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36-411: Porphyrins ( / ˈ p ɔːr f ər ɪ n s / POR -fər-ins ) are a group of heterocyclic , macrocyclic , 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

72-484: A "closed" conformation of the active site lid. The other interaction restricts solvent access from the other end of the αβ-barrel. In the inactive multimeric state, the N-terminal arm domain is not involved in the lid-stabilizing interaction, and in the crystal structure of the inactive assembly, the active site lid is disordered. As a nearly universal enzyme with a highly conserved active site, PBGS would not be

108-473: A prime target for the development of antimicrobials and/or herbicides . To the contrary, allosteric sites can be much more phylogenetically variable than active sites, thus presenting more drug development opportunities. Phylogenetic variation in PBGS allostery leads to the framing of discussion of PBGS allosteric regulation in terms of intrinsic and extrinsic factors. The allosteric magnesium ion lies at

144-503: A third large family of organic compounds. Analogs of the previously mentioned heterocycles for this third family of compounds are acridine , dibenzothiophene , carbazole , and dibenzofuran , respectively. Heterocyclic organic compounds can be usefully classified based on their electronic structure. The saturated organic heterocycles behave like the acyclic derivatives. Thus, piperidine and tetrahydrofuran are conventional amines and ethers , with modified steric profiles. Therefore,

180-440: A variety of common and systematic names. For example, with the benzo-fused unsaturated nitrogen heterocycles, pyrrole provides indole or isoindole depending on the orientation. The pyridine analog is quinoline or isoquinoline . For azepine, benzazepine is the preferred name. Likewise, the compounds with two benzene rings fused to the central heterocycle are carbazole , acridine , and dibenzoazepine. Thienothiophene are

216-430: Is a benzoporphyrin derivative. The first synthetic porphyrin isomer was reported by Emanual Vogel and coworkers in 1986. This isomer [18]porphyrin-(2.0.2.0) is named as porphycene , and the central N 4 Cavity forms a rectangle shape as shown in figure. Porphycenes showed interesting photophysical behavior and found versatile compound towards the photodynamic therapy . This inspired Vogel and Sessler to took up

252-502: Is a six-membered ring with three nitrogen heteroatoms and three boron heteroatoms. In a 7-membered ring, the heteroatom must be able to provide an empty π-orbital (e.g. boron) for "normal" aromatic stabilization to be available; otherwise, homoaromaticity may be possible. Borazocine is a eight-membered ring with four nitrogen heteroatoms and four boron heteroatoms. Heterocyclic rings systems that are formally derived by fusion with other rings, either carbocyclic or heterocyclic, have

288-432: Is also the basis for more recent methods described by Adler and Longo. The general scheme is a condensation and oxidation process starting with pyrrole and an aldehyde . 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. This technique has been applied in macular degeneration using verteporfin . PDT

324-485: Is an enzyme ( EC 4.2.1.24 ) that in humans is encoded by the ALAD gene . Porphobilinogen synthase (or ALA dehydratase , or aminolevulinate dehydratase ) synthesizes porphobilinogen through the asymmetric condensation of two molecules of aminolevulinic acid . All natural tetrapyrroles , including hemes , chlorophylls and vitamin B 12 , share porphobilinogen as a common precursor. Porphobilinogen synthase

360-444: Is called porphobilinogen synthase (or ALA dehydratase) deficiency porphyria . It is an extremely rare cause of porphyria , with less than 10 cases ever reported. All disease associated protein variants favor hexamer formation relative to the wild type human enzyme. The morpheein model of allostery exemplified by PBGS adds an additional layer of understanding to potential mechanisms for regulation of protein function and complements

396-531: 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. 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

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432-502: Is inhibited by lead , beginning at blood lead levels that were once considered to be safe (<10 μg/dL) and continuing to correlate negatively across the range from 5 to 95 μg/dL. Inhibition of ALAD by lead leads to anemia primarily because it both inhibits heme synthesis and shortens the lifespan of circulating red blood cells , but also by stimulating the excessive production of the hormone erythropoietin , leading to inadequate maturation of red cells from their progenitors. A defect in

468-535: 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,

504-424: Is modulation of a quaternary structure equilibrium between octamer and hexamer (via dimers), which is represented schematically as 6mer* ↔ 2mer* ↔ 2mer ↔ 8mer. The * represents a reorientation between two domains of each subunit that occurs in the dissociated state because it is sterically forbidden in the larger multimers. PBGS is encoded by a single gene and each PBGS multimer is composed of multiple copies of

540-481: Is possibly the only geoporphyrin mineral, as it is rare for porphyrins to occur in isolation and form crystals. The field of organic geochemistry had its origins in the isolation of porphyrins from petroleum. This finding helped establish the biological origins of petroleum. Petroleum is sometimes "fingerprinted" by analysis of trace amounts of nickel and vanadyl porphyrins. In non-photosynthetic eukaryotes such as animals, insects, fungi, and protozoa , as well as

576-597: Is the class of dithiazoles , which contain two sulfur atoms and one nitrogen atom. The 6-membered ring compounds containing two heteroatoms, at least one of which is nitrogen, are collectively called the azines . Thiazines contain a sulfur and a nitrogen atom in the ring. Dithiines have two sulfur atoms. Six-membered rings with five heteroatoms The hypothetical chemical compound with five nitrogen heteroatoms would be pentazine . Six-membered rings with six heteroatoms The hypothetical chemical compound with six nitrogen heteroatoms would be hexazine . Borazine

612-504: Is the prototype morpheein . It catalyzes the following reaction, the second step of the biosynthesis of porphyrin : It therefore catalyzes the condensation of 2 molecules of 5-aminolevulinate to form porphobilinogen (a precursor of heme , cytochromes and other hemoproteins). This reaction is the first common step in the biosynthesis of all biological tetrapyrroles. Zinc is essential for enzymatic activity. The structural basis for allosteric regulation of Porphobilinogen synthase (PBGS)

648-399: Is used as biomarker in environmental toxicology studies. While excess production of porphyrins indicate organochlorine exposure, lead inhibits ALA dehydratase enzyme. 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

684-580: The Hantzsch-Widman nomenclature for naming heterocyclic compounds. Although subject to ring strain , 3-membered heterocyclic rings are well characterized. The 5-membered ring compounds containing two heteroatoms, at least one of which is nitrogen, are collectively called the azoles . Thiazoles and isothiazoles contain a sulfur and a nitrogen atom in the ring. Dithioles have two sulfur atoms. A large group of 5-membered ring compounds with three or more heteroatoms also exists. One example

720-406: 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. With a total of 26 π-electrons, of which 18 π-electrons form a planar, continuous cycle,

756-533: The ALAD structural gene can cause increased sensitivity to lead poisoning and acute hepatic porphyria . Alternatively spliced transcript variants encoding different isoforms have been identified. A deficiency of porphobilinogen synthase is usually acquired (rather than hereditary) and can be caused by heavy metal poisoning , especially lead poisoning , as the enzyme is very susceptible to inhibition by heavy metals. Hereditary insufficiency of porphobilinogen synthase

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792-509: The cell, possibly inducing apoptosis or even necrosis. Porphyrin-based compounds are of interest as possible components of molecular electronics and photonics. Synthetic porphyrin dyes have been incorporated in prototype dye-sensitized solar cells . Porphyrins have been investigated as possible anti-inflammatory agents and evaluated on their anti-cancer and anti-oxidant activity. Several porphyrin-peptide conjugates were found to have antiviral activity against HIV in vitro . Heme biosynthesis

828-499: The challenge of preparing [18]porphyrin-(2.1.0.1) and named it as corrphycene or porphycerin . 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 . The Japanese scientist Furuta and Polish scientist Latos-Grażyński almost simultaneously reported the N-confused porphyrins . The inversion of one of

864-448: 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 : A geoporphyrin, also known as a petroporphyrin, is a porphyrin of geologic origin. They can occur in crude oil , oil shale , coal, or sedimentary rocks. Abelsonite

900-831: The fusion of two thiophene rings. Phosphaphenalenes are a tricyclic phosphorus-containing heterocyclic system derived from the carbocycle phenalene . The history of heterocyclic chemistry began in the 1800s, in step with the development of organic chemistry . Some noteworthy developments: Heterocyclic compounds are pervasive in many areas of life sciences and technology. Many drugs are heterocyclic compounds. Porphobilinogen synthase 210 17025 ENSG00000148218 ENSMUSG00000028393 P13716 P10518 NM_000031 NM_001003945 NM_001317745 NM_001276446 NM_008525 NP_000022 NP_001003945 NP_001304674 NP_001263375 NP_032551 Aminolevulinic acid dehydratase ( porphobilinogen synthase , or ALA dehydratase , or aminolevulinate dehydratase )

936-429: The highly hydrated interface of two pro-octamer dimers. It appears to be easily dissociable, and it has been shown that hexamers accumulate when magnesium is removed in vitro . Though it is not common to consider hydronium ions as allosteric regulators, in the case of PBGS, side chain protonation at locations other than the active site has been shown to affect the quaternary structure equilibrium, and thus to affect

972-572: 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: A common synthesis for porphyrins is the Rothemund reaction , first reported in 1936, which

1008-408: The porphyrin ring structure is often described as aromatic . 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 Greek πορφύρα (porphyra)  'purple'. Porphyrin complexes consist of a square planar MN 4 core. The periphery of

1044-583: The porphyrins, consisting of sp-hybridized carbons, generally display small deviations from planarity. "Ruffled" or saddle-shaped porphyrins is attributed to interactions of the system with its environment. Additionally, the metal is often not centered in the N 4 plane. For free porphyrins, the two pyrrole protons are mutually trans and project out of the N 4 plane. These nonplanar distortions are associated with altered chemical and physical properties. Chlorophyll -rings are more distinctly nonplanar, but they are more saturated than porphyrins. Concomitant with

1080-455: The preponderance of work and applications involves unstrained organic 5- and 6-membered rings. Included are pyridine , thiophene , pyrrole , and furan . Another large class of organic heterocycles refers to those fused to benzene rings . For example, the fused benzene derivatives of pyridine, thiophene, pyrrole, and furan are quinoline , benzothiophene , indole , and benzofuran , respectively. The fusion of two benzene rings gives rise to

1116-399: The pyrrolic subunits in the macrocyclic ring resulted in one of the nitrogen atoms facing outwards from the core of the macrocycle. Heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with

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1152-433: The rate of its catalyzed reaction as well. Inspection of the PBGS 6mer* reveals a surface cavity that is not present in the 8mer. Small molecule binding to this phylogenetically variable cavity has been proposed to stabilize 6mer* of the targeted PBGS and consequently inhibit activity. Such allosteric regulators are known as morphlocks because they lock PBGS in a specific morpheein form (6mer*). ALAD enzymatic activity

1188-517: The same protein. Each PBGS subunit consists of a ~300 residue αβ-barrel domain, which houses the enzyme's active site in its center, and a >25 residue N-terminal arm domain. Allosteric regulation of PBGS can be described in terms of the orientation of the αβ-barrel domain with respect to the N-terminal arm domain. Each N -terminal arm has up to two interactions with other subunits in a PBGS multimer. One of these interactions helps to stabilize

1224-421: The study of organic heterocyclic chemistry focuses on organic unsaturated rings. Some heterocycles contain no carbon. Examples are borazine (B 3 N 3 ring), hexachlorophosphazenes (P 3 N 3 rings), and tetrasulfur tetranitride S 4 N 4 . In comparison with organic heterocycles, which have numerous commercial applications, inorganic ring systems are mainly of theoretical interest. IUPAC recommends

1260-481: The synthesis, properties, and applications of organic heterocycles . Examples of heterocyclic compounds include all of the nucleic acids , the majority of drugs, most biomass ( cellulose and related materials), and many natural and synthetic dyes. More than half of known compounds are heterocycles. 59% of US FDA -approved drugs contain nitrogen heterocycles. The study of organic heterocyclic chemistry focuses especially on organic unsaturated derivatives, and

1296-583: 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

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