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Dioxygenase

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Dioxygenase
Crystal structure ofAcinetobacterstrain ADP1 protocatechuate 3,4-dioxygenase in complex with 3,4-dihydroxybenzoate
Identifiers
SymbolDioxygenase_C
PfamPF00775
PfamclanCL0287
InterProIPR000627
PROSITEPDOC00079
SCOP22pcd/SCOPe/SUPFAM
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary

Dioxygenasesareoxidoreductaseenzymes.Aerobic life,from simple single-celledbacteriaspecies to complexeukaryoticorganisms, has evolved to depend on the oxidizing power ofdioxygenin various metabolic pathways. From energeticadenosine triphosphate(ATP) generation toxenobioticdegradation, the use of dioxygen as a biologicaloxidantis widespread and varied in the exact mechanism of its use. Enzymes employ many different schemes to use dioxygen, and this largely depends on thesubstrateand reaction at hand.

Comparison with monooxygenases

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In themonooxygenases,only a single atom of dioxygen is incorporated into a substrate with the other being reduced to a water molecule. The dioxygenases (EC1.13.11) 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 a single substrate, and a variety ofcofactorschemes are utilized to achieve this. For example, in theα-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.

Iron-containing enzymes

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The most widely observed cofactor involved in dioxygenation reactions isiron,but thecatalyticscheme employed by these iron-containing enzymes 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 aRieske[2Fe-2S] cluster, and those utilizing ahemeprosthetic group.

Mononuclear iron dioxygenases

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The mononuclear iron dioxygenases, or non-hemeiron-dependent dioxygenases as they are also termed, all utilize 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.[1]For instance, carbon-carbon bond cleavage, fatty acid hydroperoxidation, carbon-sulfur bond cleavage, and thiol oxidation are all reactions catalyzed by mononuclear iron dioxygenases.[1][2][3]

Most mononuclear iron dioxygenases are members of thecupin superfamilyin which the overall domain structure is described as a six-stranded β-barrel fold (orjelly rollmotif). 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)5HXH(X)3-4E(X)6G and G(X)5-7PXG(X)2H(X)3N.[4][5]

Extradiol Ring Cleavage
Figure 1. Extradiol Ring Cleavage
Intradiol Ring Cleavage
Figure 2. Intradiol Ring Cleavage

Two important groups of mononuclear, non-heme iron dioxygenases are catechol dioxygenases and2-oxoglutarate (2OG)-dependent dioxygenases.[6]Thecatechol dioxygenases,some of the most well-studied dioxygenase enzymes, use dioxygen to cleave a carbon-carbon bond of an aromaticcatecholring system.[4]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 is coordinated by four protein ligands—twohistidineand twotyrosinate residues—in a trigonal bipyramidal manner with a water molecule occupying the fifth coordination site.[3]Once a catecholate substrate binds to the metal center in abidentatefashion through the deprotonated hydroxyl groups, the ferric iron “activates” the substrate by means of abstracting an electron to produce aradicalon the substrate. This then allows for reaction with dioxygen and subsequent intradiol cleavage to occur through a cyclic anhydride intermediate.[2][4]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.[2][4][7]This activated oxygen species then proceeds to react with the substrate ultimately cleaving the carbon-carbon bond adjacent to the hydroxyl groups through the formation of an α-keto lactone intermediate.[3]

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 is released, yielding an open coordination site for oxygen activation.[6]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.[8]In 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.[8]

Rieske dioxygenases

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The Rieske dioxygenases usually catalyze the cis-dihydroxylation of arenes to cis-dihydro-diol products. These dioxygenases also catalyze sulfoxidation, desaturation, and benzylic oxidation.[2]These enzymes are prominently found in soil bacteria such asPseudomonas,[3]and their reactions constitute the initial step in thebiodegradationof aromatic hydrocarbons.[2]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.

Figure 2. Electron transfer mechanism of Rieske dioxygenases

Rieske dioxygenases have three components: anNADH-dependent FAD reductase,aferredoxinwith two [2Fe-2S] Rieske clusters, and an α3β3 oxygenase with each α-subunit containing a mononuclear iron center and a [2Fe-2S] Rieske cluster.[2]Within each α-subunit, the iron-sulfur cluster and mononuclear iron center are separated by a distance of ~43 Å, much too far for efficientelectron 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 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.[3]

Active site of Rieske dioxygenase (naphthalene 1,2-dioxygenase fromRhodococcus sp.) (PDB 2B1X)

The mechanism of O2activation by this class of dioxygenases has been described.[7]This species could represent the active oxidant, or it could undergo hemolytic O-O bond cleavage to yield an iron(V)-oxo intermediate as the working oxidizing agent.[3][7]

Heme-containing dioxygenases

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While most iron-dependent dioxygenases utilize a non-heme iron cofactor, the oxidation of L-(and D-)tryptophan to N-formylkynurenine is catalyzed by eithertryptophan 2,3-dioxygenase(TDO) orindoleamine 2,3-dioxygenase(IDO), which are heme dioxygenases that utilize iron coordinated by a heme B prosthetic group.[9][10]While these dioxygenases are of interest in part because they uniquely use heme for catalysis, they are also of interest due to their importance intryptophanregulation in the cell, which has numerous physiological implications.[11]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.[9]While the exact reaction mechanism for the heme-dependent dioxygenases is still under debate, it is postulated that the reaction proceeds through either a dioxetane orCriegeemechanism (figures 4, 5).[9][11]

Criegee Rearrangement
Figure 4. Possible Criegee Rearrangement Mechanism by TDO/IDO
Dioxetane Mechanism
Figure 5. Possible Dioxetane Mechanism by TDO/IDO

Cambialistic dioxygenases

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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 ofquercetinto 2-protocatechuoylphloroglucinolcarboxylic acid andcarbon monoxide.[12]The most characterized enzyme, fromAspergillus japonicus,requires the presence ofcopper,[4]and bacterial quercetinases have been discovered that are quite promiscuous (cambialistic)[13]in their requirements of a metal center, with varying degrees of activity reported with substitution ofdivalentmanganese,cobalt,iron,nickeland copper.[12](Quercetin, role in metabolism). Acireductone (1,2-dihydroxy-5-(methylthio)pent-1-en-3-one) dioxygenase(ARD) is found in bothprokaryotesandeukaryotes.[4][12][14]ARD enzymes from most species bind ferrous iron and catalyze the oxidation of acireductone to 4-(methylthio)-2-oxobutanoate, the α-keto acid ofmethionine,andformic acid.However,ARDfromKlebsiella oxytocacatalyzes 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 the methylthioadenosine product of cellularS-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. ThisK. oxytocaenzyme represents a unique example whereby the metal ion present dictates which reaction is catalyzed. The quercetinases and ARD enzymes all are members of thecupin superfamily,to which the mononuclear iron enzymes also belong.[15]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.[4]The ARD enzymes allchelatethe catalytic metal (either Ni or Fe) through the 3-His-1-Glu motif.[15]In these dioxygenases, the coordinatingligandsare provided by both of the typical cupin motifs. In the ARD enzymes, the metal exists in anoctahedral arrangementwith the threehistidineresidues comprising a facial triad.[14]The bacterial quercetinase metal centers typically have atrigonal bipyramidalor 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.[4][12]Empty coordination sites in all metal centers are occupied by aqua ligands until these are displaced by the incoming substrate.

The ability of these dioxygenases to retain activity in the presence of other metal cofactors with wide ranges ofredoxpotentials 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 the intradiolcatechol dioxygenaseswhereby the metal centers activate the substrate for subsequent reaction with dioxygen.

Cofactor-independent dioxygenases

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Figure 5. QDO Catalytic Mechanism

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) and1H-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase(HDO), have been shown to require neither an organic or metal cofactor.[16]These enzymes catalyze the degradation ofquinoloneheterocycles in a manner similar toquercetin dioxygenase,but are thought to mediate a radical reaction of a dioxygen molecule with acarbanionon the substrate (figure 5).[17]Both HDO and QDO belong to theα/β hydrolasesuperfamily 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 the α/β hydrolase superfamily.[16]

Clinical significance

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Diversity in the dioxygenase family means a wide range of biological roles:

  • Tryptophan 2,3-dioxygenase(TDO) helps regulatetryptophanin the body and is expressed in many human tumors.[18]The other heme iron-dependent dioxygenase, IDO, also has relevance to human health, as it functions in inflammatory responses in the context of certain diseases.[19]IDO affects both tryptophan andkynurenineand has been linked to depression in humans.[20]
  • Alkaptonuriais a genetic disease that results in a deficiency ofhomogentisate 1,2-dioxygenase,which is responsible for catalyzing the formation of4-maleylacetoacetatefromhomogentisate.[21]Buildup of homogentisic acid can result in heart valve damage, kidney stones and damage to cartilage in the body.[22]
  • Pantothenate kinase-associated neurodegeneration(PKAN) is anautosomal recessivedisorder that can lead to the development of iron granules andLewy bodiesinneurons.A study has shown that patients diagnosed with PKAN were found to have increasedcysteinelevels in theglobus pallidusas a consequence of acysteine dioxygenasedeficiency.[23]Patients with PKAN often develop symptoms ofdementiaand often die at an early age in adulthood.
  • In DNA repair, the Fe (II)/2-oxoglutarate-dependent dioxygenaseAlkB,functions in the oxidative removal of alkylation damage to DNA. Failure to remove DNA alkylation damage can result in cytotoxicity or mutagenesis during DNA replication.
  • Cyclooxygenases(COX), which are responsible for formingprostanoidsin the human body, are the target of manyNSAIDpain relievers.[10]Inhibition of COX leads to reduced inflammation and has an analgesic effect due to the lowered level of prostaglandin and thromboxane synthesis.

References

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  1. ^abLeitgeb S, Nidetzky B (December 2008). "Structural and functional comparison of 2-His-1-carboxylate and 3-His metallocentres in non-haem iron(II)-dependent enzymes".Biochemical Society Transactions.36(Pt 6): 1180–6.doi:10.1042/BST0361180.PMID19021520.
  2. ^abcdefRunda, Michael E.; De Kok, Niels A. W.; Schmidt, Sandy (2023). "Rieske Oxygenases and Other Ferredoxin-Dependent Enzymes: Electron Transfer Principles and Catalytic Capabilities".ChemBioChem.24(15): e202300078.doi:10.1002/cbic.202300078.PMID36964978.
  3. ^abcdefSamuel de Visser; Devesh Kumar (2011).Iron-containing enzymes versatile catalysts of hydroxylation reactions in nature.Royal Society of Chemistry.ISBN978-1-84973-298-7.
  4. ^abcdefghFetzner S (April 2012)."Ring-cleaving dioxygenases with a cupin fold".Applied and Environmental Microbiology.78(8): 2505–14.Bibcode:2012ApEnM..78.2505F.doi:10.1128/AEM.07651-11.PMC3318818.PMID22287012.
  5. ^Stipanuk MH, Simmons CR, Karplus PA, Dominy JE (June 2011)."Thiol dioxygenases: unique families of cupin proteins".Amino Acids.41(1): 91–102.doi:10.1007/s00726-010-0518-2.PMC3136866.PMID20195658.
  6. ^abSolomon EI, Brunold TC, Davis MI, Kemsley JN, Lee SK, Lehnert N, et al. (January 2000). "Geometric and electronic structure/function correlations in non-heme iron enzymes".Chemical Reviews.100(1): 235–350.doi:10.1021/cr9900275.PMID11749238.
  7. ^abcBarry, Sarah M.; Challis, Gregory L. (2013)."Mechanism and Catalytic Diversity of Rieske Non-Heme Iron-Dependent Oxygenases".ACS Catalysis.3(10): 2362–2370.doi:10.1021/cs400087p.PMC3827946.PMID24244885.
  8. ^abKrebs C, Galonić Fujimori D, Walsh CT, Bollinger JM (July 2007)."Non-heme Fe(IV)-oxo intermediates".Accounts of Chemical Research.40(7): 484–92.doi:10.1021/ar700066p.PMC3870002.PMID17542550.
  9. ^abcEfimov I, Basran J, Thackray SJ, Handa S, Mowat CG, Raven EL (April 2011)."Structure and reaction mechanism in the heme dioxygenases".Biochemistry.50(14): 2717–24.doi:10.1021/bi101732n.PMC3092302.PMID21361337.
  10. ^abSono M, Roach MP, Coulter ED, Dawson JH (November 1996). "Heme-Containing Oxygenases".Chemical Reviews.96(7): 2841–2888.doi:10.1021/cr9500500.PMID11848843.
  11. ^abThackray SJ, Mowat CG, Chapman SK (December 2008)."Exploring the mechanism of tryptophan 2,3-dioxygenase".Biochemical Society Transactions.36(Pt 6): 1120–3.doi:10.1042/BST0361120.PMC2652831.PMID19021508.
  12. ^abcdSchaab MR, Barney BM, Francisco WA (January 2006). "Kinetic and spectroscopic studies on the quercetin 2,3-dioxygenase from Bacillus subtilis".Biochemistry.45(3): 1009–16.doi:10.1021/bi051571c.PMID16411777.
  13. ^"The Single Superoxide Dismutase of Rhodobacter capsulatus Is a Cambialistic, Manganese-Containing Enzyme".Jb.asm.org.Retrieved2014-03-11.
  14. ^abMaroney MJ, Ciurli S (April 2014)."Nonredox nickel enzymes".Chemical Reviews.114(8): 4206–28.doi:10.1021/cr4004488.PMC5675112.PMID24369791.
  15. ^abBoer JL, Mulrooney SB, Hausinger RP (February 2014)."Nickel-dependent metalloenzymes".Archives of Biochemistry and Biophysics.544:142–52.doi:10.1016/j.abb.2013.09.002.PMC3946514.PMID24036122.
  16. ^abFetzner S (November 2002). "Oxygenases without requirement for cofactors or metal ions".Applied Microbiology and Biotechnology.60(3): 243–57.doi:10.1007/s00253-002-1123-4.PMID12436305.S2CID24908037.
  17. ^Bugg TD (September 2003). "Dioxygenase enzymes: catalytic mechanisms and chemical models".Tetrahedron.59(36): 7075–7101.doi:10.1016/S0040-4020(03)00944-X.
  18. ^Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E, Frédérick R, De Plaen E, Uyttenhove C, Wouters J, Masereel B, Van den Eynde BJ (February 2012)."Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase".Proceedings of the National Academy of Sciences of the United States of America.109(7): 2497–502.Bibcode:2012PNAS..109.2497P.doi:10.1073/pnas.1113873109.PMC3289319.PMID22308364.
  19. ^Murakami Y, Hoshi M, Imamura Y, Arioka Y, Yamamoto Y, Saito K (2013)."Remarkable role of indoleamine 2,3-dioxygenase and tryptophan metabolites in infectious diseases: potential role in macrophage-mediated inflammatory diseases".Mediators of Inflammation.2013:391984.doi:10.1155/2013/391984.PMC3588179.PMID23476103.
  20. ^Sublette ME, Postolache TT (September 2012). "Neuroinflammation and depression: the role of indoleamine 2,3-dioxygenase (IDO) as a molecular pathway".Psychosomatic Medicine.74(7): 668–72.doi:10.1097/PSY.0b013e318268de9f.PMID22923699.
  21. ^Voet D, Voet JG (2011).Biochemistry(4th ed.). Hoboken, NJ: John Wiley & Sons. p. 1045.ISBN978-0470917459.
  22. ^Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA (December 2002)."Natural history of alkaptonuria".The New England Journal of Medicine.347(26): 2111–21.doi:10.1056/NEJMoa021736.PMID12501223.
  23. ^Stipanuk, MH; Dominy Jr, JE; Lee, JI; Coloso, RM (June 2006)."Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism".The Journal of Nutrition.136(6 Supplement): 1652S–1659S.doi:10.1093/jn/136.6.1652S.PMID16702335.Retrieved5 April2021.
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