Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.14.99.3 (heme oxygenase)
4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme oxygenase (HO) catalyzes the first steps in the breakdown of heme to biliverdin and carbon monoxide. It is a membrane-bound protein that has been shown to exist in two isoforms, HO-1 and HO-2. Recently, a soluble, truncated form of rat HO-1 (rHO) lacking the 23 amino-acid membrane anchor has been expressed in E. coli. Extended X-ray absorption fine structure (EXAFS) data on ferric rHO and its fluoride derivative support assignment of the axial iron ligands as oxygen and/or nitrogen donors having distances similar to ferric myoglobin. The electronic absorption and magnetic circular dichroism (MCD) spectra of the ferric and ferrous protoheme complexes of rHO as well as various ligand adducts are very similar to the corresponding spectra of myoglobin. The present study is the first investigation of the heme-heme oxygenase complex with EXAFS and MCD spectroscopy and establishes that the proximal ligand to the heme in rHO is histidine. Furthermore, the close similarity between the electronic absorption and MCD spectra of ferric rHO and myoglobin over the pH range 6 to 10 is consistent with distal heme ligation of ferric rHO as a water molecule or hydroxide ion, depending on pH. Taken together and in conjunction with the results of earlier studies, EXAFS, electronic absorption, and MCD spectroscopy solidly establish that the ligands to the heme in rHO are identical to those in myoglobin, namely, histidine/H2O at low pH and histidine/OH at high pH.
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PMID:Ligation of the iron in the heme-heme oxygenase complex: X-ray absorption, electronic absorption and magnetic circular dichroism studies. 869 42

The aim of the present study was to elucidate the role of carbon monoxide (CO) in learning and to compare it with that of nitric oxide (NO). Effects of an inhibitor of heme oxygenase which produces CO, Zn-protoporphyrin IX, on passive avoidance learning and spatial learning in mice were examined using step through, step down and water maze tests. Zn-protoporphyrin IX (10, 20 nmol, i.c.v.) affected neither type of learning. In contrast, N-omega-nitro-L-arginine (40 nmol, i.c.v.), an inhibitor of NO synthase, impaired spatial learning, but not passive avoidance learning. These results suggest that NO but not CO is involved in spatial learning.
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PMID:Nitric oxide but not carbon monoxide is involved in spatial learning of mice. 885 2

The workshop covered three major areas: Unconjugated bilirubin (UCB) chemistry and physical chemistry; UCB transport and intracellular trafficking; and evaluation and therapy of neonatal and congenital hyperbilirubinemias. Findings of studies in the chemistry and physical chemistry area were as follows. (1) Nuclear magnetic resonance (NMR) studies of highly enriched 13COOH mesobilirubin in water-dimethyl sulfoxide systems indicated that the pKa values of the carboxyl groups are 4.2 and 4.9, respectively. This finding differs from some reports that suggest that the two pKa values in aqueous systems are near or above pH 7.0. (2) Contrasting views of the hydrophobic interactions of UCB with bile salts were presented: one suggested that multiple bile salt monomers bind to one UCB molecule; the other suggested that UCB binds to the nonpolar surface of helical bile salt micelles. (3) Structures were proposed for the varied calcium and copper bilirubinate salts formed at various pH values and cation/UCB ratios. (4) Studies of binding of UCB to human serum albumin (HSA) showed marked diminution of UCB-binding affinity as albumin and chloride concentrations increased. (5) A unique UCB derivative, bilirubin-C10-sulfonic acid, was identified as the major bile pigment in bullfrog bile. (6) New methods were presented for removal of impurities from preparations of bile salts and UCB. Findings of studies in the transport area were as follows. (1) Four putative basolateral and two putative canalicular hepatocytic transporters of UCB and related organic anions were described. Special emphasis was given to the adenosine triphosphate (ATP)-dependent canalicular multi-specific organic anion transporter that is defective in three strains of mutant rats with congenital conjugated hyperbilirubinemia. (2) The roles of the classical and newer molecular biological approaches to identification of these transporters were contrasted, and their limitations were discussed. (3) The relative roles of the multiple carriers in UCB transport under different conditions and substrate concentrations were discussed. (4) Cytosolic UCB-binding proteins (e.g., ligandin) were shown to promote transcellular movement of UCB by solubilizing and transporting the pigment in the aqueous phase while limiting binding of UCB to the relatively immobile membranes of cell organelles. (5) Mechanisms were presented for translocation of UDP-glucuronic acid (UDPGA) into the lumenal location of UDPGA transferase in the endoplasmic reticulum, as well as the enhancement of this process by N-acetyl-glucosamine. Studies in the neonatal and congenital jaundice area were as follows. (1) Criteria were reviewed for initiating treatment of neonatal jaundice, emphasizing the primacy of serum bilirubin levels, gestational age, and hemolysis as risk factors for kernicterus. (2) New methods were presented for frequent, automated monitoring of serum bilirubin levels and breath CO levels as an index of rates of formation of UCB from heme. (3) The current status and limitations of new approaches to treatment of severe unconjugated hyperbilirubinemia were discussed: hepatocyte transplantation and gene therapy, still in the stage of development in animal models, have provided only partial and temporary relief of hyperbilirubinemia; extracorporeal liver assist devices have had some success in initial human studies; and inhibition of heme oxygenase (HO) with metalloporphyrins, especially tin mesoporphyrin, which markedly decreases bilirubin production for prolonged periods, is a new alternative to phototherapy. (4) The ontogeny of the two HO isozymes was contrasted in the liver, spleen, kidney, and lung.
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PMID:New concepts in bilirubin and jaundice: report of the Third International Bilirubin Workshop, April 6-8, 1995, Trieste, Italy. 890 13

Heme oxygenase is a key enzyme in the oxygen-dependent heme catabolism pathway. In order to clarify the role of highly conserved His132 in heme oxygenase isoform-1, we have prepared 30 kDa truncated rat heme oxygenase mutants in which His132 has been replaced by Ala, Gly, and Ser. The expressed recombinant mutant proteins were isolated in inclusion bodies and were recovered from the lysis pellet by dissolution in urea followed by dialysis. The solubilized fraction obtained, however, was composed of a mixture of a functional enzyme and an inactive fraction. The inactive fraction was removed by Sephadex G-75 gel filtration column chromatography, as it eluted out of the column at the void volume. The gel filtration-purified heme oxygenase mutants have spectroscopic and enzymatic properties identical to those of wild type. The hemin complex of the H132A mutant exhibits a transition between a high-spin acid form and a low-spin alkaline form with a pKa value of 7.6 identical to that in the wild-type complex. These results demonstrate that His132 in heme oxygenase does not link to the coordinated water molecule and is not an essential residue for the enzyme activity. These results are in accordance with our previous preliminary results [Ito-Maki, M., Ishikawa, K., Mansfield Matera, K., Sato, M., Ikeda-Saito, M., & Yoshida, T. (1995) Arch. Biochem. Biophys. 317, 253-258] but contradict a recent report that His132 is the distal base linked to the coordinated water molecule and an important residue for enzyme catalysis [Wilks, A., Ortiz de Montellano, P. R., Sun, J., & Loehr, T. M. (1996) Biochemistry 35, 930-936]. Prolonged storage of the solubilized fraction from the inclusion bodies of the mutants, H132S in particular, results in an increase in the void volume fraction with a concomitant decrease of the 30 kDa fraction. We infer that His132 plays a structural role in stabilization of the heme oxygenase protein.
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PMID:Histidine-132 does not stabilize a distal water ligand and is not an important residue for the enzyme activity in heme oxygenase-1. 912 12

We have measured liver heme oxygenase, a heat shock protein known to be increased under conditions of oxidative stress, to obtain additional evidence for an oxidative stress mechanism in hepatic uroporphyria induced by hexachlorobenzene (HCB). We have studied heme oxygenase at different times during HCB treatment and in two strains of rats (Agus and Wistar strains), which are known to differ in their sensitivity to the porphyria-inducing properties of HCB, in order to ascertain whether the same time course and genetic differences known to exist for the induction of porphyria also apply to hepatic oxidative stress. HCB induced heme oxygenase and accumulation of porphyrins in the liver of rats of both strains; no significant difference was found between the two strains in the HCB-induced heme oxygenase activity. The increased activity of the enzyme was first detected during the early phases of treatment, when a modest increase in liver porphyrins was observed; heme oxygenase remained at induced levels for several weeks during HCB treatment, and was still raised when an increase in total liver iron content and the onset of marked porphyria were also found. In contrast to the effects of HCB, phenobarbitone sodium (given in the drinking water for up to 4 weeks) produced similar elevations of total liver cytochrome P450 as HCB, but did not stimulate heme oxygenase or increase the total liver content of either iron or porphyrins. These results are compatible with an oxidative stress mechanism in HCB-induced liver toxicity and porphyria, but also suggest the existence of successive stages in the induction of hepatic porphyria, with more than one mechanism contributing to the marked accumulation of uroporphyrin.
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PMID:Stimulation of liver heme oxygenase in hexachlorobenzene-induced hepatic porphyria. 965 83

Histidine-63, one of the heme axial ligands in outer mitochondrial membrane cytochrome b5 (OM cyt b5) has been replaced by a methionine. The H63M variant performs the efficient and regioselective coupled oxidation of heme in order to produce >90% of the alpha-isomer of verdoheme. The variant was characterized by electronic, EPR, and NMR spectroscopic studies which indicate that the ferric form is a high-spin species whose heme is coordinated by histidine-39 in the proximal site and likely by water in the distal site. The coordination of methionine to the ferric heme was ruled out on the basis of NMR spectroscopic studies. Addition of imidazole to a solution of the ferric variant results in the formation of a species axially coordinated by imidazole and histidine-63. The reduction potential of the variant was found to be +110 mV in the absence of exogenous imidazole and -92 mV in the presence of imidazole. These values compare well with the reduction potential of myoglobin (50 mV) and wild-type OM cyt b5 (-102 mV), respectively, consistent with the axial ligation described above. The ferrous variant, on the other hand, is a low-spin species coordinated by histidine-39 and methionine-63. Carbon monoxide (CO) readily displaces Met-63 from its coordination site on the ferrous heme, whereas CO cannot completely displace Met-63 from its coordination site on verdoheme. Consequently, the mechanism of inhibition for the oxidation of verdoheme to iron-biliverdin in the H63M variant appears to be similar to that observed for the heme-heme oxygenase complex in the presence of CO.
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PMID:Conversion of mitochondrial cytochrome b5 into a species capable of performing the efficient coupled oxidation of heme. 974 14

UV-visible absorption and magnetic circular dichroism (MCD) data are reported for the cavity mutants of sperm whale H93G myoglobin and human H25A heme oxygenase in their ferric states at 4 degreesC. Detailed spectral analyses of H93G myoglobin reveal that its heme coordination structure has a single water ligand at pH 5.0, a single hydroxide ligand at pH 10.0, and a mixture of species at pH 7.0 including five-coordinate hydroxide-bound, and six-coordinate structures. The five-coordinate aquo structure at pH 5 is supported by spectral similarity to acidic horseradish peroxidase (pH 3.1), whose MCD data are reported herein for the first time, and acidic myoglobin (pH 3.4), whose structures have been previously assigned by resonance Raman spectroscopy. The five-coordinate hydroxide structure at pH 10.0 is supported by MCD and resonance Raman data obtained here and by comparison with those of other known five-coordinate oxygen donor complexes. In particular, the MCD spectrum of alkaline ferric H93G myoglobin is strikingly similar to that of ferric tyrosinate-ligated human H93Y myoglobin, whose MCD data are reported herein for the first time, and that of the methoxide adduct of ferric protoporphyrin IX dimethyl ester (FeIIIPPIXDME). Analysis of the spectral data for ferric H25A heme oxygenase at neutral pH in the context of the spectra of other five-coordinate ferric heme complexes with proximal oxygen donor ligands, in particular the p-nitrophenolate and acetate adducts of FeIIIPPIXDME, is most consistent with ligation by a carboxylate group of a nearby glutamyl (or aspartic) acid residue.
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PMID:Assignment of the heme axial ligand(s) for the ferric myoglobin (H93G) and heme oxygenase (H25A) cavity mutants as oxygen donors using magnetic circular dichroism. 1036 Sep 58

Hmu O, a heme degradation enzyme in Corynebacterium diphtheriae, forms a stoichiometric complex with iron protoporphyrin IX and catalyzes the oxygen-dependent conversion of hemin to biliverdin, carbon monoxide, and free iron. Using a multitude of spectroscopic techniques, we have determined the axial ligand coordination of the heme-Hmu O complex. The ferric complex shows a pH-dependent reversible transition between a water-bound hexacoordinate high spin neutral pH form and an alkaline form, having high spin and low spin states, with a pK(a) of 9. (1)H NMR, EPR, and resonance Raman of the heme-Hmu O complex establish that a neutral imidazole of a histidine residue is the proximal ligand of the complex, similar to mammalian heme oxygenase. EPR of the deoxy cobalt porphyrin IX-Hmu O complex confirms this proximal histidine coordination. Oxy cobalt-Hmu O EPR reveals a hydrogen-bonding interaction between the O(2) and an exchangeable proton in the Hmu O distal pocket and two distinct orientations for the bound O(2). Mammalian heme oxygenase has only one O(2) orientation. This difference and the mixed spin states at alkaline pH indicate structural differences in the distal environment between Hmu O and its mammalian counterpart.
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PMID:The heme complex of Hmu O, a bacterial heme degradation enzyme from Corynebacterium diphtheriae. Structure of the catalytic site. 1045 11

Islet production of nitric oxide (NO) and CO in relation to islet hormone secretion was investigated in mice given the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) in their drinking water. In these mice, the total islet NO production was paradoxically increased, reflecting induction of inducible NOS (iNOS) in background of reduced activity and immunoreactivity of constitutive NOS (cNOS). Unexpectedly, normal mice fasted for 24 h also displayed iNOS activity, which was further increased in L-NAME-drinking mice. Glucose-stimulated insulin secretion in vitro and in vivo was increased in fasted but unaffected in fed mice after L-NAME drinking. Glucagon secretion was increased in vitro. Control islets incubated with different NOS inhibitors at 20 mM glucose displayed increased insulin release and decreased cNOS activity. These NOS inhibitors potentiated glucose-stimulated insulin release also from islets of L-NAME-drinking mice. In contrast, glucagon release was suppressed. In islets from L-NAME-drinking mice, cyclic nucleotides were upregulated, and forskolin-stimulated hormone release, CO production, and heme oxygenase (HO)-2 expression increased. In conclusion, chronic NOS blockade evoked iNOS-derived NO production in pancreatic islets and elicited compensatory mechanisms against the inhibitory action of NO on glucose-stimulated insulin release by inducing upregulation of the islet cAMP and HO-CO systems.
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PMID:Chronic blockade of NO synthase paradoxically increases islet NO production and modulates islet hormone release. 1089 28

The human heme oxygenase-1 crystal structure suggests that Gly-139 and Gly-143 interact directly with iron-bound ligands. We have mutated Gly-139 to an alanine, leucine, phenylalanine, tryptophan, histidine, or aspartate, and Gly-143 to a leucine, lysine, histidine, or aspartate. All of these mutants bind heme, but absorption and resonance Raman spectroscopy indicate that the water coordinated to the iron atom is lost in several of the Gly-139 mutants, giving rise to mixtures of hexacoordinate and pentacoordinate ligation states. The active site perturbation is greatest when large amino acid side chains are introduced. Of the Gly-139 mutants investigated, only G139A catalyzes the NADPH-cytochrome P450 reductase-dependent oxidation of heme to biliverdin, but most of them exhibit a new H(2)O(2)-dependent guaiacol peroxidation activity. The Gly-143 mutants, all of which have lost the water ligand, have no heme oxygenase or peroxidase activity. The results establish the importance of Gly-139 and Gly-143 in maintaining the appropriate environment for the heme oxygenase reaction and show that Gly-139 mutations disrupt this environment, probably by displacing the distal helix, converting heme oxygenase into a peroxidase. The principal role of the heme oxygenase active site may be to suppress the ferryl species formation responsible for peroxidase activity.
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PMID:Replacement of the distal glycine 139 transforms human heme oxygenase-1 into a peroxidase. 1094 63


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