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45-676: More specifically, 1,2-CTD is an intradiol dioxygenase , a family of catechol dioxygenases that cleaves the bond between the phenolic hydroxyl groups of catechol using an Fe cofactor. Thus far, 1,2-CTD has been observed to exist in the following species of soil bacteria and fungi: Pseudomonas sp. , Pseudomonas fluorescens , Aspergillus niger , Brevibacterium fuscum , Acinetobacter calcoaceticus , Trichosporon cutaneum , Rhodococcus erythropolis , Frateuria sp. , Rhizobium trifolii , Pseudomonas putida , Candida tropicalis , Candida maltose , Rhizobium leguminosarum , and Nocardia sp. . These bacteria subsequently employ 1,2-CTD in

90-435: A cofactor to cleave the carbon-carbon bond between the phenolic hydroxyl groups of catechol, thus yielding muconic acid as its product. In contrast, 2,3-CTD utilizes Fe as a cofactor to cleave the carbon-carbon bond adjacent to the phenolic hydroxyl groups of catechol, thus yielding 2-hydroxymuconaldehye as its product. Almost all members of the 1,2-CTD family are homodimers ; the 1,2-CTD enzyme produced by Pseudomonas arvilla

135-502: A distance of 40 Å, they are not believed to allosterically effect one another. In contrast, the linker domain is composed of α helices supplied by the two catalytic domains: each domain contributes five helices from their N termini and one from a helix that spans both the catalytic domain and the linker domain. At the center of the linker domain resides an 8 by 35 Å hydrophobic tunnel with two phospholipids bound at each end. The head of each phospholipid points outward towards solution while

180-444: A greater trans effect than NH 3 . The procedure is however complicated by the production of Magnus's green salt . As a result, cisplatin is produced commercially via [PtI 4 ] as first reported by Dhara in 1970. If, on the other hand, one starts from Pt(NH 3 ) 4 , the trans product is obtained instead: The trans effect in square complexes can be explained in terms of an addition/elimination mechanism that goes through

225-486: A heme B prosthetic group. While these dioxygenases are of interest in part because they uniquely use heme for catalysis, they are also of interest due to their importance in tryptophan regulation in the cell, which has numerous physiological implications. The initial association of the substrate with the dioxygen-iron in the enzyme active site is thought to either proceed via radical or electrophilic addition, requiring either ferrous iron or ferric iron, respectively. While

270-418: A mononuclear iron center and a [2Fe-2S] Rieske cluster. Within each α-subunit, the iron-sulfur cluster and mononuclear iron center are separated by a distance of ~43 Å, much too far for efficient electron transfer . Instead, it is proposed electron transfer is mediated through these two centers in adjacent subunits, that the iron-sulfur cluster of one subunit transfers electrons to the mononuclear iron center of

315-445: A single atom of dioxygen is incorporated into a substrate with the other being reduced to a water molecule. The dioxygenases ( EC 1.13.11 ) catalyze the oxidation of a substrate without the reduction of one oxygen atom from dioxygen into a water molecule. However, this definition is ambiguous because it does not take into account how many substrates are involved in the reaction. The majority of dioxygenases fully incorporate dioxygen into

360-492: A single catalytic iron to incorporate either one or both atoms of dioxygen into a substrate. Despite this common oxygenation event, the mononuclear iron dioxygenases are diverse in how dioxygen activation is used to promote certain chemical reactions. For instance, carbon-carbon bond cleavage, fatty acid hydroperoxidation, carbon-sulfur bond cleavage, and thiol oxidation are all reactions catalyzed by mononuclear iron dioxygenases. Most mononuclear iron dioxygenases are members of

405-456: A single substrate, and a variety of cofactor schemes are utilized to achieve this. For example, in the α-ketoglutarate -dependent enzymes, one atom of dioxygen is incorporated into two substrates, with one always being α-ketoglutarate, and this reaction is brought about by a mononuclear iron center. The most widely observed cofactor involved in dioxygenation reactions is iron , but the catalytic scheme employed by these iron-containing enzymes

450-400: A trigonal bipyramidal intermediate. Ligands with a high trans effect are in general those with high π acidity (as in the case of phosphines) or low-ligand lone-pair–d π repulsions (as in the case of hydride), which prefer the more π-basic equatorial sites in the intermediate. The second equatorial position is occupied by the incoming ligand; due to the principle of microscopic reversibility ,

495-405: Is coordinated by four protein ligands—two histidine and two tyrosinate residues —in a trigonal bipyramidal manner with a water molecule occupying the fifth coordination site. Once a catecholate substrate binds to the metal center in a bidentate fashion through the deprotonated hydroxyl groups, the ferric iron “activates” the substrate by means of abstracting an electron to produce a radical on

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540-520: Is coordinated to Fe after its deprotonation by the Tyr200 ligand. In the process of deprotonating the C3 hydroxyl group, Tyr200 dissociates from the catalytic complex. Oxygen is bonded to the substrate through a series of trans influences and stabilizing hydrogen bonding between the substrate and other active site amino acid residues. His226 accepts electron density from the substrate, consequently decreasing

585-399: Is highly diverse. Iron-containing dioxygenases can be subdivided into three classes on the basis of how iron is incorporated into the active site: those employing a mononuclear iron center, those containing a Rieske [2Fe-2S] cluster, and those utilizing a heme prosthetic group. The mononuclear iron dioxygenases, or non- heme iron-dependent dioxygenases as they are also termed, all utilize

630-455: Is most often observed in octahedral transition metal complexes. In addition to this kinetic trans effect , trans ligands also have an influence on the ground state of the molecule, the most notable ones being bond lengths and stability. Some authors prefer the term trans influence to distinguish it from the kinetic effect, while others use more specific terms such as structural trans effect or thermodynamic trans effect . The discovery of

675-450: Is released, yielding an open coordination site for oxygen activation. Upon oxygen binding, a poorly understood transformation occurs during which 2OG is oxidatively decarboxylated to succinate and the O-O bond is cleaved to form a Fe(IV)-oxo ( ferryl ) intermediate. This powerful oxidant is then utilized to carry out various reactions, including hydroxylation, halogenation, and demethylation. In

720-468: Is the exception to this rule, containing two highly homologous subunits that can form either a homo- or hetero- dimer. The enzyme resembles a boomerang in shape, and can therefore be clearly divided into three domains: two catalytic domains residing at each end of the “boomerang” and a linker domain at the center. Each catalytic domain is composed of two stacked, mixed topology β sheets and several random coils . These sheets and coils subsequently encompass

765-585: The cupin superfamily in which the overall domain structure is described as a six-stranded β-barrel fold (or jelly roll motif). At the center this barrel structure is a metal ion, most commonly ferrous iron, whose coordination environment is frequently provided by residues in two partially conserved structural motifs: G(X) 5 HXH(X) 3 - 4 E(X) 6 G and G(X) 5 - 7 PXG(X) 2 H(X) 3 N. Two important groups of mononuclear, non-heme iron dioxygenases are catechol dioxygenases and 2-oxoglutarate (2OG)-dependent dioxygenases . The catechol dioxygenases , some of

810-467: The cupin superfamily , to which the mononuclear iron enzymes also belong. The metal coordination scheme for the QueD enzymes is either a 3-His or 3-His-1-Glu with the exact arrangement being organism-specific. The ARD enzymes all chelate the catalytic metal (either Ni or Fe) through the 3-His-1-Glu motif. In these dioxygenases, the coordinating ligands are provided by both of the typical cupin motifs. In

855-621: The ARD enzymes, the metal exists in an octahedral arrangement with the three histidine residues comprising a facial triad. The bacterial quercetinase metal centers typically have a trigonal bipyramidal or octahedral coordination environment when there are four protein ligands; the metal centers of the copper-dependent QueD enzymes possesses a distorted tetrahedral geometry in which only the three conserved histidine residues provide coordination ligands. Empty coordination sites in all metal centers are occupied by aqua ligands until these are displaced by

900-433: The active oxidant, or it could undergo hemolytic O-O bond cleavage to yield an iron(V)-oxo intermediate as the working oxidizing agent. While most iron-dependent dioxygenases utilize a non-heme iron cofactor, the oxidation of L-(and D-)tryptophan to N-formylkynurenine is catalyzed by either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), which are heme dioxygenases that utilize iron coordinated by

945-494: The active site: a non-heme iron(III) complex. Without heme, iron must be ligated to four amino acid residues (Tyr200, His226, Tyr164, His224) to maintain is catalytically active conformation. With Tyr200 and His226 acting as the axial ligands and Tyr164, His224, and a solvent water molecule acting as equatorial ligands, the Fe complex displays trigonal bipyramidal geometry. Since the active sites of each catalytic domain are separated by

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990-464: The adjacent subunit which is conveniently separated by ~12 Å. While this distance would appear optimal for efficient electron transfer, replacement of the bridging aspartate residue causes a loss of enzyme function, suggesting that electron transfer instead proceeds through the hydrogen-bonding network held in place by this aspartate residue. The mechanism of O 2 activation by this class of dioxygenases has been described. This species could represent

1035-436: The aforementioned step, leading to the cleavage of O 2 and the subsequent insertion of one of the oxygen molecules between C3 and C4. Rapid hydrolysis follows this reaction, yielding a primed active site and product. Dioxygenase#Iron-containing enzymes Dioxygenases are oxidoreductase enzymes . Aerobic life , from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on

1080-670: The best characterized case, the hydroxylases, the ferryl intermediate abstracts a hydrogen atom from the target position of the substrate, yielding a substrate radical and Fe(III)-OH. This radical then couples to the hydroxide ligand, producing the hydroxylated product and the Fe(II) resting state of the enzyme. The Rieske dioxygenases usually catalyze the cis-dihydroxylation of arenes to cis-dihydro-diol products. These dioxygenases also catalyze sulfoxidation, desaturation, and benzylic oxidation. These enzymes are prominently found in soil bacteria such as Pseudomonas , and their reactions constitute

1125-497: The bond between Fe and the C4 hydroxyl. At the same time the bond between the C3 hydroxyl and Fe is increased due to the electron withdrawing effects of Tyr164. These distortions, coupled with the hydrogen bonding between Arg221 and the C3 hydroxyl, induces the C3 hydroxyl group to ketonize and increases the carbanion character of C4. The newly formed C4 carbanion attacks O2, thus binding it to the substrate. Another trans influence follows

1170-420: The bonds between the metal and the ligand trans to a trans-influencing ligand. Stretching by as much as 0.2 Å occurs with strong trans-influencing ligands such as hydride. A cis influence can also be observed, but is smaller than the trans influence. The relative importance of the cis and trans influences depends on the formal electron configuration of the metal center, and explanations have been proposed based on

1215-456: The degradation of quinolone heterocycles in a manner similar to quercetin dioxygenase , but are thought to mediate a radical reaction of a dioxygen molecule with a carbanion on the substrate (figure 5). Both HDO and QDO belong to the α/β hydrolase superfamily of enzymes, although the catalytic residues in HDO and QDO do not seem to serve the same function as they do in the rest of the enzymes in

1260-413: The departing ligand must also leave from an equatorial position. The third and final equatorial site is occupied by the trans ligand, so the net result is that the kinetically favored product is the one in which the ligand trans to the one with the largest trans effect is eliminated. The structural trans effect can be measured experimentally using X-ray crystallography , and is observed as a stretching of

1305-586: The exact reaction mechanism for the heme-dependent dioxygenases is still under debate, it is postulated that the reaction proceeds through either a dioxetane or Criegee mechanism (figures 4, 5). While iron is by far the most prevalent cofactor used for enzymatic dioxygenation, it is not required by all dioxygenases for catalysis. Quercetin 2,3-dioxygenase (quercetinase, QueD) catalyzes the dioxygenolytic cleavage of quercetin to 2-protocatechuoylphloroglucinolcarboxylic acid and carbon monoxide . The most characterized enzyme, from Aspergillus japonicus , requires

1350-419: The incoming substrate. The ability of these dioxygenases to retain activity in the presence of other metal cofactors with wide ranges of redox potentials suggests the metal center does not play an active role in the activation of dioxygen. Rather, it is thought the metal center functions to hold the substrate in the proper geometry for it to react with dioxygen. In this respect, these enzymes are reminiscent of

1395-485: The initial step in the biodegradation of aromatic hydrocarbons. Rieske dioxygenases are structurally more complex than other dioxygenases due to the need for an efficient electron transfer pathway (figure 2) to mediate the additional, simultaneous two-electron reduction of the aromatic substrate. Rieske dioxygenases have three components: an NADH-dependent FAD reductase , a ferredoxin with two [2Fe-2S] Rieske clusters, and an α3β3 oxygenase with each α-subunit containing

Catechol 1,2-dioxygenase - Misplaced Pages Continue

1440-476: The intradiol catechol dioxygenases whereby the metal centers activate the substrate for subsequent reaction with dioxygen. Dioxygenases that catalyze reactions without the need for a cofactor are much more rare in nature than those that do require them. Two dioxygenases, 1H-3-hydroxy-4-oxo-quinoline 2,4-dioxygenase (QDO) and 1H-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase (HDO), have been shown to require neither an organic or metal cofactor. These enzymes catalyze

1485-544: The last step of the degradation of aromatic compounds to aliphatic products. Two families of dioxygenases were discovered by Osamu Hayaishi and Kizo Hashimoto in 1950: catechol 1,2-dioxygenase and catechol 2,3-dioxygenase (2,3-CTD). The two enzymes were identified to be a part of two separate catechol dioxygenase families: 1,2-CTD was classified as an intradiol dioxygenase while 2,3-CTD was classified as an extradiol dioxygenase . The two enzymes can be distinguished based on their reaction products and cofactors. 1,2-CTD uses Fe as

1530-441: The methylthioadenosine product of cellular S-Adenosyl methionine (SAM) reactions is eventually converted to acireductone. While the exact role of Ni-ARD is not known, it is suspected to help regulate methionine levels by acting as a shunt in the salvage pathway. This K. oxytoca enzyme represents a unique example whereby the metal ion present dictates which reaction is catalyzed. The quercetinases and ARD enzymes all are members of

1575-409: The most well-studied dioxygenase enzymes, use dioxygen to cleave a carbon-carbon bond of an aromatic catechol ring system. Catechol dioxygenases are further classified as being “extradiol” or “intradiol,” and this distinction is based on mechanistic differences in the reactions (figures 1 & 2). Intradiol enzymes cleave the carbon-carbon bond between the two hydroxyl groups. The active ferric center

1620-432: The oxidation of acireductone to 4-(methylthio)-2-oxobutanoate, the α-keto acid of methionine , and formic acid . However, ARD from Klebsiella oxytoca catalyzes an additional reaction when nickel(II) is bound: it instead produces 3-(methylthio)propionate, formate, and carbon monoxide from the reaction of acireductone with dioxygen. The activity of Fe-ARD is closely interwoven with the methionine salvage pathway, in which

1665-409: The oxidizing power of dioxygen in various metabolic pathways. From energetic adenosine triphosphate (ATP) generation to xenobiotic degradation, the use of dioxygen as a biological oxidant is widespread and varied in the exact mechanism of its use. Enzymes employ many different schemes to use dioxygen, and this largely depends on the substrate and reaction at hand. In the monooxygenases , only

1710-446: The phenolic hydrocarbons vital in lipid membrane structure. The catalytic mechanism of catechol 1,2-dioxygenase was elucidated using a combination of O labeling experiments and crystallography . Upon entering the active site, the hydroxyl group on the fourth carbon (C4) of catechol binds to Fe; this binding is facilitated by the hydroxide ligand, which deprotonates the C4 hydroxyl group. The second catechol hydroxyl group on carbon 3 (C3)

1755-509: The presence of copper , and bacterial quercetinases have been discovered that are quite promiscuous (cambialistic) in their requirements of a metal center, with varying degrees of activity reported with substitution of divalent manganese , cobalt , iron, nickel and copper. (Quercetin, role in metabolism). Acireductone (1,2-dihydroxy-5-(methylthio)pent-1-en-3-one) dioxygenase (ARD) is found in both prokaryotes and eukaryotes . ARD enzymes from most species bind ferrous iron and catalyze

1800-408: The substrate ultimately cleaving the carbon-carbon bond adjacent to the hydroxyl groups through the formation of an α-keto lactone intermediate. In the 2OG-dependent dioxygenases, ferrous iron ( Fe(II) ) is also coordinated by a (His)2(Glu/Asp)1 "facial triad" motif. Bidentate coordination of 2OG and water completes a pseudo-octahedral coordination sphere. Following substrate binding, the water ligand

1845-509: The substrate. This then allows for reaction with dioxygen and subsequent intradiol cleavage to occur through a cyclic anhydride intermediate. Extradiol members utilize ferrous iron as the active redox state, and this center is commonly coordinated octahedrally through a 2-His-1-Glu motif with labile water ligands occupying empty positions. Once a substrate binds to the ferrous center, this promotes dioxygen binding and subsequent activation. This activated oxygen species then proceeds to react with

Catechol 1,2-dioxygenase - Misplaced Pages Continue

1890-417: The tails are embedded within the enzyme. The function of this hydrophobic tunnel is unknown, though two hypotheses have been postulated concerning its utility. The first is that the binding of the terminal phospholipids alters the conformation of the active sites, implying that the tunnel acts as an effector, only allowing the enzyme to be active in certain areas of the cell. The second hypothesis postulates that

1935-500: The trans effect is attributed to Ilya Ilich Chernyaev , who recognized it and gave it a name in 1926. The intensity of the trans effect (as measured by the increase in rate of substitution of the trans ligand) follows this sequence: One classic example of the trans effect is the synthesis of cisplatin and its trans isomer . The complex PtCl 4 reacts with ammonia to give [PtCl 3 NH 3 ] . A second substitution by ammonia gives cis-[PtCl 2 (NH 3 ) 2 ], showing that Cl- has

1980-438: The tunnel regulates lipid membrane rigidity through its degradation of phenolic hydrocarbons and ability to bind to other lipids. Studies have shown that phenolic hydrocarbons affect the functional and structural properties of cell membranes. 1,2-CTD degrades phenolic hydrocarbons key to the synthesis lipid membranes. Therefore, 1,2-CTD may bind to the cell lipid membrane via its terminal phospholipids and thus have greater access to

2025-497: The α/β hydrolase superfamily. Diversity in the dioxygenase family means a wide range of biological roles: Trans effect In inorganic chemistry , the trans effect is the increased lability of ligands that are trans to certain other ligands, which can thus be regarded as trans-directing ligands. It is attributed to electronic effects and it is most notable in square planar complexes , although it can also be observed for octahedral complexes. The analogous cis effect

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