Dioxygenase

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Dioxygenase
PDB 1eob EBI.jpg
Crystal structure of Acinetobacter strain ADP1 protocatechuate 3,4-dioxygenase in complex with 3,4-dihydroxybenzoate
Identifiers
SymbolDioxygenase_C
Pfam PF00775
Pfam clan CL0287
InterPro IPR000627
PROSITE PDOC00079
SCOP2 2pcd / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Dioxygenases are oxidoreductase enzymes. Aerobic life, from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on 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.

Contents

Comparison with monooxygenases

In the monooxygenases, only 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 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.

Iron-containing enzymes

The most widely observed cofactor involved in dioxygenation reactions is iron, but the catalytic scheme 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 a Rieske [2Fe-2S] cluster, and those utilizing a heme prosthetic group.

Mononuclear iron dioxygenases

The mononuclear iron dioxygenases, or non-heme iron-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 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)5HXH(X)3-4E(X)6G and G(X)5-7PXG(X)2H(X)3N. [4] [5]

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

Two important groups of mononuclear, non-heme iron dioxygenases are catechol dioxygenases and 2-oxoglutarate (2OG)-dependent dioxygenases. [6] The catechol dioxygenases, some of the most well-studied dioxygenase enzymes, use dioxygen to cleave a carbon-carbon bond of an aromatic catechol ring 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—two histidine and two tyrosinate 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 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 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

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 as Pseudomonas , [3] and their reactions constitute the initial step in the biodegradation of 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.png
Figure 2. Electron transfer mechanism of Rieske dioxygenases

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 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 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 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 from Rhodococcus sp.) (PDB 2B1X) 2B1X Active Site.png
Active site of Rieske dioxygenase (naphthalene 1,2-dioxygenase from Rhodococcus sp.) (PDB 2B1X)

The mechanism of O2 activation 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

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 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 in tryptophan regulation 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 or Criegee mechanism (figures 4, 5). [9] [11]

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

Cambialistic dioxygenases

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. [12] The most characterized enzyme, from Aspergillus japonicus , requires the presence of copper, [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 of divalent manganese, cobalt, iron, nickel and copper. [12] (Quercetin, role in metabolism). Acireductone (1,2-dihydroxy-5-(methylthio)pent-1-en-3-one) dioxygenase (ARD) is found in both prokaryotes and eukaryotes. [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 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 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 the cupin 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 all chelate the catalytic metal (either Ni or Fe) through the 3-His-1-Glu motif. [15] In these dioxygenases, the coordinating ligands are provided by both of the typical cupin motifs. In the ARD enzymes, the metal exists in an octahedral arrangement with the three histidine residues comprising a facial triad. [14] 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. [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 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 the intradiol catechol dioxygenases whereby the metal centers activate the substrate for subsequent reaction with dioxygen.

Cofactor-independent dioxygenases

Figure 5. QDO Catalytic Mechanism 1H-3-hydroxy-4-oxoquinoline 2,4-dioxygenase Catalytic Mechanism.png
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) and 1H-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 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). [17] 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 the α/β hydrolase superfamily. [16]

Clinical significance

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

Related Research Articles

<span class="mw-page-title-main">Metalloprotein</span> Protein that contains a metal ion cofactor

Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins contain zinc-binding protein domains although there may be up to 3000 human zinc metalloproteins.

<span class="mw-page-title-main">Phenylalanine hydroxylase</span> Mammalian protein found in Homo sapiens

Phenylalanine hydroxylase (PAH) (EC 1.14.16.1) is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin (BH4, a pteridine cofactor) and a non-heme iron for catalysis. During the reaction, molecular oxygen is heterolytically cleaved with sequential incorporation of one oxygen atom into BH4 and phenylalanine substrate. In humans, mutations in its encoding gene, PAH, can lead to the metabolic disorder phenylketonuria.

<span class="mw-page-title-main">Cofactor (biochemistry)</span> Non-protein chemical compound or metallic ion

A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst. Cofactors can be considered "helper molecules" that assist in biochemical transformations. The rates at which these happen are characterized in an area of study called enzyme kinetics. Cofactors typically differ from ligands in that they often derive their function by remaining bound.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for example, they have not been found in Escherichia coli. In mammals, these enzymes oxidize steroids, fatty acids, xenobiotics, and participate in many biosyntheses. By hydroxylation, CYP450 enzymes convert xenobiotics into hydrophilic derivatives, which are more readily excreted.

<span class="mw-page-title-main">Cysteine dioxygenase</span> Enzyme

Cysteine dioxygenase (CDO) is a non-heme iron enzyme that catalyzes the conversion of L-cysteine to cysteine sulfinic acid. CDO plays an important role in cysteine catabolism, regulating intracellular levels of cysteine and responding changes in cysteine availability. As such, CDO is highly regulated and undergoes large changes in concentration and efficiency. It oxidizes cysteine to the corresponding sulfinic acid by activation of dioxygen, although the exact mechanism of the reaction is still unclear. In addition to being found in mammals, CDO also exists in some yeast and bacteria, although the exact function is still unknown. CDO has been implicated in various neurodegenerative diseases and cancers, which is likely related to cysteine toxicity.

Aromatic-ring-hydroxylating dioxygenases (ARHD) incorporate two atoms of dioxygen (O2) into their substrates in the dihydroxylation reaction. The product is (substituted) cis-1,2-dihydroxycyclohexadiene, which is subsequently converted to (substituted) benzene glycol by a cis-diol dehydrogenase.

An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14.

<span class="mw-page-title-main">Catechol 1,2-dioxygenase</span> Enzyme

Catechol 1,2- dioxygenase is an enzyme that catalyzes the oxidative ring cleavage of catechol to form cis,cis-muconic acid:

In chemistry, a (redox) non-innocent ligand is a ligand in a metal complex where the oxidation state is not clear. Typically, complexes containing non-innocent ligands are redox active at mild potentials. The concept assumes that redox reactions in metal complexes are either metal or ligand localized, which is a simplification, albeit a useful one.

<span class="mw-page-title-main">Formate dehydrogenase</span>

Formate dehydrogenases are a set of enzymes that catalyse the oxidation of formate to carbon dioxide, donating the electrons to a second substrate, such as NAD+ in formate:NAD+ oxidoreductase (EC 1.17.1.9) or to a cytochrome in formate:ferricytochrome-b1 oxidoreductase (EC 1.2.2.1). This family of enzymes has attracted attention as inspiration or guidance on methods for the carbon dioxide fixation, relevant to global warming.

<span class="mw-page-title-main">Isopenicillin N synthase</span>

Isopenicillin N synthase (IPNS) is a non-heme iron protein belonging to the 2-oxoglutarate (2OG)-dependent dioxygenases oxidoreductase family. This enzyme catalyzes the formation of isopenicillin N from δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (LLD-ACV).

<span class="mw-page-title-main">Phytanoyl-CoA dioxygenase</span> Class of enzymes

In enzymology, a phytanoyl-CoA dioxygenase (EC 1.14.11.18) is an enzyme that catalyzes the chemical reaction

In enzymology, a taurine dioxygenase (EC 1.14.11.17) is an enzyme that catalyzes the chemical reaction.

<span class="mw-page-title-main">Tryptophan 2,3-dioxygenase</span> Mammalian protein found in Homo sapiens

In enzymology, tryptophan 2,3-dioxygenase (EC 1.13.11.11) is a heme enzyme that catalyzes the oxidation of L-tryptophan (L-Trp) to N-formyl-L-kynurenine, as the first and rate-limiting step of the kynurenine pathway.

<span class="mw-page-title-main">D-lysine 5,6-aminomutase</span>

In enzymology, D-lysine 5,6-aminomutase is an enzyme that catalyzes the chemical reaction

A transition metal oxo complex is a coordination complex containing an oxo ligand. Formally O2-, an oxo ligand can be bound to one or more metal centers, i.e. it can exist as a terminal or (most commonly) as bridging ligands (Fig. 1). Oxo ligands stabilize high oxidation states of a metal. They are also found in several metalloproteins, for example in molybdenum cofactors and in many iron-containing enzymes. One of the earliest synthetic compounds to incorporate an oxo ligand is potassium ferrate (K2FeO4), which was likely prepared by Georg E. Stahl in 1702.

<span class="mw-page-title-main">Galactose oxidase</span>

Galactose oxidase is an enzyme that catalyzes the oxidation of D-galactose in some species of fungi.

Alpha-ketoglutarate-dependent hydroxylases are a major class of non-heme iron proteins that catalyse a wide range of reactions. These reactions include hydroxylation reactions, demethylations, ring expansions, ring closures, and desaturations. Functionally, the αKG-dependent hydroxylases are comparable to cytochrome P450 enzymes. Both use O2 and reducing equivalents as cosubstrates and both generate water.

This article covers protein engineering of cytochrome (CYP) P450 enzymes. P450s are involved in a range of biochemical catabolic and anabolic process. Natural P450s can perform several different types of chemical reactions including hydroxylations, N,O,S-dealkylations, epoxidations, sulfoxidations, aryl-aryl couplings, ring contractions and expansions, oxidative cyclizations, alcohol/aldehyde oxidations, desaturations, nitrogen oxidations, decarboxylations, nitrations, as well as oxidative and reductive dehalogenations. Engineering efforts often strive for 1) improved stability 2) improved activity 3) improved substrate scope 4) enabled ability to catalyze unnatural reactions. P450 engineering is an emerging field in the areas of chemical biology and synthetic organic chemistry (chemoenzymatic).

<span class="mw-page-title-main">Non-heme iron protein</span>

In biochemistry, non-heme iron proteins describe families of enzymes that utilize iron at the active site but lack heme cofactors. Iron-sulfur proteins, including those that are enzymes, are not included in this definition.

References

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