxidized to protoporphyrinogen IX by coproporphyrinogen oxidase, an oxygen-dependent enzyme acting on the propionate side chains. Protoporphyrinogen IX is then dehydrogenated to PPIX by protoporphyrinogen oxidase, a flavin-dependent enzyme that introduces six double bonds, resulting in the characteristic conjugated tetrapyrrole structure. Overall, eight molecules of ALA are required to synthesize one molecule of PPIX.^[19] Regulation of the pathway in animals is primarily exerted at the ALAS step through feedback inhibition by heme, which binds to ALAS and prevents its import into mitochondria, thereby reducing ALA production; this mechanism operates in non-erythroid tissues, while erythroid-specific ALAS2 is additionally controlled by iron availability and transcriptional factors like GATA1.^[19] In microbes, particularly bacteria, the core pathway from ALA to PPIX mirrors that in animals via the protoporphyrin-dependent (PPD) branch, involving the same sequence of intermediates and enzymes such as coproporphyrinogen oxidase and protoporphyrinogen oxidase to yield PPIX before iron insertion by ferrochelatase. However, bacterial ALA synthesis often utilizes the glutamyl-tRNA pathway instead of the glycine-succinyl-CoA route: glutamate is attached to tRNA, reduced to glutamate-1-semialdehyde by glutamyl-tRNA reductase, and transaminated to ALA by glutamate-1-semialdehyde-2,1-aminomutase, though some bacteria employ the animal-like C4 pathway. Certain Gram-positive bacteria diverge via the coproporphyrin-dependent (CPD) branch, bypassing PPIX by oxidizing coproporphyrinogen III directly to coproporphyrin III, inserting iron to form coproheme III, and decarboxylating to heme without forming PPIX.^[20]

Variations in Plants and Stress Responses

In plants, protoporphyrin IX (PPIX) biosynthesis proceeds via the C5 pathway, initiating from glutamate that is activated to glutamyl-tRNA by glutamyl-tRNA synthetase and subsequently reduced by glutamyl-tRNA reductase (GluTR) to form glutamate-1-semialdehyde, which is then converted to 5-aminolevulinic acid (ALA).^[21] This route differs from the C4 pathway in animals, which relies on δ-aminolevulinic acid synthase to combine glycine and succinyl-CoA for ALA production.^[22] ALA then advances through common enzymatic steps—porphobilinogen synthase, hydroxymethylbilane synthase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase, coproporphyrinogen III oxidase, and protoporphyrinogen IX oxidase—to yield PPIX in plastids.^[23] From PPIX, the pathway branches in plants: magnesium chelatase inserts Mg²⁺ to form Mg-PPIX, the precursor for chlorophyll synthesis, which is further modified by Mg-protoporphyrin IX monomethyl ester cyclase and other enzymes to protochlorophyllide.^[24] Protochlorophyllide oxidoreductase (POR) then catalyzes the reduction of protochlorophyllide to chlorophyllide, a key step in chlorophyll formation.^[25] Alternatively, ferrochelatase incorporates Fe²⁺ into PPIX to produce heme, essential for cytochromes and other proteins.^[26] Under environmental stresses, plants modulate PPIX-derived intermediates to enhance tolerance and mitigate damage. Accumulation of Mg-PPIX serves as a plastid-to-nucleus retrograde signal, promoting cold tolerance by upregulating antioxidant enzymes such as superoxide dismutase, peroxidase, and ascorbate peroxidase, while maintaining redox balance through increased glutathione levels.^[27] In water-stressed conditions, sustained porphyrin levels, including controlled PPIX and Mg-PPIX accumulation, correlate with drought tolerance in transgenic rice by preventing excessive photooxidative damage from reactive oxygen species.^[28] Recent research highlights Mg-PPIX's role in abiotic stress responses via retrograde signaling; for instance, during drought (2025), Mg-PPIX modulation in arbuscular mycorrhizal symbioses enhances plant resilience by integrating with proline signaling pathways.^[29] Variations in PPIX regulation occur across plant lineages, particularly in the conversion of Mg-PPIX derivatives to chlorophyll. In higher plants like angiosperms, this process is predominantly light-dependent, relying on light-activated POR to reduce protochlorophyllide in the presence of light, which prevents accumulation of phototoxic intermediates in etiolated tissues.^[25] In contrast, algae, cyanobacteria, and some gymnosperms possess both light-dependent POR and light-independent dark operative POR (DPOR), enabling chlorophyll synthesis in the dark and providing flexibility in low-light or shaded environments.^[30]

Natural Occurrence and Biological Roles

Occurrence in Organisms

Protoporphyrin IX serves as the immediate precursor to heme in animals, where ferrochelatase inserts iron into the porphyrin ring to form heme, which is essential for oxygen transport in hemoglobin and electron transfer in cytochromes.^[31] In certain pathological conditions, such as erythropoietic protoporphyria, protoporphyrin IX accumulates due to deficiencies in ferrochelatase activity, leading to photosensitivity and tissue damage.^[32] In microorganisms, protoporphyrin IX acts as a key intermediate in both heme biosynthesis and the production of bacteriochlorophyll, the photosynthetic pigment in anoxygenic bacteria.^[33] For instance, in the purple nonsulfur bacterium Rhodobacter sphaeroides, protoporphyrin IX is utilized during aerobic respiration and anaerobic photosynthesis to synthesize heme for cytochromes and bacteriochlorophyll for light-harvesting complexes.^[34] Plants maintain protoporphyrin IX as a transient intermediate at the branch point between heme and chlorophyll biosynthesis pathways, with magnesium insertion directing it toward chlorophyll and iron insertion toward heme.^[35] Due to rapid enzymatic conversion by magnesium chelatase and ferrochelatase, steady-state levels of protoporphyrin IX remain low in healthy plant tissues, preventing potential phototoxicity from its accumulation.^[36] Protoporphyrin IX is deposited as a pigment in the eggshells of certain birds, particularly contributing to the brown coloration observed in chicken eggs, where it is secreted by the shell gland during eggshell formation.^[37] This pigment embeds in the eggshell's cuticular layer, providing visual characteristics without significant metabolic roles in the embryo.^[38] Under conditions of iron deficiency, zinc protoporphyrin forms as a substitute for heme in various organisms, where zinc is incorporated into protoporphyrin IX by ferrochelatase in place of iron, serving as a biomarker for impaired iron utilization.^[39] This substitution occurs in erythrocytes and other tissues, reflecting functional iron deficiency even when serum iron levels appear normal.^[40]

Environmental Distribution

Protoporphyrin IX (PPIX) is ubiquitous in aquatic environments, particularly as a microbial byproduct in marine sediments and water columns, where it contributes to biogeochemical cycles such as carbon and nitrogen processing through its role in heme and chlorophyll synthesis.^[41] In estuarine and coastal waters, such as the Jiulong River Estuary and Xiamen Bay, PPIX concentrations range from 43 to 591 pM, with higher levels observed in the upper estuary during summer months due to nutrient-rich conditions favoring microbial production.^[41] These distributions highlight PPIX's presence as a dissolved and particulate component, often correlating positively with organic matter and chlorophyll-a derivatives.^[42] In soil and sediments, PPIX accumulates from the decay of organisms, forming geoporphyrins during diagenesis, and serves as a potential biomarker for environmental stress or pollution through microbial transformations.^[43] Concentrations in coastal sediments typically range from 7.38 to 91.33 ng/g, showing greater spatial variation than seasonal changes, with distinct patterns in brackish versus saltwater environments.^[44] This accumulation reflects past biological inputs and can indicate alterations in sedimentary organic matter dynamics influenced by anthropogenic inputs.^[43] Recent research from 2023 to 2025 has emphasized microbial PPIX in ocean ecosystems as a tracer for metabolic activity, with studies quantifying its distribution in water samples (20–170 ng/L) and linking it to microbial community composition via 16S rRNA analysis.^[42]^[41] Vertical profiles in coastal sediment cores reveal decreasing PPIX with depth, underscoring its role in sedimentology and microbial ecology.^[45] These findings demonstrate how PPIX patterns correlate with oxygen levels, aiding in the assessment of metabolic processes in low-oxygen marine zones.^[41] PPIX acts as a precursor in environmental porphyrin degradation pathways, where microbial uptake and transformation, such as by bacteria like Pseudomonas stutzeri, deplete sedimentary complexes like cobalt protoporphyrin.^[43] Spatio-temporal factors significantly influence PPIX distribution, with elevated levels in hypoxic zones due to shifts in microbial respiration and heme-related metabolism.^[41] Concentrations are modulated by pH, which affects microbial activity, and metal availability (e.g., Fe²⁺ and Mg²⁺), essential for PPIX incorporation into prosthetic groups.^[41] In estuarine systems, PPIX decreases linearly with increasing salinity, reflecting transitions from freshwater to marine influences.^[42] A 2024 study on Prorocentrum donghaiense blooms revealed PPIX's role in influencing bacterial communities with different lifestyles, highlighting its ecological interactions during phytoplankton events.^[46]

Derivatives

Metalloprotoporphyrin Complexes

Metalloprotoporphyrin complexes form when divalent or trivalent metal ions are chelated into the central cavity of protoporphyrin IX, coordinating with the four nitrogen atoms of the pyrrole rings to create a planar tetrapyrrole structure. This insertion typically occurs enzymatically in biological systems, such as via ferrochelatase for iron or magnesium chelatase for magnesium, and alters the electronic properties of the porphyrin ring, including shifts in UV-visible absorption spectra due to metal-ligand interactions. In many cases, these complexes exhibit axial ligation, where additional ligands bind perpendicular to the porphyrin plane; for instance, in heme proteins, a histidine residue often serves as the proximal axial ligand to the iron center, stabilizing the complex and facilitating biological functions.^[47]^[48]^[49] The most prominent metalloprotoporphyrin is heme, the iron(II) complex of protoporphyrin IX, where Fe²⁺ occupies the central position. Heme is essential as a prosthetic group in hemoproteins, particularly hemoglobin and myoglobin, where it enables reversible oxygen binding and transport in vertebrates by coordinating O₂ at one axial position while the opposite site is ligated by a protein residue such as histidine. In hemoglobin, this facilitates cooperative oxygen delivery from lungs to tissues, while in myoglobin, it supports oxygen storage in muscle cells. The incorporation of iron into protoporphyrin IX occurs via ferrochelatase in the final step of heme biosynthesis, ensuring tight regulation to prevent oxidative damage from free porphyrins.^[47]^[50]^[51] Under iron-deficient conditions, zinc protoporphyrin IX (Zn-PPIX) accumulates as zinc(II) substitutes for iron during chelation, serving as a biomarker for iron deficiency anemia in animals. This complex forms when ferrochelatase inserts Zn²⁺ into protoporphyrin IX due to limited iron availability, leading to elevated levels in erythrocytes and impaired heme synthesis. In both plants and animals, Zn-PPIX exhibits antioxidant properties by modulating oxidative stress responses, such as inhibiting heme oxygenase-1 to reduce reactive oxygen species and attenuate ferroptosis, thereby providing cytoprotection during nutrient stress.^[52]^[53] Magnesium protoporphyrin IX (Mg-PPIX) represents a key branch point in tetrapyrrole biosynthesis, acting as an intermediate in chlorophyll production in plants and photosynthetic bacteria. The enzyme magnesium chelatase catalyzes the insertion of Mg²⁺ into protoporphyrin IX, diverting the pathway from heme toward chlorophyll synthesis and committing the molecule to light-harvesting roles in photosynthesis. This complex lacks strong axial ligation in its free form but integrates into larger pigment structures, with its accumulation often regulated to balance photosynthetic efficiency.^[54] These complexes generally display modified absorption spectra compared to free protoporphyrin IX, with the Soret band—a intense peak around 400 nm—shifting based on the metal and ligation state; for example, heme in ferric form shows a prominent Soret band at 418 nm, reflecting the influence of iron coordination and protein environment on electronic transitions.^[55]

Synthetic and Modified Derivatives

Protoporphyrin IX (PpIX) can be synthesized through total synthetic routes involving the coupling of unsymmetrical diiodo dipyrrylmethane intermediates with known dipyrrylmethane precursors, enabling the construction of the porphyrin macrocycle in high yield. Alternatively, direct modifications of commercially available PpIX dimethyl ester allow for the preparation of functionalized derivatives; for instance, selective reduction of the vinyl groups yields porphyrin alcohols, while ozonolysis followed by reductive workup produces aldehydes, providing handles for further conjugation.^[56] These methods facilitate the attachment of substituents to the vinyl or propionate side chains, such as through hydrobromination of vinyl groups followed by nucleophilic substitution or metal-catalyzed cross-coupling reactions like olefin metathesis and Heck coupling.^[57] The disodium salt of PpIX, known commercially as palepron, is a key synthetic derivative that addresses the poor water solubility of the parent compound, making it suitable for laboratory solubilization and biochemical assays.^[58] This salt form, with a molecular weight of 606.6 g/mol, is readily available from chemical suppliers and exhibits enhanced aqueous stability compared to the free acid.^[59] Amphiphilic derivatives of PpIX have been developed recently to improve delivery in photodynamic therapy (PDT), featuring polyethylene glycol (PEG) 550 headgroups attached to hydrophobic or fluorinated alkyl tails (4-10 carbons) for balanced solubility and cellular uptake.^[60] These compounds are synthesized in a four-step process involving hydrobromination of PpIX vinyl groups followed by coupling with PEG and tail moieties, yielding water-soluble products with hydrophilic-lipophilic balance values of 12.14-18.75.^[60] Derivatives with fluorinated tails, such as those incorporating perfluoroalkyl chains, demonstrate enhanced photostability and reduced photobleaching during irradiation, alongside improved singlet oxygen generation and photocytotoxicity against tumor cell lines like 4T1 and WiDr compared to unmodified PpIX.^[60]^[61] Halogenated PpIX variants, particularly those with fluorinated substituents on the side chains, exhibit superior photostability in therapeutic contexts by minimizing auto-oxidation and photodegradation pathways, thereby sustaining reactive oxygen species production over extended light exposure.^[61] These modifications leverage the heavy atom effect to promote intersystem crossing, enhancing triplet state population and PDT efficiency without compromising bioavailability.^[62] PpIX conjugates with nanoparticles, such as gold nanoparticles (AuNPs), enable targeted delivery by encapsulating the hydrophobic photosensitizer on the nanoparticle surface, improving cellular internalization and PDT efficacy in cancer models.^[63] Covalent or electrostatic linkages form stable PpIX-AuNP assemblies, with particle sizes around 20-100 nm facilitating enhanced permeability and retention in tumors.^[64] For antibody-mediated targeting, PpIX-loaded nanoparticles can be functionalized with monoclonal antibodies to achieve specificity toward overexpressed receptors on cancer cells, such as in lung or breast malignancies, thereby reducing off-target effects.^[65]

Clinical and Therapeutic Applications

Photodynamic Therapy

Protoporphyrin IX (PpIX) serves as an endogenous photosensitizer in photodynamic therapy (PDT), where administration of 5-aminolevulinic acid (5-ALA) induces its selective accumulation in tumor cells through the heme biosynthesis pathway. Tumor cells exhibit upregulated porphyrin synthesis due to reduced ferrochelatase activity and limited iron availability, leading to PpIX buildup primarily in mitochondria. Upon illumination with light at approximately 630 nm, excited PpIX transfers energy to molecular oxygen, generating singlet oxygen and other reactive oxygen species (ROS) that damage cellular components, including membranes, proteins, and DNA, ultimately triggering apoptosis or necrosis in targeted cells.^[66] This mechanism underpins PpIX-mediated PDT applications in treating superficial malignancies, such as actinic keratosis and basal cell carcinoma, where topical 5-ALA application followed by red light exposure achieves high clearance rates with minimal scarring. In deeper tumors like glioblastoma, systemic 5-ALA enables intraoperative PDT to ablate residual malignant tissue after resection, improving survival outcomes in phase I/II trials by enhancing tumor cell killing without significant neurotoxicity. For prostate cancer, interstitial 5-ALA-PDT has demonstrated rapid ROS-mediated cytotoxicity in preclinical models of localized disease, with early clinical studies showing feasibility for focal therapy in recurrent cases post-radiotherapy.^[67]^[68]^[66] Recent advances from 2023 to 2025 have focused on overcoming resistance in heterogeneous tumor populations, with 5-ALA-PDT showing doubled efficacy against glioma stem cells by exploiting upregulated transporters like PEPT2 and PPOX, as demonstrated in spheroid models resistant to chemotherapy. In prostate cancer, PpIX accumulation in dormant PC-3 cells linked to altered lipid metabolism has enhanced PDT sensitivity, targeting quiescent populations that evade conventional treatments. Combination strategies, such as pairing 5-ALA with MEK inhibitors, boost PpIX levels by inhibiting the MEK/ERK signaling pathway, amplifying ROS production and therapeutic response in glioblastoma models.^[67]^[69]^[70] The primary advantages of PpIX-based PDT include its tumor selectivity, which minimizes damage to surrounding healthy tissue, and its minimally invasive nature, often requiring only outpatient light exposure for skin lesions. Unlike systemic chemotherapies, it avoids broad immunosuppression, making it suitable for elderly patients with actinic keratosis.^[66]^[67] Challenges persist, including PpIX's poor aqueous solubility, which limits delivery and causes accumulation saturation above 1 mM concentrations, often addressed through lipophilic derivatives or nanoparticle encapsulation. Prolonged photosensitivity post-treatment can cause skin reactions lasting weeks, necessitating strict light avoidance protocols. Variability in patient PpIX production due to metabolic differences also complicates dosing, though ongoing trials in glioblastoma and prostate cancer are refining protocols with inhibitors to enhance uniformity and efficacy.^[67]^[68]

Diagnostic and Surgical Uses

Protoporphyrin IX (PPIX) plays a pivotal role in fluorescence-guided surgery, particularly for high-grade gliomas such as glioblastoma, where it is induced by the administration of 5-aminolevulinic acid (5-ALA), a precursor in the heme biosynthesis pathway. Upon oral intake of 5-ALA, tumor cells preferentially accumulate PPIX due to their disrupted metabolic regulation, leading to visible red fluorescence under blue-violet light excitation during resection procedures. This technique enhances the surgeon's ability to delineate tumor margins, improving the extent of safe tumor removal compared to white-light surgery alone. In Europe, 5-ALA (marketed as Gliolan) has been approved by the European Medicines Agency since 2007 for visualizing malignant glioma tissue in adults.^[71] The U.S. Food and Drug Administration granted approval in 2017 for similar use in patients with glioblastoma undergoing resection.^[72] The red fluorescence of PPIX, peaking at approximately 635 nm and 705 nm, allows for real-time distinction between healthy and cancerous tissue, as normal brain tissue exhibits minimal accumulation and thus low fluorescence. This contrast aids in reducing residual tumor volume, with studies showing improved progression-free survival in patients undergoing fluorescence-guided resection. Beyond neurosurgery, PPIX fluorescence supports diagnostics in dermatology, where topical 5-ALA application induces detectable emission in basal cell carcinoma lesions, enabling non-invasive margin assessment prior to excision.^[73] In gastrointestinal applications, emerging endoscopic techniques use systemic or local 5-ALA to highlight premalignant and malignant lesions in the upper GI tract, such as esophageal and gastric cancers, facilitating targeted biopsies and early detection.^[74] Recent advancements from 2023 to 2025 have expanded PPIX's diagnostic utility, including its integration into liquid biopsy approaches for non-invasive glioma monitoring. Elevated serum PPIX levels post-5-ALA administration correlate with high-grade glioma presence, offering a potential biomarker for disease tracking without surgical intervention.^[75] Enhanced imaging technologies, such as hyperspectral imaging combined with mass spectrometry, have improved PPIX detection sensitivity in tumor tissue, overcoming spectral overlaps for more precise intraoperative quantification.^[76] Despite these benefits, PPIX-based fluorescence faces limitations, including interference from tissue autofluorescence, which can obscure weak tumor signals and reduce specificity in low-PpIX-accumulating regions. Quantification challenges arise from variability in excitation light penetration and photobleaching, necessitating advanced spectroscopic corrections to ensure reliable measurements.^[77]

History

Early Discovery and Isolation

The discovery of protoporphyrin IX emerged from investigations into the reddish pigments observed in the urine of patients with porphyria, a condition first clinically described in the late 19th century by figures such as Johann Schultz in 1874, who noted intermittent attacks accompanied by dark urine.^[78] These early observations linked the pigments to metabolic disorders, prompting chemical analyses of urine and blood to identify the responsible compounds.^[78] In 1904, David Laidlaw conducted pioneering work on blood pigments, isolating a porphyrin compound from mixtures derived from urine and animal tissues during experiments involving hematin reduction.^[79] His methods included acid treatment and extraction to separate pigments, yielding a substance later recognized as protoporphyrin IX, though not explicitly named at the time; this isolation built on prior hematin studies from animal sources, such as those by Felix Hoppe-Seyler in 1871, who extracted related iron-containing pigments from blood.^[79]^[78] Hans Fischer advanced the field significantly between 1915 and the 1930s through systematic classification of porphyrins obtained from heme degradation in animal tissues and porphyric urine. In 1915, he isolated and characterized uroporphyrin from a porphyria patient, distinguishing it from other pigments.^[78] By the mid-1920s, Fischer proposed the nomenclature "protoporphyrin" for the naturally occurring porphyrin derived from heme, specifically designating the isomer as protoporphyrin IX after synthesizing multiple variants; this work, culminating in his 1929 synthesis of hemin, solidified its identity as a key heme precursor.^[78]

Structural Determination and Key Developments

The structural elucidation of protoporphyrin IX began in the early 1920s through the work of German chemist Hans Fischer, who isolated and characterized the porphyrin core from heme, identifying it as a tetrapyrrole macrocycle with specific vinyl and methyl substituents characteristic of protoporphyrin IX.^[80] Fischer's team progressively degraded heme derivatives to confirm the asymmetric arrangement of substituents on the pyrrole rings, culminating in the full structural proposal for protoporphyrin IX by 1926.^[7] In a landmark achievement, Fischer achieved the total synthesis of protoporphyrin IX in 1929, followed by the synthesis of hemin (iron-protoporphyrin IX) in the same year, which required assembling four pyrrole units via bilene intermediates under acidic conditions.^[81] This synthetic confirmation validated the proposed structure and earned Fischer the Nobel Prize in Chemistry in 1930 for his pioneering work on the constitutions of haemin and chlorophyll, emphasizing the synthesis of haemin as a key contribution.^[82] Following World War II, advances in understanding protoporphyrin IX's biosynthesis accelerated, particularly through isotopic labeling studies that mapped its enzymatic formation. In the early 1950s, biochemist David Shemin and colleagues at Columbia University discovered 5-aminolevulinic acid (ALA) as the committed precursor in the heme biosynthetic pathway, using radioactively labeled glycine and succinate in avian erythrocytes to trace the condensation steps leading to porphobilinogen and ultimately protoporphyrin IX.^[83] By the 1950s, Shemin's group and others had delineated the full linear pathway, identifying enzymes such as ALA synthase, porphobilinogen deaminase, and uroporphyrinogen decarboxylase, with protoporphyrin IX emerging as the final non-metalated intermediate before ferrochelatase insertion of iron.^[84] These findings shifted focus from purely chemical synthesis to biological regulation, revealing feedback inhibition by heme on ALA synthase as a control mechanism for protoporphyrin IX accumulation.^[85] In the 1960s, protoporphyrin IX was firmly established as a branch point intermediate in chlorophyll biosynthesis, linking heme and photosynthetic pigment pathways across eukaryotes and bacteria. Studies on Chlorella and barley mutants demonstrated that magnesium insertion into protoporphyrin IX by Mg-chelatase diverts it toward protochlorophyllide, with isotopic experiments confirming the shared early steps from ALA up to this divergence.^[86] This identification resolved long-standing questions about pigment homology and highlighted evolutionary conservation, as protoporphyrin IX's structure allows chelation of either iron for heme or magnesium for chlorophyll.^[87] Research in the 1980s deepened insights into protoporphyrin's pathological roles, particularly in porphyrias, where its accumulation due to ferrochelatase deficiencies causes photosensitization. Biochemical analyses of erythropoietic protoporphyria (EPP) patients revealed elevated free protoporphyrin IX in erythrocytes and skin, triggering oxidative damage upon light exposure via singlet oxygen generation.^[31] Enzymatic and genetic studies during this period mapped partial deficiencies in the terminal pathway, establishing protoporphyrin IX as a biomarker for EPP diagnosis and linking its lipophilic properties to hepatic and biliary complications.^[88] Recent developments up to 2025 have leveraged genomics to dissect protoporphyrin IX biosynthetic regulation, identifying key gene variants and regulatory networks. Genetic analyses of EPP cohorts have uncovered mutations in the FECH gene encoding ferrochelatase, with over 220 variants correlated to protoporphyrin IX buildup and disease severity.^[89] Concurrently, metabolic engineering studies optimized microbial pathways, achieving high-yield protoporphyrin IX production in E. coli by overexpressing hem genes while mitigating toxicity through efflux pumps.^[90] In therapeutic milestones, 5-ALA-induced protoporphyrin IX accumulation gained expanded approvals for photodynamic therapy (PDT), including FDA clearance in 2017 for fluorescence-guided resection in high-grade gliomas and ongoing trials for non-muscle invasive bladder cancer as of 2025.^[91]

References

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protoporphyrin IX | C34H34N4O4 | CID 4971 - PubChem
It has a role as a photosensitizing agent, a metabolite, an Escherichia coli metabolite and a mouse metabolite. It is a conjugate acid of a protoporphyrinate ...Missing: significance | Show results with:significance
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319466/
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https://www.nobelprize.org/prizes/chemistry/1930/fischer/lecture/
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Porphyrins and the Porphyrias | Veterian Key
Jul 15, 2017 · The nomenclature of the enzymes of porphyrin synthesis varies among authors, so a guide to the nomenclature of the enzymes is provided in Table ...
[6]
Chemical Manipulation of the Vinyl Groups in Protoporphyrin-IX
The type-IX orientation of substituents is that name given by Hans Fischer to the arrangement common to all natural heme and chlorophyll pigments;3 in the case ...
[7]
[PDF] Hans Fischer - Nobel Lecture
The constitution of the latter compound, and of the three porphyrins mentioned, was subsequently practically completely clarified by synthetic means.Missing: etymology | Show results with:etymology
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Fluorescence Spectroscopy of Porphyrins and Phthalocyanines
Fluorescence spectroscopy of porphyrins and phthalocyanines: some insights into supramolecular self-assembly, microencapsulation, and imaging microscopy.
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https://www.sigmaaldrich.com/US/en/product/sigma/p8293
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Protoporphyrin IX | 553-12-8 - ChemicalBook
Protoporphyrin IX ; Molecular Formula: C34H34N4O4 ; Molecular Weight: 562.66 ; MDL Number: MFCD00151109 ; MOL File: 553-12-8.mol ; MSDS File: SDS.
[11]
Photophysical Properties of Protoporphyrin IX, Pyropheophorbide-a ...
As expected, UV-visible absorption spectra of PpIX (Figure 2A) exhibited an intense Soret band centered at around 406 nm and four weaker Q bands in the visible ...
[12]
Identification of excimer delayed fluorescence by Protoporphyrin IX
We can see the main absorption peak at 405 nm (Soret band) and the subpeaks at 506, 539, 575 and 630 nm (Q-bands). Concerning emission, two main peaks at 630 ...
[13]
https://doi.org/10.1016/S0006-3061(00)80023-X
[14]
Effects of serum albumin on the photophysical characteristics ... - NIH
The pKa of PpIXs is 4.94 (33). There are three points of possible protonation in the PpIXs structure. However, the porphyrin ring structure is the main factor, ...
[15]
Protoporphyrin IX: the Good, the Bad, and the Ugly - PMC - NIH
Its tetrapyrrole structure enables it to chelate transition metals to form metalloporphyrins, which perform a variety of biologic functions.Missing: chemical | Show results with:chemical
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Protoporphyrin IX plasma and blood pharmacokinetics and brain ...
Jul 1, 2025 · Protoporphyrin IX (PPIX) is a fundamental intermediate in the heme biosynthesis pathway with significant roles in various medical applications ...
[17]
Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded ...
Jan 12, 2023 · In turn, both Fe2+-loaded and Zn2+-loaded frataxins specifically associate to protoporphyrin IX with micromolar affinity, while apo-frataxin ...
[18]
Formation of the Metal Complexes between Protoporphyrin IX and ...
The formation constant (Kf) of the metal protoporphyrin IX complexes reacted with Cu2+, Zn2+, Fe2+ in acetonitrile-water mixture solution (1∶1v/v) were found to ...
[19]
The enzymic conversion of protoporphyrinogen IX to ... - PubMed
Feb 25, 1975 · The oxidation of protoporphyrinogen IX to protoporphyrin IX in yeast cells is enzyme-dependent. The enzyme, protoporphyrinogen oxidase ...Missing: chemical mechanism
[20]
Protoporphyrinogen Oxidase - an overview | ScienceDirect Topics
PROTO'GEN IX is oxidized to protoporphyrin IX (PROTO IX) by the enzyme protoporphyrinogen oxidase (PPO) (Fig. 9). The six electron oxidation requires oxygen as ...
[21]
https://pmc.ncbi.nlm.nih.gov/articles/PMC520805/
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https://pmc.ncbi.nlm.nih.gov/articles/PMC2895239/
[23]
Gene Expression Profiling of the Tetrapyrrole Metabolic Pathway in ...
This pathway, the so-called C5 pathway, starts at glutamyl-tRNAGlu, and the subsequently formed 5-aminolevulinic acid (ALA) is metabolized to form tetrapyrroles ...
[24]
Structure and function of enzymes in heme biosynthesis - PMC
The initial substrate of the C5-pathway, glutamyl-tRNA, is provided by glutamyl-tRNA synthetase and is shared between heme and protein biosyntheses.
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Post-translational control of tetrapyrrole biosynthesis in plants, algae ...
Structure and function of glutamyl-tRNA reductase, the first enzyme of tetrapyrrole biosynthesis in plants and prokaryotes. ,. Photosynthesis Research. ,. 2002.
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Mutation in Mg-Protoporphyrin IX Monomethyl Ester (Oxidative ...
Jul 6, 2022 · Researchers have identified two different ALA synthesis pathways, including the C4 pathway and C5 pathway (involved in the chlorophyll branch), ...
[27]
Plant Protochlorophyllide Oxidoreductases A and B - NIH
The enzyme protochlorophyllide oxidoreductase (POR, EC 1.3.1.33) has a key role in plant development. It catalyzes one of the later steps in chlorophyll ...
[28]
Post-translational regulation of metabolic checkpoints in plant ...
Apart from its contribution to retrograde signaling, GUN4 protein binds protoporphyrin and Mg protoporphyrin, and stimulates Mg chelation by interacting with ...
[29]
Mg-Protoporphyrin IX Signals Enhance Plant's Tolerance to Cold ...
Recent studies showed that Mg-Proto-IX-derived signals strongly regulate plant resistance to environmental stresses (Zhang et al., 2015). Mg-Proto IX signals ...Missing: PPIX pathogen
[30]
(PDF) Porphyrin Biosynthesis Control under Water Stress: Sustained ...
Aug 7, 2025 · Both transgenic and wild-type plants responded to the onset of drought stress, even prior to changes in shoot water potential and oxidative ...
[31]
Low temperature and high humidity affect dynamics of chlorophyll ...
Sep 30, 2024 · ... Mg-protoporphyrin IX (Mg-proto IX, G), Mg-protoporphyrin monomethyl ester (Mpe, H), and protochlorophyllide (Pchlide, I) content of cucumber ...
[32]
Arbuscular mycorrhizal symbiosis enhances the drought tolerance of ...
Sep 28, 2025 · The Mg-Protoporphyrin IX (Mg-Proto IX), Protoporphyrin IX (Proto IX) ... Proline, a multifaceted signalling molecule in plant responses to abiotic ...
[33]
Light-Dependent Protochlorophyllide Oxidoreductase: Phylogeny ...
POR catalyzes the penultimate reaction of chlorophyll biosynthesis, ie, the light-triggered reduction of protochlorophyllide to chlorophyllide.
[34]
Heme biosynthesis and the porphyrias - PMC - NIH
Heme is a term used for ferrous protoporphyrin IX (PPIX) that is easily oxidized in vitro to hemin, termed- ferric PPIX. In heme the ferrous iron atom (Fe2+) ...
[35]
A precursor-inducible zebrafish model of acute protoporphyria ... - NIH
Protoporphyria is a metabolic disease that causes excess production of protoporphyrin IX (PP-IX), the final biosynthetic precursor to heme. Hepatic PP-IX ...
[36]
Porphyrin Excretion Resulting From Mutation of a Gene Encoding a ...
Feb 22, 2019 · Protoporphyrinogen IX is converted by protoporphyrinogen IX oxidase to protoporphyrin IX, the precursor in common to both heme- and BChl- ...
[37]
Transcriptomic analysis of aerobic respiratory and anaerobic ... - NIH
... protoporphyrin IX for production of haem and bacteriochlorophyll (Fig. 4) ... RegA control of bacteriochlorophyll and carotenoid synthesis in Rhodobacter ...
[38]
Knock-out of the Magnesium Protoporphyrin IX Methyltransferase ...
Protoporphyrin IX is the last common intermediate between the heme and chlorophyll biosynthesis pathways. The addition of magnesium directs this molecule ...
[39]
Thiol-dependent degradation of protoporphyrin IX by plant ... - PubMed
Protoporphyrin IX (PP) is the last porphyrin intermediate in common between heme and chlorophyll biosynthesis. This pigment normally does not accumulate in ...
[40]
Eggshell color in brown-egg laying hens — a review - PMC
The major pigment in eggshells of brown-egg laying hens is protoporphyrin IX, but traces of biliverdin and its zinc chelates are also present.
[41]
Mechanisms associated with the depigmentation of brown eggshells
Highly fluorescent monomers of protoporphyrin IX (color pigment) are embedded in the cuticular layer of the brown eggshell in a protein phase and represent ...
[42]
Zinc protoporphyrin: A metabolite with a mission - PubMed
During periods of iron insufficiency or impaired iron utilization, zinc becomes an alternative metal substrate for ferrochelatase, leading to increased ZnPP ...
[43]
THE ZINC PROTOPORPHYRIN/HEME RATIO IN PREMATURE ...
Zinc protoporphyrin level reflects incomplete iron incorporation into protoporphyrin, as zinc substitutes for iron when supply is limited.
[44]
Spatio-temporal distribution characteristics and influencing factors of ...
Jan 7, 2024 · Protoporphyrin IX is a fundamental precursor for synthesizing of heme and chlorophyll in cells. •. Protoporphyrin IX is ubiquitous in aquatic ...
[45]
A new technique of quantifying protoporphyrin IX in microbial cells in ...
Sep 8, 2022 · Protoporphyrin IX (PPIX), a fundamental precursor in the synthesis of heme and chlorophyll, plays a vital role in the biological metabolism ...
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Sedimentary Cobalt Protoporphyrin as a Potential Precursor of ... - NIH
Dec 20, 2021 · One of the most important porphyrins is protoporphyrin IX (PPIX) (C34H34N4O4), which plays a crucial role in the metabolism of living organisms ...Missing: soil | Show results with:soil
[47]
Distribution and potential roles of microbial protoporphyrin IX in ...
Protoporphyrin IX (PPIX) is a precursor in porphyrin biosynthesis, necessary for microorganisms, and widely distributed in marine sediments, with spatial ...
[48]
Vertical distribution of intracellular protoporphyrin IX in coastal ...
This study highlighted the significance of PPIX in microbial ecology and its potential impact on biogeochemical cycles in marine sedimentary environments.
[49]
Persistent organic pollutants and porphyrin levels in excreta of ...
Sep 19, 2016 · We predicted that the levels of organic pollutants in excreta would correlate with those of porphyrins. Determining organic pollutant levels in ...<|control11|><|separator|>
[50]
Biochemistry, Heme Synthesis - StatPearls - NCBI Bookshelf
Heme is a porphyrin ring complexed with ferrous iron and protoporphyrin IX. Heme is an essential prosthetic group in proteins that is necessary as a subcellular ...Missing: complex | Show results with:complex
[51]
[PDF] DETERMINANTS OF AXIAL HEME LIGATION IN GROUP I ...
Heme uses four pyrrole nitrogens to coordinate iron in a square planar geometry, ... pyrrole nitrogens of the porphyrin. Endogenous hexacoordination is observed ...
[52]
Structural Adaptability Facilitates Histidine Heme Ligation in a ... - NIH
The hemes are superimposable in the Cys- and Ser-ligated structures, and there is no change in the conformation of the proximal loop that contains the axial ...
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Heme: a versatile signaling molecule controlling the activities of ...
Aug 8, 2006 · Heme serves as a prosthetic group in proteins and enzymes that sense, transport or use oxygen. For example, heme is essential for the formation ...
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[PDF] Biological Chemistry I: Protein Structure and Function Continued
Both Mb and Hb reversibly bind to O2 via Fe2+ in protoporphyrin IX (heme, see Figure 3), a key cofactor (see Lexicon). An octahedral complex is formed in which ...
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Free erythrocyte protoporphyrin fluorescence as an ... - Nature
Jul 4, 2025 · Elevated ZnPP levels are an early indicator of disrupted erythropoiesis, notably in conditions such as iron deficiency anemia, anemia of ...Missing: properties | Show results with:properties
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Protoporphyrin Zinc - an overview | ScienceDirect Topics
Zinc protoporphyrin 9 (ZnPP) has been shown to attenuate ferroptosis and reduce intracellular iron accumulation by inhibiting heme oxygenase-1 (HO-1). This ...
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Simultaneous determination of protoporphyrin IX and magnesium ...
Mar 30, 2023 · Insertion of Mg2+ into protoporphyrin IX (PPIX) to produce magnesium-protoporphyrin IX (Mg-PPIX) was the first step toward chlorophyll ...
[58]
Synthesis of nanoparticles of cobalt protoporphyrin IX (Co(iii)PPIX ...
Oct 3, 2025 · PPIX is a biosynthetic precursor of heme, chlorophyll, and cobalamin (vitamin B12) compounds. PPIX is the last intermediate product in the ...
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[PDF] Insertion of cobalt into tetrapyrroles
CbiK catalyzes cobalt insertion into a precursor of vitamin B12 and CfbA catalyzes nickel insertion during cofactor F430 biosynthesis. 5. Insertion of cobalt ...
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Characterization of heme environment and mechanism of peroxide ...
Resting PGIS exhibited an absorption spectrum consistent with a low-spin ferric P450, with a Soret peak at 418 nm and α and β bands at 570 and 537 nm, ...
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Improved Methods for the Synthesis of Porphyrin Alcohols and ...
Improved Methods for the Synthesis of Porphyrin Alcohols and Aldehydes from Protoporphyrin IX Dimethyl Ester and Their Further Modification. Click to copy ...
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(PDF) Modern Aspects of the Chemistry of Protoporphyrin IX
Aug 9, 2025 · Numerous recently published data on the methods for modification of protoporphyrin IX and its derivatives have been summarized and analyzed.
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Protoporphyrin disodium | C34H32N4Na2O4 | CID 71484 - PubChem
Synonyms. 50865-01-5; protoporphyrin disodium; Protoporphyrin IX disodium salt; Disodium protoporphyrin IX; Palepron ; Molecular Weight. 606.6 g/mol. Computed by ...
[64]
https://pubs.acs.org/doi/abs/10.1021/nn300327c
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Amphiphilic Protoporphyrin IX Derivatives as New Photosensitizing ...
A series of amphiphilic PpIX derivatives endowed with PEG 550 headgroups and hydrogenated or fluorinated tails was synthetized.
[66]
Recent Photosensitizer Developments, Delivery Strategies and ...
Nov 26, 2022 · These derivatives showed an increase in solubility, higher singlet oxygen quantum yield and phototoxicity, lower photobleaching of the ligands ...
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Halogenated porphyrins as PDT sensitizers, something more than ...
Aug 9, 2025 · The tri-cationic porphyrin derivatives Tri-Py+-Me-PF, Tri-Py+-Me-Ph and Tri-Py+-Me-CO2Me showed a promising ability, making them good ...
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Sonodynamic Therapy Using Protoporphyrin IX Conjugated to Gold ...
Molecular bindings to the GNPs such as antibodies, carbohydrates and pharmacologic agents, target cancer cells easily. ... nanoparticle–protoporphyrin IX ...
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Gold Nanoparticle-Enhanced and Size-Dependent Generation of ...
Photosensitizer, protoporphyrin IX (PpIX), was conjugated with Au nanoparticles (Au NPs) of 19, 66, and 106 nm diameter to study the size-dependent enhancement ...
[70]
Recent Advances in Porphyrin-Based Inorganic Nanoparticles for ...
For this reason, NPs conjugated with targeting ligands, such as antibodies show prolonged immunosuppressive effects [9] and improved specificity to cancer cells ...
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Fundamentals of 5‐aminolevulinic acid photodynamic therapy and ...
Jan 13, 2020 · 5-Aminolevulinic acid-based photodynamic therapy (ALA-PDT) comprises photochemical and biological reactions, finally generating tumor destruction.
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Protoporphyrin IX Beyond Conventional Applications: A Review of ...
Sep 26, 2025 · 5-Aminolevulinic acid (5-ALA) is used clinically for photodynamic therapy and fluorescence-guided diagnosis and surgery due to its selective ...
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Photodynamic therapy for the precise treatment of localized prostate ...
Feb 4, 2025 · Although PDT is in the early stages of clinical development, it holds promise for the effective treatment of localized prostate cancer. Herein, ...Missing: glioblastoma | Show results with:glioblastoma
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https://pmc.ncbi.nlm.nih.gov/articles/PMC4528019/
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https://www.nature.com/articles/s41598-024-54478-y
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[PDF] Gliolan, INN-5-aminolevulinic acid hydrochloride
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION. Date of first authorisation: 07 September 2007. Date of latest renewal: 30 August 2012. Page 10. 10.
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[PDF] 208630Orig1s000 - accessdata.fda.gov
The objective of this study was to determine the efficacy and safety of fluorescence-guided resection of malignant gliomas with 5-Aminolevulinic acid (5-ALA) ( ...
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Techniques for fluorescence detection of protoporphyrin IX in skin ...
Fluorescent dyes can be used to detect the morphological characteristics of diseased skin (BCC, AKs) and can also be applied for the non-invasive monitoring of ...
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Clinical applications of 5-aminolevulinic acid-mediated fluorescence ...
Fluorescence navigation by photodynamic diagnosis (PDD) using ALA provides good visualization and detection of gastric cancer lesions.
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Protoporphyrin IX in serum of high-grade glioma patients - Nature
Feb 21, 2024 · PpIX is a new target for liquid biopsy in glioma. More extensive clinical studies are required to characterize its full potential.Baseline Ppix Serum Levels · Serum Ppix After 5-Ala... · Assessment Of Ppix As Hgg...Missing: PDT trials
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https://pmc.ncbi.nlm.nih.gov/articles/PMC7319466/
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Characterization of autofluorescence and quantitative ... - Nature
Oct 8, 2021 · Fluorescence occurs in a characteristic double emission peak at around 635 nm and 705 nm. The difference in wavelength between absorption and ...
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An Historical Introduction to Porphyrin and Chlorophyll Synthesis
Moore*. Historical Introduction to Porphyrins and Porphyrias. Introduction. Porphyrins are the extroverts of chemistry. Bright purple and fluorescent, they are.
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Some observations on blood pigments
### Summary of Laidlaw's Work on Porphyrin/Protoporphyrin (1904)
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Hans Fischer – Facts - NobelPrize.org
Hans Fischer mapped the composition of the hem group and in 1929 succeeded in producing the substance by artificial means.
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Synthetic Advances and Emerging Applications of Protoporphyrin IX ...
Protoporphyrin IX (PPIX) is the porphyrin scaffold of heme b, a ubiquitous prosthetic group of proteins responsible for oxygen binding (hemoglobin, myoglobin), ...
[87]
The Nobel Prize in Chemistry 1930 - NobelPrize.org
The Nobel Prize in Chemistry 1930 was awarded to Hans Fischer for his researches into the constitution of haemin and chlorophyll and especially for his ...Missing: protoporphyrin 1920s-
[88]
THE BIOSYNTHESIS OF PORPHYRINS - Conference on Hemoglobin
DAVID SHEMIN. The over-all pathway of porphyrin synthesis in the cell is now known. This paper will first summarize this pathway, with the pertinent ...Missing: ALA discovery 1940s
[89]
The Evolution of Fluorescence-Guided Surgery - PMC - NIH
Sep 19, 2022 · ... pathway, was discovered by David Shemin in the late 1940s [16]. 5-ALA is intracellularly metabolized to produce protoporphyrin IX, which ...
[90]
[PDF] An Historical Introduction to Porphyrin and Chlorophyll Synthesis
Although the first verifiable cases of porphyria were identified in the middle of the 19th. Century, some of the writings of the ancients seem to show clear ...
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Biosynthesis of chlorophylls from protoporphyrin IX - PubMed
A review of the biosynthesis of chlorophylls and bacteriochlorophylls from protoporphyrin IX with 235 references. The literature on the enzymes magnesium ...
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https://www.worldscientific.com/doi/pdf/10.1142/9789812813503_0005
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From chemistry to genomics: A concise history of the porphyrias
May 20, 2024 · Hans Fischer was awarded the ... Zinc-chelated and metal-free forms of erythrocyte protoporphyrin were first identified during the 1970s.
[94]
Heme Biosynthetic Gene Expression Analysis With dPCR ... - Frontiers
The aim of this work was to for the first time analyze the mRNA expression of all HB genes in peripheral blood samples of patients with EPP.<|separator|>
[95]
Generation and characterization of human U-2 OS cell lines with the ...
Oct 12, 2022 · Here we report the generation and characterization of human cell lines, in which PPO was inactivated using the CRISPR/Cas9 system.
[96]
Engineering Escherichia coli for High-Yield Protoporphyrin IX ...
Oct 30, 2025 · Engineering Escherichia coli for High-Yield Protoporphyrin IX Biosynthesis via Cytotoxicity Mitigation and Pathway Optimization. October 2025 ...
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Trial watch: an update of clinical advances in photodynamic therapy ...
Jun 18, 2023 · Another important milestone in PDT was the approval of the first targeted photosensitizer, which is often defined as a characteristic of “third ...