Biology:Porphyrin

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Short description: Heterocyclic organic compound with four modified pyrrole subunits
Porphine, the parent porphyrin.

Porphyrins (/ˈpɔːrfərɪn/ POR-fər-in) 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.

The parent of porphyrins is porphine, a rare chemical compound of exclusively theoretical interest. Substituted porphines are called porphyrins.[1] With a total of 26 π-electrons, of which 18 π-electrons form a planar, continuous cycle, the porphyrin ring structure is often described as aromatic.[2][3] One result of the large conjugated system is that porphyrins typically absorb strongly in the visible region of the electromagnetic spectrum, i.e. they are deeply colored. The name "porphyrin" derives from the Greek word πορφύρα (porphyra), meaning purple.[4]

Structure

Porphyrin complexes consist of a square planar MN4 core. The periphery of the porphyrins, consisting of sp2-hybridized carbons, generally display small deviations from planarity. "Ruffled" or saddle-shaped porphyrins is attributed to interactions of the system with its environment.[5] Additionally, the metal is often not centered in the N4 plane.[6] For free porphyrins, the two pyrrole protons are mutually trans and project out of the N4 plane.[7] These nonplanar distortions are associated with altered chemical and physical properties. Chlorophyll-rings are more distinctly nonplanar, but they are more saturated than porphyrins.[8]

Complexes of porphyrins

Main page: Chemistry:Transition metal porphyrin complexes

Concomitant with the displacement of two N-H protons, porphyrins bind metal ions in the N4 "pocket". The metal ion usually has a charge of 2+ or 3+. A schematic equation for these syntheses is shown:

H2porphyrin + [MLn]2+ → M(porphyrinate)Ln−4 + 4 L + 2 H+, where M = metal ion and L = a ligand
  • Representative porphyrins and derivatives

  • Derivatives of protoporphyrin IX are common in nature, the precursor to hemes.

  • Octaethylporphyrin (H2OEP) is a synthetic analogue of protoporphyrin IX. Unlike the natural porphyrin ligands, OEP2− is highly symmetrical.

  • Tetraphenylporphyrin (H2TPP)is another synthetic analogue of protoporphyrin IX. Unlike the natural porphyrin ligands, TPP2− is highly symmetrical. Another difference is that its methyne centers are occupied by phenyl groups.

  • Simplified view of heme, a complex of a protoporphyrin IX.

  • A macrocycle of 40 porphyrin molecules, model

  • A macrocycle of 40 porphyrin molecules, STM image

Ancient porphyrins

A geoporphyrin, also known as a petroporphyrin, is a porphyrin of geologic origin.[9] They can occur in crude oil, oil shale, coal, or sedimentary rocks.[9][10] Abelsonite is possibly the only geoporphyrin mineral, as it is rare for porphyrins to occur in isolation and form crystals.[11]

The field of organic geochemistry had its origins in the isolation of porphyrins from petroleum.[citation needed] This finding helped establish the biological origins of petroleum. Petroleum is sometimes "fingerprinted" by analysis of trace amounts of nickel and vanadyl porphyrins.[citation needed]

Biosynthesis

In non-photosynthetic eukaryotes such as animals, insects, fungi, and protozoa, as well as the α-proteobacteria group of bacteria, the committed step for porphyrin biosynthesis is the formation of δ-aminolevulinic acid (δ-ALA, 5-ALA or dALA) by the reaction of the amino acid glycine with succinyl-CoA from the citric acid cycle. In plants, algae, bacteria (except for the α-proteobacteria group) and archaea, it is produced from glutamic acid via glutamyl-tRNA and glutamate-1-semialdehyde. The enzymes involved in this pathway are glutamyl-tRNA synthetase, glutamyl-tRNA reductase, and glutamate-1-semialdehyde 2,1-aminomutase. This pathway is known as the C5 or Beale pathway.

Two molecules of dALA are then combined by porphobilinogen synthase to give porphobilinogen (PBG), which contains a pyrrole ring. Four PBGs are then combined through deamination into hydroxymethyl bilane (HMB), which is hydrolysed to form the circular tetrapyrrole uroporphyrinogen III. This molecule undergoes a number of further modifications. Intermediates are used in different species to form particular substances, but, in humans, the main end-product protoporphyrin IX is combined with iron to form heme. Bile pigments are the breakdown products of heme.

The following scheme summarizes the biosynthesis of porphyrins, with references by EC number and the OMIM database. The porphyria associated with the deficiency of each enzyme is also shown:

Heme B biosynthesis pathway and its modulators. Major enzyme deficiences are also shown.
Enzyme Location Substrate Product Chromosome EC OMIM Disorder
ALA synthase Mitochondrion Glycine, succinyl CoA δ-Aminolevulinic acid 3p21.1 2.3.1.37 125290 X-linked dominant protoporphyria, X-linked sideroblastic anemia
ALA dehydratase Cytosol δ-Aminolevulinic acid Porphobilinogen 9q34 4.2.1.24 125270 aminolevulinic acid dehydratase deficiency porphyria
PBG deaminase Cytosol Porphobilinogen Hydroxymethyl bilane 11q23.3 2.5.1.61 176000 acute intermittent porphyria
Uroporphyrinogen III synthase Cytosol Hydroxymethyl bilane Uroporphyrinogen III 10q25.2-q26.3 4.2.1.75 606938 congenital erythropoietic porphyria
Uroporphyrinogen III decarboxylase Cytosol Uroporphyrinogen III Coproporphyrinogen III 1p34 4.1.1.37 176100 porphyria cutanea tarda, hepatoerythropoietic porphyria
Coproporphyrinogen III oxidase Mitochondrion Coproporphyrinogen III Protoporphyrinogen IX 3q12 1.3.3.3 121300 hereditary coproporphyria
Protoporphyrinogen oxidase Mitochondrion Protoporphyrinogen IX Protoporphyrin IX 1q22 1.3.3.4 600923 variegate porphyria
Ferrochelatase Mitochondrion Protoporphyrin IX Heme 18q21.3 4.99.1.1 177000 erythropoietic protoporphyria

Laboratory synthesis

Main page: Chemistry:Rothemund reaction
Brilliant crystals of meso-tetratolylporphyrin, prepared from 4-methylbenzaldehyde and pyrrole in refluxing propionic acid

A common synthesis for porphyrins is the Rothemund reaction, first reported in 1936,[12][13] which is also the basis for more recent methods described by Adler and Longo.[14] The general scheme is a condensation and oxidation process starting with pyrrole and an aldehyde.

H2TPPsyn.png

Potential applications

Photodynamic therapy

Porphyrins have been evaluated in the context of photodynamic therapy (PDT) since they strongly absorb light, which is then converted to heat in the illuminated areas.[15] This technique has been applied in macular degeneration using verteporfin.[16]

PDT is considered a noninvasive cancer treatment, involving the interaction between light of a determined frequency, a photo-sensitizer, and oxygen. This interaction produces the formation of a highly reactive oxygen species (ROS), usually singlet oxygen, as well as superoxide anion, free hydroxyl radical, or hydrogen peroxide.[17] These high reactive oxygen species react with susceptible cellular organic biomolecules such as; lipids, aromatic amino acids, and nucleic acid heterocyclic bases, to produce oxidative radicals that damage the cell, possibly inducing apoptosis or even necrosis.[18]

Molecular electronics and sensors

Porphyrin-based compounds are of interest as possible components of molecular electronics and photonics.[19] Synthetic porphyrin dyes have been incorporated in prototype dye-sensitized solar cells.[20][21]

Biological applications

Porphyrins have been investigated as possible anti-inflammatory agents[22] and evaluated on their anti-cancer and anti-oxidant activity.[23] Several porphyrin-peptide conjugates were found to have antiviral activity against HIV in vitro.[24]

Toxicology

Heme biosynthesis is used as biomarker in environmental toxicology studies. While excess production of porphyrins indicate organochlorine exposure, lead inhibits ALA dehydratase enzyme.[25]

Gallery

  • Lewis structure for meso-tetraphenylporphyrin

  • UV–vis readout for meso-tetraphenylporphyrin

  • Light-activated porphyrin. Monatomic oxygen. Cellular aging

Related species

In nature

Several heterocycles related to porphyrins are found in nature, almost always bound to metal ions. These include

Caption text
N4-macrocycle Cofactor name metal comment
chlorin chlorophyll magnesium several versions of chlorophyll exist (sidechain; exception being chlorophyll c)
bacteriochlorin bacteriochlorophyll (in part) magnesium several versions of bacteriochlorophyll exist (sidechain; some use a usual chlorin ring)
sirohydrochlorin (an isobacteriochlorin) siroheme iron Important cofactor in sulfur assimilation
biosynthetic intermediate en route to cofactor F430 and B12
corrin vitamin B12 cobalt several variants of B12 exist (sidechain)
corphin Cofactor F430 nickel highly reduced macrocycle

Synthetic

A benzoporphyrin is a porphyrin with a benzene ring fused to one of the pyrrole units. e.g. verteporfin is a benzoporphyrin derivative.[26]

Non-natural porphyrin isomers

File:First Porphycene synthesis.tif

The first synthetic porphyrin isomer was reported by Emanual Vogel and coworkers in 1986.[27] This isomer [18]porphyrin-(2.0.2.0) is named as porphycene, and the central N4 Cavity forms a rectangle shape as shown in figure.[28] Porphycenes showed interesting photophysical behavior and found versatile compound towards the photodynamic therapy.[29] This inspired Vogel and Sessler to took up the challenge of preparing [18]porphyrin-(2.1.0.1) and named it as corrphycene or porphycerin.[30] The third porphyrin that is [18]porphyrin-(2.1.1.0), was reported by Callot and Vogel-Sessler. Vogel and coworkers reported successful isolation of [18]porphyrin-(3.0.1.0) or isoporphycene.[31] The Japanese scientist Furuta[32] and Polish scientist Latos-Grażyński[33] almost simultaneously reported the N-confused porphyrins. The inversion of one of the pyrrolic subunits in the macrocyclic ring resulted in one of the nitrogen atoms facing outwards from the core of the macrocycle.

Various reported Isomers of porphyrin

See also

  • A porphyrin-related disease: porphyria
  • Porphyrin coordinated to iron: heme
  • A heme-containing group of enzymes: Cytochrome P450
  • Porphyrin coordinated to magnesium: chlorophyll
  • The one-carbon-shorter analogues: corroles, including vitamin B12, which is coordinated to a cobalt
  • Corphins, the highly reduced porphyrin coordinated to nickel that binds the Cofactor F430 active site in methyl coenzyme M reductase (MCR)
  • Nitrogen-substituted porphyrins: phthalocyanine

References

  1. ↑ "Catalytic activity of multi-wall carbon nanotube supported manganese (III) porphyrin: an efficient, selective and reusable catalyst for oxidation of alkenes and alkanes with urea–hydrogen peroxide". Journal of Experimental Nanoscience 11 (11): 872. 2016. doi:10.1080/17458080.2016.1179802. Bibcode: 2016JENan..11..872R. 
  2. ↑ "Deciphering aromaticity in porphyrinoids via adaptive natural density partitioning". Organic & Biomolecular Chemistry 12 (32): 6145–6150. August 2014. doi:10.1039/C4OB01018C. PMID 25002069. 
  3. ↑ "Origin of aromatic character in porphyrinoid systems". Journal of Porphyrins and Phthalocyanines 15 (11n12): 1093–1115. 2011. doi:10.1142/S1088424611004063. 
  4. ↑ "porphyria (n.)". http://www.etymonline.com/index.php?allowed_in_frame=0&search=porphyrin&searchmode=none. 
  5. ↑ "Conformational control of cofactors in nature - the influence of protein-induced macrocycle distortion on the biological function of tetrapyrroles". Chemical Communications 51 (96): 17031–17063. December 2015. doi:10.1039/C5CC06254C. PMID 26482230. 
  6. ↑ "Iron Porphyrin Chemistry". Encyclopedia of Inorganic and Bioinorganic Chemistry. 2011. doi:10.1002/9781119951438.eibc0104. ISBN 9781119951438. 
  7. ↑ "Conservation of the conformation of the porphyrin macrocycle in hemoproteins". Biophysical Journal 74 (2 Pt 1): 753–763. February 1998. doi:10.1016/S0006-3495(98)74000-7. PMID 9533688. Bibcode: 1998BpJ....74..753J. 
  8. ↑ "Chlorophylls, Symmetry, Chirality, and Photosynthesis". Symmetry 6 (3): 781–843. 2014. doi:10.3390/sym6030781. Bibcode: 2014Symm....6..781S. 
  9. ↑ 9.0 9.1 The Porphyrin Handbook. Elsevier. 1999. p. 381. ISBN 9780123932006. https://books.google.com/books?id=Ci7rIe0Ohn8C&pg=PA381. 
  10. ↑ "Total synthesis of the porphyrin mineral abelsonite and related petroporphyrins with five-membered exocyclic rings". Tetrahedron Letters 44 (39): 7253. September 2003. doi:10.1016/j.tetlet.2003.08.007. 
  11. ↑ "Review of the stratigraphic distribution and diagenetic history of abelsonite". Organic Geochemistry 14 (6): 585. 1989. doi:10.1016/0146-6380(89)90038-7. Bibcode: 1989OrGeo..14..585M. 
  12. ↑ "A New Porphyrin Synthesis. The Synthesis of Porphin". J. Am. Chem. Soc. 58 (4): 625–627. 1936. doi:10.1021/ja01295a027. 
  13. ↑ "Formation of Porphyrins from Pyrrole and Aldehydes". J. Am. Chem. Soc. 57 (10): 2010–2011. 1935. doi:10.1021/ja01313a510. 
  14. ↑ "A simplified synthesis for meso-tetraphenylporphine". J. Org. Chem. 32 (2): 476. 1967. doi:10.1021/jo01288a053. 
  15. ↑ "Porphyrin conjugates for cancer therapy". Handbook of Porphyrin Science. 27. 2014. pp. 303–416. 
  16. ↑ "Photodynamic therapy for neovascular age-related macular degeneration". The Cochrane Database of Systematic Reviews (3): CD002030. July 2007. doi:10.1002/14651858.CD002030.pub3. PMID 17636693. https://researchonline.lshtm.ac.uk/id/eprint/6367/1/Wormald_et_al-2007-The_Cochrane_library.pdf. 
  17. ↑ "A role for hydrogen peroxide in the pro-apoptotic effects of photodynamic therapy". Photochemistry and Photobiology 85 (6): 1491–1496. 2009. doi:10.1111/j.1751-1097.2009.00589.x. PMID 19659920. 
  18. ↑ "Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics". Chemical Reviews 115 (18): 10261–10306. September 2015. doi:10.1021/acs.chemrev.5b00244. PMID 26317756. 
  19. ↑ "Synthesis of π-extended porphyrins via intramolecular oxidative coupling". Chemical Communications 48 (81): 10069–10086. October 2012. doi:10.1039/c2cc31279d. PMID 22649792. 
  20. ↑ "Porphyrins and phthalocyanines in solar photovoltaic cells". Journal of Porphyrins and Phthalocyanines 14 (9): 759–792. 2010. doi:10.1142/S1088424610002689. 
  21. ↑ "Porphyrin-sensitized solar cells with cobalt (II/III)-based redox electrolyte exceed 12 percent efficiency". Science 334 (6056): 629–634. November 2011. doi:10.1126/science.1209688. PMID 22053043. Bibcode: 2011Sci...334..629Y. 
  22. ↑ "Synthesis, antinociceptive and anti-inflammatory effects of porphyrins". Bioorganic & Medicinal Chemistry 23 (10): 2529–2537. May 2015. doi:10.1016/j.bmc.2015.03.043. PMID 25863493. 
  23. ↑ "Synthesis and bioactivity of oxovanadium(IV)tetra(4-methoxyphenyl)porphyrinsalicylates". BMC Chemistry 13 (1): 15. December 2019. doi:10.1186/s13065-019-0523-9. PMID 31384764. 
  24. ↑ "Penetrating the Blood-Brain Barrier with New Peptide-Porphyrin Conjugates Having anti-HIV Activity". Bioconjugate Chemistry 32 (6): 1067–1077. June 2021. doi:10.1021/acs.bioconjchem.1c00123. PMID 34033716. 
  25. ↑ Principles of Ecotoxicology. Boca Raton, FL: CRC Press. 2012. pp. 182. ISBN 978-1-4665-0260-4. 
  26. ↑ "Verteporfin". Drugs & Aging 16 (2): 139–146; discussion 146–8. February 2000. doi:10.2165/00002512-200016020-00005. PMID 10755329. 
  27. ↑ "Porphycene—a Novel Porphin Isomer". Angewandte Chemie 25 (3): 257. March 1986. doi:10.1002/anie.198602571. 
  28. ↑ "3,6,13,16-Tetrapropylporphycene: Rational Synthesis, Complexation, and Halogenation". The Journal of Organic Chemistry 87 (5): 2721–2729. March 2022. doi:10.1021/acs.joc.1c02652. PMID 35061396. 
  29. ↑ "Basic principles of photodynamic therapy". Journal of Porphyrins and Phthalocyanines 5 (2): 105. 2001. doi:10.1002/jpp.328. 
  30. ↑ "New Porphycene Ligands: Octaethyl‐ and Etioporphycene (OEPc and EtioPc)—Tetra‐ and Pentacoordinated Zinc Complexes of OEPc". Angewandte Chemie International Edition 32 (11): 1600. November 1993. doi:10.1002/anie.199316001. 
  31. ↑ "Isoporphycene: The Fourth Constitutional Isomer of Porphyrin with an N(4) Core-Occurrence of E/Z Isomerism". Angewandte Chemie 38 (19): 2919–2923. October 1999. doi:10.1002/(SICI)1521-3773(19991004)38:19<2919::AID-ANIE2919>3.0.CO;2-W. PMID 10540393. 
  32. ↑ ""N-Confused Porphyrin": A New Isomer of Tetraphenylporphyrin". J. Am. Chem. Soc. 116 (2): 767. 1994. doi:10.1021/ja00081a047. 
  33. ↑ "Tetra‐p‐tolylporphyrin with an Inverted Pyrrole Ring: A Novel Isomer of Porphyrin". Angewandte Chemie International Edition 33 (7): 779. 18 April 1994. doi:10.1002/anie.199407791. 

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