Porphyrin#biosynthsis

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.{{cite journal | vauthors = Senge MO, MacGowan SA, O'Brien JM | title = Conformational control of cofactors in nature - the influence of protein-induced macrocycle distortion on the biological function of tetrapyrroles | journal = Chemical Communications | volume = 51 | issue = 96 | pages = 17031–17063 | date = December 2015 | pmid = 26482230 | doi = 10.1039/C5CC06254C | hdl-access = free | hdl = 2262/75305 }} Additionally, the metal is often not centered in the N₄ plane.{{cite book |doi=10.1002/9781119951438.eibc0104 |chapter=Iron Porphyrin Chemistry |title=Encyclopedia of Inorganic and Bioinorganic Chemistry |year=2011 | vauthors = Walker FA, Simonis U |isbn=9781119951438 }} For free porphyrins, the two pyrrole protons are mutually trans and project out of the N₄ plane. {{cite journal | vauthors = Jentzen W, Ma JG, Shelnutt JA | title = Conservation of the conformation of the porphyrin macrocycle in hemoproteins | journal = Biophysical Journal | volume = 74 | issue = 2 Pt 1 | pages = 753–763 | date = February 1998 | pmid = 9533688 | pmc = 1302556 | doi = 10.1016/S0006-3495(98)74000-7 | bibcode = 1998BpJ....74..753J }} These nonplanar distortions are associated with altered chemical and physical properties. Chlorophyll-rings are more distinctly nonplanar, but they are more saturated than porphyrins.{{Cite journal | vauthors = Senge MO, Ryan AA, Letchford KA, MacGowan SA, Mielke T | year = 2014 | title = Chlorophylls, Symmetry, Chirality, and Photosynthesis | journal = Symmetry | volume = 6 | issue = 3 | pages = 781–843 | doi = 10.3390/sym6030781 | bibcode = 2014Symm....6..781S | doi-access = free | hdl = 2262/73843 | hdl-access = free }}

{{main|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, where M = metal ion and L = a ligand:

:{{chem2|H2porphyrin + [ML_{n}](2+) -> M(porphyrinate)L_{n−4} + 4 L + 2 H+}}

File:PPIXtransH.png|Derivatives of protoporphyrin IX are common in nature, the precursor to hemes.

File:H2octaethylporphyrin.png |Octaethylporphyrin (H₂OEP) is a synthetic analogue of protoporphyrin IX. Unlike the natural porphyrin ligands, OEP²⁻ is highly symmetrical.

File:H2TPP.png|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.

File:Heme B.svg|Simplified view of heme, a complex of a protoporphyrin IX.

CP40model.png|A nanoring of 40 porphyrin molecules, model

CP40-STM.png|A nanoring of 40 porphyrin molecules, STM image

A geoporphyrin, also known as a petroporphyrin, is a porphyrin of geologic origin.{{cite book|title=The Porphyrin Handbook|publisher=Elsevier|isbn=9780123932006|url=https://books.google.com/books?id=Ci7rIe0Ohn8C&pg=PA381| veditors = Kadish KM |page=381|date=1999}} They can occur in crude oil, oil shale, coal, or sedimentary rocks.{{cite journal| vauthors = Zhang B, Lash TD |title=Total synthesis of the porphyrin mineral abelsonite and related petroporphyrins with five-membered exocyclic rings|journal=Tetrahedron Letters|date=September 2003|volume=44|issue=39|page=7253|doi=10.1016/j.tetlet.2003.08.007}} Abelsonite is possibly the only geoporphyrin mineral, as it is rare for porphyrins to occur in isolation and form crystals.{{cite journal| vauthors = Mason GM, Trudell LG, Branthaver JF |title=Review of the stratigraphic distribution and diagenetic history of abelsonite|journal=Organic Geochemistry|year=1989|volume=14|issue=6|page=585|doi=10.1016/0146-6380(89)90038-7|bibcode=1989OrGeo..14..585M }}

The field of organic geochemistry had its origins in the isolation of porphyrins from petroleum. These findings helped establish the biological origins of petroleum.Kvenvolden, Keith A. (2006). "Organic geochemistry – A retrospective of its first 70 years". Organic Geochemistry. 37: 1–11. doi:10.1016/j.orggeochem.2005.09.001Treibs, A.E. (1936). "Chlorophyll- und Häminderivate in organischen Mineralstoffen". Angewandte Chemie. 49: 682–686. doi:10.1002/ange.19360493803 Petroleum is sometimes "fingerprinted" by analysis of trace amounts of nickel and vanadyl porphyrins. Metalloporphyrins in general are highly stable organic compounds, and the detailed structures of the extracted derivatives made clear that they originated from chlorophyll.

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:

File:Heme-Synthesis-Chemical-Details-Mirror.svg

{{main|Rothemund reaction}}

Image:Tetratolylporphyrin.jpg and pyrrole in refluxing propionic acid]]

A common synthesis for porphyrins is the Rothemund reaction, first reported in 1936,{{cite journal | vauthors = Rothemund P | title = A New Porphyrin Synthesis. The Synthesis of Porphin | year = 1936 | journal = J. Am. Chem. Soc. | volume = 58 | issue = 4 | pages = 625–627 | doi = 10.1021/ja01295a027| bibcode = 1936JAChS..58..625R }}{{cite journal | vauthors = Rothemund P | title = Formation of Porphyrins from Pyrrole and Aldehydes | year = 1935 | journal = J. Am. Chem. Soc. | volume = 57 | issue = 10 | pages = 2010–2011 | doi=10.1021/ja01313a510| bibcode = 1935JAChS..57.2010R }} which is also the basis for more recent methods described by Adler and Longo.{{cite journal | vauthors = Adler AD, Longo FR, Finarelli JD, Goldmacher J, Assour J, Korsakoff L | title = A simplified synthesis for meso-tetraphenylporphine | year = 1967 | journal = J. Org. Chem. | volume = 32 | issue = 2 | pages = 476 | doi = 10.1021/jo01288a053}} The general scheme is a condensation and oxidation process starting with pyrrole and an aldehyde.

:Image:H2TPPsyn.png

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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.{{cite encyclopedia|title=Porphyrin conjugates for cancer therapy| vauthors = Giuntini F, Boyle R, Sibrian-Vazquez M, Vicente MG | veditors = Kadish KM, Smith KM, Guilard R |encyclopedia=Handbook of Porphyrin Science|year=2014|volume=27|pages=303–416}} This technique has been applied in macular degeneration using verteporfin.{{cite journal | vauthors = Wormald R, Evans J, Smeeth L, Henshaw K | title = Photodynamic therapy for neovascular age-related macular degeneration | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD002030 | date = July 2007 | pmid = 17636693 | doi = 10.1002/14651858.CD002030.pub3 | url = https://researchonline.lshtm.ac.uk/id/eprint/6367/1/Wormald_et_al-2007-The_Cochrane_library.pdf }}

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.{{cite journal | vauthors = Price M, Terlecky SR, Kessel D | title = A role for hydrogen peroxide in the pro-apoptotic effects of photodynamic therapy | journal = Photochemistry and Photobiology | volume = 85 | issue = 6 | pages = 1491–1496 | year = 2009 | pmid = 19659920 | pmc = 2783742 | doi = 10.1111/j.1751-1097.2009.00589.x }} 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.{{cite journal | vauthors = Singh S, Aggarwal A, Bhupathiraju NV, Arianna G, Tiwari K, Drain CM | title = Glycosylated Porphyrins, Phthalocyanines, and Other Porphyrinoids for Diagnostics and Therapeutics | journal = Chemical Reviews | volume = 115 | issue = 18 | pages = 10261–10306 | date = September 2015 | pmid = 26317756 | pmc = 6011754 | doi = 10.1021/acs.chemrev.5b00244 }}

Porphyrin-based compounds are of interest as possible components of molecular electronics and photonics.{{cite journal | vauthors = Lewtak JP, Gryko DT | title = Synthesis of π-extended porphyrins via intramolecular oxidative coupling | journal = Chemical Communications | volume = 48 | issue = 81 | pages = 10069–10086 | date = October 2012 | pmid = 22649792 | doi = 10.1039/c2cc31279d }} Synthetic porphyrin dyes have been incorporated in prototype dye-sensitized solar cells.{{cite journal | journal = Journal of Porphyrins and Phthalocyanines | year = 2010 | volume = 14 | pages = 759–792 | doi= 10.1142/S1088424610002689 | title = Porphyrins and phthalocyanines in solar photovoltaic cells | vauthors = Walter MG, Rudine AB, Wamser CC | issue = 9}}{{cite journal | vauthors = Yella A, Lee HW, Tsao HN, Yi C, Chandiran AK, Nazeeruddin MK, Diau EW, Yeh CY, Zakeeruddin SM, Grätzel M | display-authors = 6 | title = Porphyrin-sensitized solar cells with cobalt (II/III)-based redox electrolyte exceed 12 percent efficiency | journal = Science | volume = 334 | issue = 6056 | pages = 629–634 | date = November 2011 | pmid = 22053043 | doi = 10.1126/science.1209688 | bibcode = 2011Sci...334..629Y | s2cid = 28058582 }}

Porphyrins have been investigated as possible anti-inflammatory agents{{cite journal | vauthors = Alonso-Castro AJ, Zapata-Morales JR, Hernández-Munive A, Campos-Xolalpa N, Pérez-Gutiérrez S, Pérez-González C | title = Synthesis, antinociceptive and anti-inflammatory effects of porphyrins | journal = Bioorganic & Medicinal Chemistry | volume = 23 | issue = 10 | pages = 2529–2537 | date = May 2015 | pmid = 25863493 | doi = 10.1016/j.bmc.2015.03.043 }} and evaluated on their anti-cancer and anti-oxidant activity.{{cite journal | vauthors = Bajju GD, Ahmed A, Devi G | title = Synthesis and bioactivity of oxovanadium(IV)tetra(4-methoxyphenyl)porphyrinsalicylates | journal = BMC Chemistry | volume = 13 | issue = 1 | pages = 15 | date = December 2019 | pmid = 31384764 | pmc = 6661832 | doi = 10.1186/s13065-019-0523-9 | doi-access = free }} Several porphyrin-peptide conjugates were found to have antiviral activity against HIV in vitro.{{cite journal | vauthors = Mendonça DA, Bakker M, Cruz-Oliveira C, Neves V, Jiménez MA, Defaus S, Cavaco M, Veiga AS, Cadima-Couto I, Castanho MA, Andreu D, Todorovski T | display-authors = 6 | title = Penetrating the Blood-Brain Barrier with New Peptide-Porphyrin Conjugates Having anti-HIV Activity | journal = Bioconjugate Chemistry | volume = 32 | issue = 6 | pages = 1067–1077 | date = June 2021 | pmid = 34033716 | pmc = 8485325 | doi = 10.1021/acs.bioconjchem.1c00123 }}

Heme biosynthesis is used as biomarker in environmental toxicology studies. While excess production of porphyrins indicate organochlorine exposure, lead inhibits ALA dehydratase enzyme.{{Cite book|title=Principles of Ecotoxicology| vauthors = Walker CH, Silby RM, Hopkin SP, Peakall DB |publisher=CRC Press|year=2012|isbn=978-1-4665-0260-4|location=Boca Raton, FL|pages=182}}

File:H2TPP.png|Lewis structure for meso-tetraphenylporphyrin

File:Meso-tetraphenylporphyrin UV-vis.JPG|UV–vis readout for meso-tetraphenylporphyrin

File:Porfirina activada con la luz.svg|Light-activated porphyrin. Monatomic oxygen. Cellular aging

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

A benzoporphyrin is a porphyrin with a benzene ring fused to one of the pyrrole units. e.g. verteporfin is a benzoporphyrin derivative.{{cite journal | vauthors = Scott LJ, Goa KL | title = Verteporfin | journal = Drugs & Aging | volume = 16 | issue = 2 | pages = 139–146; discussion 146–8 | date = February 2000 | pmid = 10755329 | doi = 10.2165/00002512-200016020-00005 | s2cid = 260491296 }}

File:First Porphycene synthesis.tif]]

The first synthetic porphyrin isomer was reported by Emanual Vogel and coworkers in 1986.{{cite journal | vauthors = Vogel E, Köcher M |title=Porphycene—a Novel Porphin Isomer |journal=Angewandte Chemie |date=March 1986 |volume=25 |issue=3 |page=257 |doi=10.1002/anie.198602571 }} 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.{{cite journal | vauthors = Nagamaiah J, Dutta A, Pati NN, Sahoo S, Soman R, Panda PK |title=3,6,13,16-Tetrapropylporphycene: Rational Synthesis, Complexation, and Halogenation |journal=The Journal of Organic Chemistry |date=March 2022 |volume=87 |issue=5 |pages=2721–2729 |doi=10.1021/acs.joc.1c02652 |pmid=35061396 |s2cid=246165814 }} Porphycenes showed interesting photophysical behavior and found versatile compound towards the photodynamic therapy.{{cite journal | vauthors = Dougherty TJ |title=Basic principles of photodynamic therapy |journal=Journal of Porphyrins and Phthalocyanines |date=2001 |volume=5 |issue=2 |page=105 |doi=10.1002/jpp.328 }} This result was followed by the preparation of [18]porphyrin-(2.1.0.1), named it as corrphycene or porphycerin.{{cite journal | vauthors = Vogel E, Guilard R |title=New Porphycene Ligands: Octaethyl- and Etioporphycene (OEPc and EtioPc)—Tetra- and Pentacoordinated Zinc Complexes of OEPc |journal=Angewandte Chemie International Edition |date=November 1993 |volume=32 |issue=11 |page=1600 |doi=10.1002/anie.199316001 }} Other non-natural porphyrins include [18]porphyrin-(2.1.1.0) and [18]porphyrin-(3.0.1.0) or isoporphycene.{{cite journal | vauthors = Vogel E, Scholz P, Demuth R, Erben C, Bröring M, Schmickler H, Lex J, Hohlneicher G, Bremm D, Wu YD | display-authors = 6 | title = Isoporphycene: The Fourth Constitutional Isomer of Porphyrin with an N(4) Core-Occurrence of E/Z Isomerism | journal = Angewandte Chemie | volume = 38 | issue = 19 | pages = 2919–2923 | date = October 1999 | pmid = 10540393 | doi = 10.1002/(SICI)1521-3773(19991004)38:19<2919::AID-ANIE2919>3.0.CO;2-W }} The N-confused porphyrins feature one of the pyrrolic subunits with the nitrogen atoms facing outwards from the core of the macrocycle.{{cite journal | vauthors = Hiroyuki F |title="N-Confused Porphyrin": A New Isomer of Tetraphenylporphyrin |journal=J. Am. Chem. Soc. |year=1994 |volume=116 |issue=2 |page=767 |doi=10.1021/ja00081a047 |bibcode=1994JAChS.116..767F }}{{cite journal | vauthors = Chmielewski PJ, Latos-Grażyński L, Rachlewicz K, Glowiak T |title=Tetra-p-tolylporphyrin with an Inverted Pyrrole Ring: A Novel Isomer of Porphyrin |journal=Angewandte Chemie International Edition |date=18 April 1994 |volume=33 |issue=7 |page=779 |doi=10.1002/anie.199407791 }}

File:Isomers of porphyrins soman.jpg

• 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, tetrapyrazinoporphyrazine

{{reflist}}

{{Commons category|Porphyrins}}

• [http://www.worldscinet.com/jpp/ Journal of Porphyrins and Phthalocyanines]
• [https://web.archive.org/web/20100331125114/http://www.worldscibooks.com/chemistry/7376.html Handbook of Porphyrin Science]
• [https://web.archive.org/web/20180709131903/http://www.porphyrin.net/ Porphynet – an informative site about porphyrins and related structures]

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