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)

Extracts of the phycocyanin-containing unicellular red alga, Cyanidium caldarium, catalyzed enzymatic cleavage of the heme macrocycle to form the linear tetrapyrrole bilin structure. This is the key first step in the branch of the tetrapyrrole biosynthetic pathway leading to phycobilin photosynthetic accessory pigments. A mixed-function oxidase mechanism, similar to the biliverdin-forming reaction catalyzed by animal cell-derived microsomal heme oxygenase, was indicated by requirements for O2 and a reduced pyridine nucleotide. To avoid enzymatic conversion of the bilin product to phycocyanobilins and subsequent degradation during incubation, mesoheme IX was substituted for the normal physiological substrate, protoheme IX. Mesobiliverdin IX alpha was identified as the primary incubation product by comparative reverse-phase high-pressure liquid chromatography and absorption spectrophotometry. The enzymatic nature of the reaction was indicated by the requirement for cell extract, absence of activity in boiled cell extract, high specificity for NADPH as cosubstrate, formation of the physiologically relevant IX alpha bilin isomer, and over 75% inhibition by 1 microM Sn-protoporphyrin, which has been reported to be a competitive inhibitor of animal microsomal heme oxygenase. On the other hand, coupled oxidation of mesoheme, catalyzed by ascorbate plus pyridine or myoglobin, yielded a mixture of ring-opening mesobiliverdin IX isomers, was not inhibited by Sn-protoporphyrin, and could not use NADPH as the reductant. Unlike the animal microsomal heme oxygenase, the algal reaction appeared to be catalyzed by a soluble enzyme that was not sedimentable by centrifugation for 1 h at 200,000g. Although NADPH was the preferred reductant, small amounts of activity were obtained with NADH or ascorbate. A portion of the activity was retained after gel filtration of the cell extract to remove low-molecular-weight components. Considerable stimulation of activity, particularly in preparations that had been subjected to gel filtration, was obtained by addition of ascorbate to the incubation mixture containing NADPH. The results indicate that C. caldarium possesses a true heme oxygenase system, with properties somewhat different from that catalyzing heme degradation in animals. Taken together with previous results indicating that biliverdin is a precursor to phycocyanobilin, the results suggest that algal heme oxygenase is a component of the phycobilin biosynthetic pathway.
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PMID:Enzymatic heme oxygenase activity in soluble extracts of the unicellular red alga, Cyanidium caldarium. 654 21

Male albino mice were raised on diets containing less than 10 ppb selenium (Se-) or supplemented with 0.5 ppm selenium (Se+) for 6 months. In the (Se-) group total liver selenium was less than 10% of the control, liver selenium-dependent glutathione peroxidase (GSH-Px) less than 2%. The specific activities of catalase and superoxide dismutase showed essentially no differences between the dietary groups. Several phase I-related specific enzyme activities were measured in liver microsomes. No significant differences between the two animal groups were found for cytochrome P-450 and b 5 content, NADH-cytochrome b 5 reductase, as well as for aniline hydroxylation and aminopyrine dealkylation rates. In (Se-) microsomes, NADPH-cytochrome P-450 reductase activity was about half that found in (Se+) microsomes. An increase in microsomes from (Se-) mice was found for 7-ethoxycoumarine deethylation rate (460%), cytochrome P-450 hydroperoxidase activity (170%), and heme oxygenase (276%). The N-oxidation rate of the flavin-containing monooxygenase decreased by 35%, the N-demethylation rate by 50% in (Se-) animals. Stopped-flow measurements of the reduction rates of microsomal pigments did not support evidence for limitations in microsomal electron supply during selenium deficiency. Among the phase II reactions examined, sulfotransferase activity towards 4-nitrophenol was 47% of the controls in Se-deficient liver cytosols while UDP-glucuronyl transferase activity towards this substrate increased to 215%. Glutathione-S-transferase activity was much higher in (Se-) livers than in (Se+): 310% with 1,2-dichloro-4-nitrobenzene, 255% with 1-chloro-2,4-dinitrobenzene and 120% with ethacrynic acid as substrate. The data indicate that in addition to GSH-Px many other enzyme activities in mouse liver are affected by prolonged dietary selenium deficiency. These effects might be useful in assessing the severity of selenium deficiency. A microsomal selenium-dependent metabolic modulator is discussed as a possible mechanism.
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PMID:Selenium and drug metabolism--I. Multiple modulations of mouse liver enzymes. 663 74

Biliverdin reductase regulates heme oxygenase activity by removing the inhibitory product of the oxygenase activity, biliverdin; and reducing it to bilirubin. The other products of the oxygenase are carbon monoxide and Fe. To date, biliverdin reductase remains unique among all enzymes described by using 2 different cofactors (NADPH and NADH) at different pH ranges. The present study reports on the developmentally regulated changes in the pattern of protein expression and the level of biliverdin reductase transcript in rat brain. Biliverdin reductase activity of the brain cytosol with both NADPH (pH 8.7) and NADH (pH 6.7) exhibited developmental changes with the activity increasing after birth, reaching an adult level by day 28 postpartum. When analyzed by Western blotting the immunoreactive protein detected increased as the animal matured (day 1 to 28 postparturition). Northern blot hybridization of RNA isolated from rat brain revealed the presence of approximately 1.5 kb biliverdin reductase transcript at all stages of development ranging from 1 day post partum to 20 months. The level of the transcript was developmentally regulated and a gradual increase ( approximately 4-fold) was observed from day 1 after birth to adulthood and was maintained in 20 month old animals. Cellular localization, using immunohistochemical technique, revealed age-related pattern of expression of the reductase in select regions such as the cortex, substantia nigra, hippocampus and in the cerebellum; the changes, however, did not follow the same pattern. To elaborate, in the cortex, the reductase expression increased when 7-day-old animals were compared with young adults (2 months old) and then declined in the 20-month-old animals. In the substantia nigra the level of reductase expression progressively declined with age when 7-day-old neonate, 2- and 20-month-old animals were compared. In the hippocampus, a distinct reductase-expressing cell population residing between CA1 and the dentate gyrus was observed in the 7-day-old animals; these cells were not detected in the adults (2 or 20 months old). In the cerebellum, the expression of the reductase reflected the developmental organization of this region. We postulate that age-dependent increase of the brain reductase at the transcript and protein levels in the course of maturation serves to control heme oxygenase activity which also displays a developmental pattern in the organ. As such, the reductase modulates generation of biologically active heme degradation products; bilirubin, carbon monoxide and Fe.
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PMID:Immunohistochemical localization of biliverdin reductase in rat brain: age related expression of protein and transcript. 774 51

Two heme oxygenase (HO) isozymes--HO-1, which is a heat shock protein (HSP32), and HO-2--catalyze the isomer-specific production of biliverdin IX alpha and carbon monoxide. The latter has the potential of functioning as a neurotransmitter, whereas the reduced form of biliverdin, bilirubin, has potent antioxidant activity. Formation of bilirubin is catalyzed by biliverdin reductase (BVR). The reductase is a unique enzyme in being dual pyridine nucleotide and dual pH dependent. Here, we show that the reductase is resistant to thermal stress at both the protein and message level. We further demonstrate that the reductase is coexpressed in cells that display HO-1 and/or HO-2 under normal conditions, as well as in regions and cell types that have the potential to express heat shock-inducible HO-1 protein. Exposure of male rats to 42 degrees C for 20 min did not decrease brain BVR activity, but caused a slight increase in NADPH- and NADH-dependent activities at 1 and 6 h following hyperthermia. High levels of the approximately 1.5-kb BVR mRNA were detected in control brain; it too displayed thermal tolerance. Similarly, the pattern of multiplicity of net charge variants of the enzyme purified from brain of heat-shocked rats did not differ from the control pattern. Immunochemical localization of BVR protein in normal brain correlated well with the presence of HO-1 and/or HO-2 throughout the forebrain, diencephalon, cerebellum, and brainstem regions. There were select neuronal and nonneuronal cells in the substantia nigra and cerebellum that did express the reductase under normal conditions, wherein no HO isozymes could be detected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biliverdin reductase is heat resistant and coexpressed with constitutive and heat shock forms of heme oxygenase in brain. 836 Jun 69

Biliverdin reductase is classified into two isoforms in substrate specificity; biliverdin-IX alpha reductase and biliverdin-IX beta reductase with a molecular mass of 22 kDa and 34-42 kDa, respectively. We have cloned the cDNA encoding human biliverdin-IX alpha reductase from MOLT4 cDNA library. The cDNA of 1146 bp in nucleotide length contained an entire reading frame coding 296 amino acid residues. The NADH/NADPH binding consensus sequence was found in the amino-terminal region. Comparison between human and rat biliverdin-IX alpha reductases showed 82.8% identity in amino acid sequences and 80.3% identity in the coding nucleotides. The amino acid sequence of human biliverdin-IX alpha reductase showed no significant homology to that of human biliverdin-IX beta reductase. Northern blot analysis of poly(A) RNA from eight different human tissues revealed that the reductase mRNA was abundant in the brain, lung and pancreas but not in the liver. The distribution pattern of biliverdin-IX alpha message was different from that of heme oxygenase activity which is known to be high in the liver and to be low in the heart and lung.
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PMID:Cloning and characterization of the cDNA encoding human biliverdin-IX alpha reductase. 895 Jan 84

A full-length heme oxygenase gene from the pathogenic bacterium Corynebacterium diphtheriae has been subcloned and expressed in Escherichia coli. The enzyme is expressed at high levels as a soluble catalytically active protein that results in the accumulation of biliverdin within the E. coli cells. The purified heme oxygenase forms a 1:1 complex with heme (Kd = 2.5 +/- 1 microM) and has hemeprotein spectra similar to those previously reported for the purified eukaryotic heme oxygenases. In the presence of an E. coli NADPH-dependent reductase isolated during the purification of Hmu O, the heme-Hmu O complex is catalytically turned over to yield biliverdin IXalpha and carbon monoxide. A number of redox partners were investigated for their ability to reconstitute Hmu O activity in vitro. Of these the most efficient appeared to be the recombinant NADH-dependent putidaredoxin/putidaredoxin reductase from Pseudomonas putida. As with the E. coli NADPH-dependent reductase the final products of the reaction were biliverdin IXalpha and carbon monoxide. This is the first bacterial heme oxygenase to be described to date. The close relationship between iron acquisition and pathogenesis suggests that the release of iron from heme by heme oxygenase may play a crucial role in the pathogenicity of C. diphtheriae.
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PMID:Expression and characterization of a heme oxygenase (Hmu O) from Corynebacterium diphtheriae. Iron acquisition requires oxidative cleavage of the heme macrocycle. 942 39

Many cytochrome P450 (P450)-dependent reactions have been shown to be stimulated by another microsomal protein, cytochrome b(5) (b(5)). Two major explanations are (i) direct electron transfer from b(5) and (ii) a conformational effect in the absence of electron transfer. Some P450s (e.g. 3A4, 2C9, 17A, and 4A7) are stimulated by either b(5) or b(5) devoid of heme (apo-b(5)), indicating a lack of electron transfer, whereas other P450s (e.g. 2E1) are stimulated by b(5) but not by apo-b(5). Recently, a proposal has been made by Guryev et al. (Biochemistry 40, 5018-5031, 2001) that the stimulation by apo-b(5) can be explained only by transfer of heme from P450 preparations to apo-b(5), enabling electron transfer. We have repeated earlier findings of stimulation of catalytic activity of testosterone 6beta-hydroxylation activities with four P450 preparations, in which nearly all of the heme was accounted for as P450. Spectral analysis of mixtures indicated that only approximately 5% of the heme can be transferred to apo-b(5), which cannot account for the observed stimulation. The presence of the heme scavenger apomyoglobin did not inhibit the stimulation of P450 3A4-dependent testosterone or nifedipine oxidation activity. Further evidence against the presence of loosely bound P450 3A4 heme was provided in experiments with apo-heme oxygenase, in which only 3% of the P450 heme was converted to biliverdin. Finally, b(5) supported NADH-b(5) reductase/P450 3A4-dependent testosterone 6beta-hydroxylation, but apo-b(5) did not. Thus, apo-b(5) can stimulate P450 3A4 reactions as well as b(5) in the absence of electron transfer, and heme transfer from P450 3A4 to apo-b(5) cannot be used to explain the catalytic stimulation.
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PMID:Stimulation of cytochrome P450 reactions by apo-cytochrome b5: evidence against transfer of heme from cytochrome P450 3A4 to apo-cytochrome b5 or heme oxygenase. 1141 49

NADPH-cytochrome P-450 reductase is the electron transfer partner for the cytochromes P-450, heme oxygenase, and squalene monooxygenase and is a component of the nitric-oxide synthases and methionine-synthase reductase. P-450 reductase shows very high selectivity for NADPH and uses NADH only poorly. Substitution of tryptophan 677 with alanine has been shown to yield a 3-fold increase in turnover with NADH, but profound inhibition by NADP(+) makes the enzyme unsuitable for in vivo applications. In the present study site-directed mutagenesis of amino acids in the 2'-phosphate-binding site of the NADPH domain, coupled with the W677A substitution, was used to generate a reductase that was able to use NADH efficiently without inhibition by NADP(+). Of 11 single, double, and triple mutant proteins, two (R597M/W677A and R597M/K602W/W677A) showed up to a 500-fold increase in catalytic efficiency (k(cat)/K(m)) with NADH. Inhibition by NADP(+) was reduced by up to 4 orders of magnitude relative to the W677A protein and was equal to or less than that of the wild-type reductase. Both proteins were 2-3-fold more active than wild-type reductase with NADH in reconstitution assays with cytochrome P-450 1A2 and with squalene monooxygenase. In a recombinant cytochrome P-450 2E1 Ames bacterial mutagenicity assay, the R597M/W677A protein increased the sensitivity to dimethylnitrosamine by approximately 2-fold, suggesting that the ability to use NADH afforded a significant advantage in this in vivo assay.
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PMID:Modification of the nucleotide cofactor-binding site of cytochrome P-450 reductase to enhance turnover with NADH in Vivo. 1238 19

The YLR205c gene of Saccharomyces cerevisiae does not show significant sequence identity to any known gene, except for heme oxygenase (22% to human HO-1). The YLR205 ORF was cloned and overexpressed in both Escherichia coli and S. cerevisiae. Both expression systems yielded proteins that bound heme tightly. The isolated YLR205c protein underwent reduction in the presence of either NADPH-cytochrome P450 reductase or NADH-putidaredoxin-putidaredoxin reductase but did not exhibit heme oxygenase activity. The protein exhibited modest H(2)O(2)-dependent peroxidase activities with guaiacol, potassium iodide, and 2,2(')-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS). Thus, YLR205c codes for a hemoprotein of unknown physiological function that exhibits peroxidase activity.
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PMID:Cloning and expression of a heme binding protein from the genome of Saccharomyces cerevisiae. 1269 99

The activity of hepatic heme oxygenase (HO) in rats is elevated in response to copper deficiency. However, the mechanism responsible for the increase in HO activity is poorly understood. Oxidative stress is a common denominator for many of the signals that induce HO-1, the inducible isoform of HO. The present study evaluated the role of H(2)O(2) and the mitochondrial electron transport chain as a potential mechanism for the induction of HO-1 during copper deficiency. Mitochondria isolated from the livers of young male rats fed a copper-deficient diet for 5 wk had significantly (P < 0.05) reduced levels of NADH:cytochrome c reductase (31% reduction), succinate:cytrochrome c reductase (42% reduction), and cytochrome c oxidase (70% reduction) activities and significantly increased production of H(2)O(2) (48% increase) when glutamate was used as a substrate. Hepatic levels of HO-1 protein and mRNA were also significantly elevated (48 and 20%, respectively) in copper-deficient rats, indicating that copper deficiency stimulated the expression of the HO-1 gene. Furthermore, hepatic HO-1 protein content was best described by a regression model that included mitochondrial NADH:cytochrome c reductase and succinate:cytochrome c reductase activities, but not cytochrome c oxidase activity (R(2) = 0.54, P < 0.02). Hydrogen peroxide is a known inducer of HO-1, and our results suggest that increased mitochondrial H(2)O(2) production resulting from inhibition of respiratory complex activities contributes to the induction of HO-1 during copper deficiency. The levels of HO-1 protein and mRNA were also elevated (85 and 95%, respectively) in hearts from copper-deficient rats, indicating that the effects of copper deficiency on HO-1 gene expression are not limited to hepatic tissue.
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PMID:Increased heme oxygenase-1 expression during copper deficiency in rats results from increased mitochondrial generation of hydrogen peroxide. 1517 92


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