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PubMed1991

Human tryptophan oxygenase localized to 4q31: possible implications for alcoholism and other behavioral disorders.

A human tryptophan oxygenase clone was isolated by screening a liver cDNA library with a rat tryptophan oxygenase cDNA clone. Analysis showed extensive homology between the rat and the human DNA and protein sequences. The combined use of cell hybrids and in situ hydridization indicated that human tryptophan oxygenase was localized to chromosome band 4q31. The tryptophan oxygenase gene may be important in some human behavior disorders, especially those associated with abnormalities of serotonin metabolism.

Alcoholism↗
PubMed2005

Evidence for the hydrophobic cavity of heme oxygenase-1 to be a CO-trapping site.

Carbon monoxide (CO) is produced during the heme catabolism by heme oxygenase. In brain or blood vessels, CO functions as a neurotransmitter or an endothelial-derived relaxing factor. To verify whether crystallographically proposed CO-trapping sites of rat and cyanobacterial heme oxygenase-1 really work, heme catabolism by heme oxygenase-1 from rat and cyanobacterial Synechocystis sp. PCC 6803 has been scrutinized in the presence of 2-propanol. If 2-propanol occupies the trapping sites, formation of CO-bound verdoheme should be enhanced. Although effects of 2-propanol on the rat heme oxygenase-1 reaction were obscure, the reaction of cyanobacterial enzyme in the presence of NADPH/ferredoxin reductase/ferredoxin was apparently affected. Relative amount of CO-verdoheme versus CO-free verdoheme detected by optical absorption spectra increased as the equivalent of 2-propanol increased, thereby supporting indirectly that the hydrophobic cavity in cyanobacterial enzyme traps CO to reduce CO inhibition of verdoheme degradation.

2-Propanol↗
PubMed2006

Structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins.

Mononuclear non-heme ferrous iron dependent oxygenases and oxidases constitute an extended enzyme family that catalyze a wide range of oxidation reactions. The largest known sub-group employs 2-oxoglutarate as a cosubstrate and catalysis by these and closely related enzymes is proposed to proceed via a ferryl intermediate coordinated to the active site via a conserved HXD/E...H motif. Crystallographic studies on the 2-oxoglutarate oxygenases and related enzymes have revealed a common double-stranded beta-helix core fold that supports the residues coordinating the iron. This fold is common to proteins of the cupin and the JmjC transcription factor families. The crystallographic studies on 2-oxoglutarate oxygenases and closely related enzymes are reviewed and compared with other metallo-enzymes/related proteins containing a double-stranded beta-helix fold. Proposals regarding the suitability of the active sites and folds of the 2-oxoglutarate oxygenases to catalyze reactions involving reactive oxidizing species are described.

Binding Sites↗
PubMed2000

Separation and identification of the regioisomers of verdoheme by reversed-phase ion-pair high-performance liquid chromatography, and characterization of their complexes with heme oxygenase.

We report an HPLC method for separating the four regioisomers of verdoheme formed in the coupled oxidation of hemin with oxygen and ascorbate in aqueous pyridine. The reversed-phase ion-pair system uses hexafluoroacetone and pyridine as ion-pair agents. The regiochemistry of the separated isomers was established both by HPLC of the corresponding biliverdin IX derivatives and by 1H NMR of each isomer. Optical spectra of the pyridine verdohemochrome isomers were similar to each other, but showed differences in the absorption maxima in the red region, which appear at 680, 663, 648 and 660 nm for the alpha, beta, gamma, and delta-isomers, respectively. Each of the four isomers was incorporated anaerobically into heme oxygenase-1, yielding the corresponding verdoheme-enzyme complex. The ferrous forms had absorption maxima at 690, 667, 655, and 663 nm, and their CO-bound forms had maxima at 638, 624, 616, and 626 nm for alpha, beta, gamma, and delta-isomer, respectively. Addition of ferricyanide to the alpha-verdoheme-heme oxygenase complex brought about a ferric low-spin heme-like signal, which is identical with the ferric alpha-verdoheme complexed with the heme oxygenase that was observed in the heme oxygenase reaction.

Ascorbic Acid↗
PubMed1999

Hemozoin stability and dormant induction of heme oxygenase in hemozoin-fed human monocytes.

Human monocytes avidly ingest malarial pigment, hemozoin. Phagocytosed hemozoin persists in the monocyte for a long time and modifies important monocyte functions. Stability of phagocytosed hemozoin may depend on modifications of the hemozoin heme moiety or reduced ability to express heme-inducible heme oxygenase. We show here that the spectral characteristics of alkali-solubilized hemozoin were identical to those of authentic heme, although hemozoin was solubilized by alkali much more slowly than authentic heme. Alkali-solubilized hemozoin was a substrate of microsomal rat heme oxygenase and bilirubin reductase, with bilirubin as the main final product. Hemozoin feeding to human monocytes did not induce heme oxygenase, but authentic heme and alkali-solubilized hemozoin supplemented to hemozoin-fed monocytes induced heme oxygenase and were degraded normally. Lysosomes isolated from hemozoin-fed monocytes released only traces of heme while lysosomes from erythrocyte-fed monocytes liberated considerable quantities of heme. Lack of heme release from hemozoin did not depend on proteolysis-resistant, heme-binding proteins, since lysosomal proteases fully degraded hemozoin-associated proteins but did not solubilize hemozoin. In conclusion, our data indicate that lack of induction of HO1 is due to the intrinsic structural characteristics of hemozoin and not to hemozoin-mediated impairment of the mechanism of HO1 induction.

Animals↗
PubMedDate not supplied

The Anopheles gambiae tryptophan oxygenase gene expressed from a baculovirus promoter complements Drosophila melanogaster vermilion.

An Anopheles gambiae cDNA encoding tryptophan oxygenase was placed under the control of the constitutive baculovirus promoter, ie-1. The chimeric construct, expressed transiently in vermilion (tryptophan oxygenase) mutants of Drosophila melanogaster, partially rescued adult eye color. The successful genetic complementation by this construct demonstrated both the proper function of the tryptophan oxygenase product and the effectiveness of the ie-1 promoter in directing expression of foreign genes in live insects. The functionality of An. gambiae tryptophan oxygenase in a higher fly fulfils predictions based on its structural conservation throughout millions of years of independent evolution.

Animals↗
PubMed2002

Enhanced heme oxygenase activity increases the antioxidant defense capacity of guinea pig liver upon acute cobalt chloride loading: comparison with rat liver.

Changes in the activity of so-called oxidative stress defensive enzymes, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and heme oxygenase, as well as changes in lipid peroxidation and reduced glutathione levels, were measured in guinea pig and rat liver after acute cobalt loading. Cobalt chloride administration produced a much higher degree of lipid peroxidation in guinea pig than in rat liver compared with the control animals. The intrahepatic reduced glutathione content in control guinea pig was higher than that in rat, but was equally decreased in both species after cobalt administration. The enzymatic scavengers of free radicals, superoxide dismutase, catalase and glutathione peroxidase, were significantly decreased in rat liver after acute cobalt loading, and as a compensatory reaction, the heme oxygenase activity was increased (seven-fold). In guinea pig liver, only superoxide dismutase activity was depleted in response to cobalt-induced oxidative stress, while catalase and glutathione peroxidase were highly activated and the heme oxygenase activity was dramatically increased (13-fold). It is assumed that enhanced heme oxygenase activity may have important antioxidant significance by increasing the liver oxidative-stress defense capacity.

Animals↗
PubMed1977

Enzymatic oxidation of cobalt protoporphyrin IX: observations on the mechanism of heme oxygenase action.

Studies on the enzymatic mechanism of microsomal heme oxygenase were made utilizing various porphyrins and metalloporphyrins of different ring substituents and central metal ions. Co-heme (cobalt protoporphyrin IX) was shown to be a substrate for the enzyme and the product of its oxidative metabolism was identified as the natural bile pigment, biliverdin IXalpha isomer. Metalloporphyrins, which do not bind molecular oxygen (Ni, Mn, and Sn protoporphyrin IX), were not substrates for heme oxygenase, although they could competitively inhibit oxidation of reactive substrates for the enzyme. The presence of lipophilic substitutents on pyrrole rings I and II, as well as a central metal atom, were required for the heme oxidation reaction to occur. The oxidative cleavage of Co-heme displayed typical characteristics of an enzyme-mediated reaction, and the oxidation of this substrate, as well as that of Fe-heme (iron protoporphyrin IX), could be supported with either reduced nicotinamide adenine dinucleotide phosphate or reduced nicotinamide adenine dinucleotide. A hypothesis is proposed on the mode of action of heme oxygenase in which the enzyme and its substrate are considered to form a "transitory" hemoprotein which can activate molecular oxygen for cleavage of the heme tetrapyrrole ring. In this formulation, heme as substrate for heme oxygenase is synonymous with heme as prosthetic group for the enzyme.

Animals↗
PubMed1997

Unusual mechanism of oxygen atom transfer and product rearrangement in the catalytic reaction of 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase.

The oxygenation reaction of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase with the substrate, MHPC, was investigated. Two oxygenated flavin intermediates C(4a)-hydroperoxy flavin and C(4a)-hydroxy flavin were found, implying that the enzyme functions similarly to flavoprotein hydroxylases. This finding is supported by the results of independent oxygen-18 tracer experiments, which showed that one atom of oxygen from 18O2 and one atom of oxygen from H218O are incorporated in the product. MHPC oxygenase normally catalyzes both the oxygenation and the hydrolytic ring opening of the pyridine ring of MHPC to yield the acyclic compound, alpha-(N-acetylaminomethylene)succinic acid. Using 5-hydroxynicotinic acid (5HN), which has no 2-methyl group, we tested whether the hydrolytic reaction was due to the presence of the 2-methyl group on MHPC (that prevented rearomatization of the initial product) or to the specific properties of MHPC oxygenase. Product analysis of the enzymatic reaction of 5HN and MHPC oxygenase shows that the enzyme catalyzes the hydroxylation and subsequent hydrolysis of the hydroxylated substrate to yield an acyclic product. The investigation of the oxygenation reaction demonstrates that the enzyme uses the same mechanism to catalyze the 5HN reaction as it does in the MHPC reaction.

Azides↗
PubMed2005

Azide-inhibited bacterial heme oxygenases exhibit an S = 3/2 (dxz,dyz)3(dxy)1(dz2)1 spin state: mechanistic implications for heme oxidation.

The azide complexes of heme oxygenase from Pseudomonas aeruginosa (pa-HO) and Neisseriae meningitidis (nm-HO) have been studied with the aid of (1)H and (13)C NMR spectroscopy. These complexes have been shown to exist as an equilibrium mixture of two populations, one exhibiting an S = (1)/(2), (d(xy))(2)(d(xz), d(yz))(3) electron configuration and planar heme and a second with a novel S = (3)/(2), (d(xz), d(yz))(3)(d(xy))(1)(d(z)(2))(1) spin state and nonplanar heme. At physiologically relevant temperatures, the equilibrium shifts in the direction of the population exhibiting the latter electron configuration and nonplanar heme, whereas at temperatures approaching the freezing point of water, the equilibrium shifts in the direction of the population with the former electronic structure and planar heme. These findings indicate that the microenvironment of the distal pocket in heme oxygenase is unique among heme-containing proteins in that it lowers the sigma-donating (field strength) ability of the distal ligand and, therefore, promotes the attainment of heme electronic structures thus far only observed in heme oxygenase. When the field strength of the distal ligand is slightly lower than that of azide, such as OH(-) (J. Am. Chem. Soc. 2003, 125, 11842), the corresponding complex exists as a mixture of populations with nonplanar hemes and electronic structures that place significant spin density at the meso positions. The ease with which these unusual heme electronic structures are attained by heme oxygenase is likely related to activation of meso carbon reactivity which, in turn, facilitates hydroxylation of a meso carbon by the obligatory ferric hydroperoxide intermediate.

Absorption↗
PubMed2005

The ferrous verdoheme-heme oxygenase complex is six-coordinate and low-spin.

A biosynthetic and enzymatic method was developed for the preparation of 13C-labeled verdoheme, which permits the 13C NMR spectroscopic characterization of this elusive intermediate in the heme oxidation path catalyzed by the enzyme heme oxygenase. The 13C NMR data indicate that the ferrous verdoheme complex of Neisseria meningitides heme oxygenase is hexacoordinate and diamagnetic, with a proximal histidine and likely a distal hydroxide as axial ligands. The coordination number and spin state of the ferrous verdoheme-heme oxygenase complex is in stark contrast to the pentacoordinate and paramagnetic nature of the heme-heme oxygenase complex and heme centers in general.

Carbon Isotopes↗
PubMed2001

Regulation of heme oxygenase activity in rat liver during oxidative stress induced by cobalt chloride and mercury chloride.

Activities of heme oxygenase and tryptophan-2,3-dioxygenase and cytochrome P450 content in liver as well as absorption of the Soret band and optical density at 280 nm in serum were determined 2 and 24 h after administration of HgCl(2) and CoCl(2) and after co-administration of the metal salts with alpha-tocopherol. Administration of HgCl(2) and CoCl(2) increased the contents of hemolysis products in the serum, induced heme oxygenase, and decreased cytochrome P450 content in the liver. Injection of HgCl(2) increased the activity of tryptophan-2,3-dioxygenase holoenzyme and enzyme saturation with the heme, but administration of CoCl(2) decreased these parameters. Pretreatment with alpha-tocopherol completely blocked the changes induced by HgCl(2) after 24 h. Induction of heme oxygenase induced by CoCl(2) was not blocked by alpha-tocopherol, but this antioxidant normalized the increase in the level of hemolysis products in the serum and decrease in tryptophan-2,3-dioxygenase holoenzyme activity and cytochrome P450 content. Mechanisms of regulation of heme oxygenase by mercury and cobalt ions are discussed.

Animals↗
PubMed2004

A small family of LLS1-related non-heme oxygenases in plants with an origin amongst oxygenic photosynthesizers.

Conservation of Lethal-leaf spot 1 (Lls1) lesion mimic gene in land plants including moss is consistent with its recently reported function as pheophorbide a oxygenase (Pao) which catalyzes a key step in chlorophyll degradation (Pruzinska et al., 2003). A bioinformatics survey of complete plant genomes reveals that LLS1(PAO) belongs to a small 5-member family of non-heme oxygenases defined by the presence of Rieske and mononuclear iron-binding domains. This gene family includes chlorophyll a oxygenase (Cao), choline monooxygenase (Cmo), the gene for a 55 kDa protein associated with protein transport through the inner chloroplast membrane (Tic 55) and a novel 52 kDa protein isolated from chloroplasts (Ptc 52). Analysis of gene structure reveals that these genes diverged prior to monocot/dicot divergence. Homologues of LLS1(PAO), CAO, TIC55 and PTC52 but not CMO are found in the genomes of several cyanobacteria. LLS1(PAO), PTC52, TIC55 and a set of related cyanobacterial homologues share an extended carboxyl terminus containing a novel F/Y/W-x(2)-H-x(3)-C-x(2)-C motif not present in CAO. These proteins appear to have evolved during the transition to oxygenic photosynthesis to play various roles in chlorophyll metabolism. In contrast, CMO homologues are found only in plants and are most closely related to aromatic ring-hydroxylating enzymes from soil-dwelling bacteria, suggesting a more recent evolution of this enzyme, possibly by horizontal gene transfer. Our phylogenetic analysis of 95 extant non-heme dioxygenases provides a useful framework for the classification of LLS1(PAO)-related non-heme oxygenases.

Amino Acid Motifs↗
PubMed1974

Microbial oxidation of amines. Partial purification of a trimethylamine mono-oxygenase from Pseudomonas aminovorans and its role in growth on trimethylamine.

1. A mono-oxygenase, which oxidizes trimethylamine and other tertiary amines bearing methyl or ethyl groups, was partially purified sixfold from Pseudomonas aminovorans grown on trimethylamine as sole carbon source. 2. The preferred electron donor was NADPH. The enzyme had a pH optimum of 8.0-9.4 for trimethylamine oxidation, and 8.8-9.2 for dimethylamine oxidation. 3. The oxidation product of trimethylamine was shown to be trimethylamine N-oxide. Other tertiary amines were probably also converted into N-oxides. 4. The enzyme also oxidized secondary amines. 5. The oxidation of trimethylamine was only slightly inhibited by CO and not at all by KCN or proadifen hydrochloride (SKF 525-A), but was inhibited by trimethylsulphonium chloride, tetramethylammonium chloride, 2,4-dichloro-6-phenylphenoxyethylamine (Lilly 53325) and its NN-diethyl derivative (Lilly 18947). 6. The oxidation of dimethylamine showed a similar response to inhibitors and a parallel loss in activity on heating at 35 degrees C. 7. The activities of the trimethylamine mono-oxygenase, trimethylamine N-oxide demethylase and the secondary-amine mono-oxygenase increased severalfold during adaptation of succinate-grown bacteria to growth on trimethylamine, and the trimethylamine mono-oxygenase was the first enzyme to show an increase in activity. It is concluded that all three enzymes are involved in growth on trimethylamine by this organism.

Amines↗
PubMed1979

Induction of liver cell haem oxygenase in iron-overloaded rats.

Rats were chronically iron-overloaded by intraperitonel injections of iron-dextran. Electron microscopy revealed that the excess iron was deposited in ferritin-like particles packed in lysosomes and scattered in hepatic cytoplasm. No mitochondrial iron deposition or damage was seen. Furthermore, mitochondrial preparations from chronically iron-overloaded animals were found to be contaminated with lysosomes, which could explain previously reported increases in mitochondrial iron by chemical analysis. Mitochondrial function, as measured by cytochromes a-a3, b and c concentrations as well as activity of the rate-limiting enzyme of haem synthesis, delta-aminolaevulinate synthetase, was not diminished by chronic iron-overloading. Microsomal haem was decreased by 30% at the time that haem oxygenase, the rate-limiting enzyme of haem degradation, was increased approx. 3-fold. Animals were given a single intraperitoneal injection of iron-dextran and the activities of delta-aminolaevulinate synthetase and haem oxygenase were measured over 24 h. delta-Aminolaevulinate synthetase activity increased approx. 2-fold in these acutely iron-overloaded rat livers, but at a time after the increase in haem oxygenase. These results suggest that an early consequence of excess iron in liver is acceleration of the rate of haem degradation, possible by haem oxygenase.

5-Aminolevulinate Synthetase↗
PubMed1995

Induction by prostaglandin A1 of haem oxygenase in myoblastic cells: an effect independent of expression of the 70 kDa heat shock protein.

Prostaglandins of the A type (PGA) induce the synthesis of 70 kDa heat shock proteins (hsp70) in a large variety of mammalian cells. Induction of hsp70 has been associated with a cytoprotective effect of PGA1 after virus infection or thermal injury. In the present report we provide evidence that, in murine myoblasts, PGA1 is not able to induce hsp70 expression, whereas it increases the synthesis of the constitutive protein, hsc70, and dramatically induces the synthesis of a 32 kDa protein (p32). The p32 protein has been identified as haem oxygenase. PGA1 acts at the transcriptional level by inducing haem oxygenase mRNA synthesis, and the signal for induction appears to be associated with decreased intracellular GSH levels. Haem oxygenase, a low-molecular-mass stress protein induced in mammalian cells by oxidant stress, is known to be part of a general inducible antioxidant defence pathway. The fact that prostaglandin synthesis is stimulated in muscle during contraction and in the heart in response to ischaemia raises the possibility that induction of haem oxygenase by PGA in myoblasts could be part of a protective mechanisms in operation during stress and hypoxia.

Animals↗
PubMed1971

The prematurely evoked synthesis of liver tryptophan oxygenase.

Livers of normal rats are devoid of catalytically or immunochemically reactive tryptophan oxygenase (EC 1.13.1.12) up to the 10th postnatal day; the enzyme reaches adult concentrations on about the twentieth day. Premature tryptophan oxygenase synthesis can be evoked in 4-day-old rats: if an injection of glucocorticoid is followed, a day later, by an injection of tryptophan, adult levels of tryptophan oxygenase activity and antigen content can be attained within 5 hr. The prematurely evoked tryptophan oxygenase is degraded in about 2 days, but the preparatory action of the glucocorticoid is longlasting. Even 4 days later, an injection of tryptophan can evoke significant enzyme formation. Actinomycin D, injected together with or 12 hr before the tryptophan, is not inhibitory, but if injected with the glucocorticoid it prevents enzyme formation upon later injection of tryptophan. The observations suggest that appearance of the new enzyme in developing tissue results from the sequential action of more than one stimulus and that the potentiality for its transcription may develop long before its actual synthesis.

Age Factors↗
PubMed1997

Calmodulin promotes dimerization of the oxygenase domain of human endothelial nitric-oxide synthase.

The active form of endothelial nitric-oxide synthase (eNOS) is a homodimer. The activity of the enzyme is regulated in vivo by calcium signaling involving the binding of calmodulin (CAM), which triggers the activation of eNOS. We have examined the possible role of calcium-mediated CAM binding in promoting dimerization of eNOS through the oxygenase domain of the enzyme. A recombinant form of the oxygenase domain of human eNOS was expressed in a prokaryotic expression system. This recombinant domain contains the catalytic cytochrome P-450 site for arginine oxidation by molecular oxygen as well as the binding sites for tetrahydrobiopterin and Ca2+-CAM but lacks the reductase domain and associated FAD, FMN, and NADPH binding sites. Binding of Ca2+-CAM caused an association of monomeric eNOS oxygenase domain as determined by changes in fluorescence, both intrinsic and extrinsic, and by gel filtration, chemical cross-linking, and particle-sizing. Dimerization of the domain was not dependent on the presence of the substrate, arginine, or the cofactor, tetrahydrobiopterin. A truncated form of the eNOS oxygenase domain lacking the Ca2+-CAM binding region did not undergo self-association to form dimers. These results show that the eNOS reductase domain is not required for Ca2+-CAM-induced dimerization of eNOS and suggest that this dimerization may be a primary event in the activation of eNOS by Ca2+.

Calmodulin↗