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At least 631 records · Page 35Linked to original sources
PubMed2003

Heme oxygenase in Candida albicans is regulated by hemoglobin and is necessary for metabolism of exogenous heme and hemoglobin to alpha-biliverdin.

Candida albicans is an opportunistic pathogen that has adapted uniquely to life in mammalian hosts. One of the host factors recognized by this yeast is hemoglobin, which binds to a specific cell surface receptor. In addition to its regulating the expression of adhesion receptors on the yeast, we have found that hemoglobin induces the expression of a C. albicans heme oxygenase (CaHmx1p). Hemoglobin transcriptionally induces the CaHMX1 gene independent of the presence of inorganic iron in the medium. A Renilla luciferase reporter driven by the CaHMX1 promoter demonstrated rapid activation of transcription by hemoglobin and (cobalt protoporphyrin IX) globin but not by apoglobin or other proteins. In contrast, iron deficiency or exogenous hemin did not activate the reporter until after 3 h, suggesting that induction of the promoter by hemoglobin is mediated by receptor signaling rather than heme or iron flux into the cell. As observed following disruption of the Saccharomyces cerevisiae ortholog, HMX1, a CaHMX1 null mutant was unable to grow under iron restriction. This suggests a role for CaHmx1p in inorganic iron acquisition. CaHMX1 encodes a functional heme oxygenase. Exogenous heme or hemoglobin is exclusively metabolized to alpha-biliverdin. CaHMX1 is required for utilization of these exogenous substrates, indicating that C. albicans heme oxygenase confers a nutritional advantage for growth in mammalian hosts.

Amino Acid Sequence↗
PubMed2005

Functional analyses of oxygenases in jadomycin biosynthesis and identification of JadH as a bifunctional oxygenase/dehydrase.

A novel angucycline metabolite, 2,3-dehydro-UWM6, was identified in a jadH mutant of Streptomyces venezuelae ISP5230. Both UWM6 and 2,3-dehydro-UWM6 could be converted to jadomycin A or B by a ketosynthase alpha (jadA) mutant of S. venezuelae. These angucycline intermediates were also converted to jadomycin A by transformant of the heterologous host Streptomyces lividans expressing the jadFGH oxygenases in vivo and by its cell-free extracts in vitro; thus the three gene products JadFGH are implicated in catalysis of the post-polyketide synthase biosynthetic reactions converting UWM6 to jadomycin aglycone. Genetic and biochemical analyses indicate that JadH possesses dehydrase activity, not previously associated with polyketide-modifying oxygenase. Since the formation of aromatic polyketides often requires multiple dehydration steps, bifunctionality of oxygenases modifying aromatic polyketides may be a general phenomenon.

Amino Acid Sequence↗
PubMed2002

Heme oxygenase and the kidney.

Heme plays a significant pathogenic role in several diseases involving the kidney. The cellular content of heme, derived either from the delivery of filtered heme proteins such as hemoglobin and myoglobin, or from the breakdown of ubiquitous intracellular heme proteins, is regulated via the heme oxygenase enzyme system. Heme oxygenases catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, which is subsequently converted to bilirubin by biliverdin reductase. Recent attention has focused on the biological effects of product(s) of this enzymatic reaction, which have important antioxidant, anti-inflammatory, and cytoprotective functions. Three isoforms of heme oxygenase (HO) enzyme have been described: an inducible isoform, HO-1, and two constitutively expressed isoforms, HO-2 and HO-3. Induction of HO-1 occurs as an adaptive and beneficial response to several injurious stimuli, and has been implicated in many clinically relevant disease states including atherosclerosis, transplant rejection, endotoxic shock, hypertension, acute lung injury, acute renal injury, as well as others. This review will focus predominantly on the role of HO-1 in the kidney.

Animals↗
PubMed1995

Difference between in vivo and in vitro effects of propofol on defluorination and metabolic activities of hamster hepatic cytochrome P450-dependent mono-oxygenases.

We have compared the in vivo and in vitro effects of propofol on cytochrome P450-dependent monooxygenase activities in hamster liver microsomes. Propofol (Diprivan) 10 mg/100 g body weight was injected i.p. twice a day for 2 weeks to induce cytochrome P450 enzymes. Liver microsomes were prepared by differential centrifugation. Metabolism of the cytochrome P450-dependent mono-oxygenase system was evaluated by measuring aniline hydroxylation, benzphetamine demethylation and benzo(a)pyrene hydroxylation. Defluorination of enflurane was assayed by detecting free fluoride metabolites. At similar concentrations as in the in vivo group, propofol in vitro exhibited concentration-dependent inhibition of metabolism of benzphetamine and benzo(a)pyrene. Aniline hydroxylation and defluorination of enflurane were inhibited to 78% of control with propofol 0.25 mmol litre-1. In propofol-treated hamsters, there was only minimal inhibitory or inductive effects on either mono-oxygenase activities or capacity for defluorination. This difference between the in vitro and in vivo effects of propofol on cytochrome P450 mono-oxygenase activities emphasizes the need for care when comparing in vitro and clinical data.

Anesthetics, Intravenous↗
PubMed1992

Endogenous glutathione levels modulate both constitutive and UVA radiation/hydrogen peroxide inducible expression of the human heme oxygenase gene.

Induction of the expression of the mammalian heme oxygenase gene appears to be a general response to oxidant stress. In view of the role of glutathione in protecting cells against solar UVA radiation and other forms of oxidant stress, we have investigated the relationship between intracellular glutathione levels and the inducibility of the human heme oxygenase gene after treatment of populations of cultured skin fibroblasts with either UVA radiation or hydrogen peroxide. We observe a clear relationship between cellular glutathione status and both the constitutive and oxidant-inducible accumulation of heme oxygenase mRNA. Glutathione depletion may lead to enhanced gene expression either as a result of the potentiated accumulation of active oxygen intermediates or as a result of the direct influence of glutathione on a critical target involved in signal transduction.

Antimetabolites↗
PubMed2005

RNAi-induced silencing of embryonic tryptophan oxygenase in the Pyralid moth, Plodia interpunctella.

Gene silencing through the introduction of double-stranded RNA (RNA interference, RNAi) provides a powerful tool for the elucidation of gene function in many systems, including those where genomics and proteomics are incomplete. The use of RNAi technology for gene silencing in Lepidoptera has lacked significant attention compared to other systems. To demonstrate that RNAi can be utilized in the lepidopteran, Plodia interpunctella, we cloned a cDNA for tryptophan oxygenase, and showed that silencing of tryptophan oxygenase through RNAi during embryonic development resulted in loss of eye-color pigmentation. The complete amino acid sequence of Plodia tryptophan oxygenase can be accessed through NCBI Protein Database.

Amino Acid Sequence↗
PubMed1996

Participation of altered upstream stimulatory factor in the induction of rat heme oxygenase-1 by cadmium.

We have reported that an upstream stimulatory factor (USF) binding site is functional in transcription of the heme oxygenase-1 gene. In this study, we examined the role of USF in the induced state. By transient expression analyses with the chloramphenicol acetyl-transferase gene, we found that the USF binding site plays an important role in the induction of rat heme oxygenase-1 by cadmium, but not by hemin. To elucidate the role of USF, we prepared USF-rich nuclear extracts from control and cadmium-treated rat liver. On electrophoretic mobility shift assay using control nuclear proteins, one slowly migrating band was detected, whereas using nuclear proteins of cadmium-treated rat liver, two fast migrating bands were detected. The molecular masses of the two subunits of USF prepared from cadmium-treated rat liver were approximately 34 kDa as determined by UV cross-linking and subsequent SDS-PAGE, while the two subunits of native USF were 43 kDa and 44 kDa. DNase I footprinting analysis revealed that both the nuclear proteins bound to the same region including the USF binding site. We therefore suppose that cadmium causes some structural changes in the two proteins of USF and that the altered USF participates in the effective initiation of transcription of the rat heme oxygenase-1 gene.

Animals↗
PubMed2003

Haem, haem oxygenase and ferritin in vascular endothelial cell injury.

Iron-derived reactive oxygen species (ROS) are implicated in the pathogenesis of numerous vascular disorders including atherosclerosis, microangiopathic haemolytic anaemia, vasculitis and reperfusion injury. One abundant source of redox-active iron is haem, which is inherently dangerous when released from intracellular haem proteins. The present review concerns the likely involvement of haem in vascular endothelial cell damage and the strategies used by endothelium to minimize such damage. Exposure of endothelial cells to haem greatly potentiates cell killing mediated by polymorphonuclear leukocytes and other sources of ROS. Free haem also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. If only because of its abundance, haemoglobin probably represents the most important potential source of haem within the vascular endothelium; free haemoglobin in plasma, when oxidized, can transfer haem to endothelium, thereby enhancing cellular susceptibility to oxidant-mediated injury. As a defence against such toxicity, upon exposure to free haem, endothelial cells up-regulate haem oxygenase-1 and ferritin. Haem oxygenase is a haem-degrading enzyme that opens the porphyrin ring, producing biliverdin, carbon monoxide and a most dangerous product-free redox-active iron. The latter can be controlled effectively by sequestration within ferritin, a multimeric protein with a very high capacity for storing iron. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of exogenous haem and oxidants. The central importance of this protective system was highlighted recently by the discovery of a child diagnosed with haem oxygenase-1 deficiency, who exhibited extensive endothelial damage.

Cell Death↗
PubMed1990

Induction in mouse peritoneal macrophages of 34 kDa stress protein and heme oxygenase by sulfhydryl-reactive agents.

The synthesis of 34-kDa stress protein was enhanced, with a simultaneous increase in heme oxygenase activity, when mouse macrophages were exposed to diethylmaleate or sodium arsenite. After 7 h of exposure to the sulfhydryl agents, the 34-kDa protein was the most actively synthesized protein. Immunoblot analysis showed that the induced 34-kDa protein reacted with an antibody raised against bovine heme oxygenase. Cadmium ions or 1-chloro-2,4-dinitrobenzene also induced the 34-kDa protein which reacted with the antibody. Treatments of the cells with buthionine sulfoximine or hydrogen peroxide weakly induced the protein, while diamide treatment or heat shock was without effect. These results are consistent with our previous findings that heavy metal ions including arsenite and cadmium ions induce heme oxygenase (32-kDa stress protein) in human cell lines [Taketani, S., Kohno, H., Yoshinaga, T., & Tokunaga, R. (1989) FEBS Lett. 245, 173-176], and also suggest that the formation of glutathione conjugate with sulfhydryl-reactive agents may mediate the induction of the stress protein in mouse peritoneal macrophages.

Animals↗
PubMed1993

Functional analysis of cDNAs for two types of human heme oxygenase and evidence for their separate regulation.

We cloned a cDNA coding for a putative human heme oxygenase isozyme, designated type 2 (HO-2), and analyzed its function by transient expression assays. HeLa cells transfected with either HO-2 cDNAs or a cDNA coding for authentic heme oxygenase (HO-1) expressed the activity of heme oxygenase, although no activity was detected in the mock transfected cells. Using specific anti-HO-1 antibody, we showed that expression of a HO-1 cDNA resulted in the increase in its protein levels, but HO-1 protein was not detectable in the cells expressing HO-2 cDNAs. We thus confirmed the functional identity of HO-1 and HO-2. Then, we analyzed their expression in an erythroid cell line, YN-1-0-A. Treatment with hemin or by heat shock (42 degrees C) led to a remarkable increase in the HO-1 mRNA levels, while HO-2 mRNA expression was not induced at all, suggesting that they are under separate regulation.

Cell Line↗
PubMed1998

A model for the catabolism of rhizopine in Rhizobium leguminosarum involves a ferredoxin oxygenase complex and the inositol degradative pathway.

Rhizopines are nodule-specific compounds that confer an intraspecies competitive nodulation advantage to strains that can catabolize them. The rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) catabolic moc gene cluster mocCABRDE(F) in Rhizobium leguminosarum bv. viciae strain 1a is located on the Sym plasmid. MocCABR are homologous to the mocCABR gene products from Sinorhizobium meliloti. MocD and MocE contain motifs corresponding to a TOL-like oxygenase and a [2Fe-2S] Rieske-like ferredoxin, respectively. The mocF gene encodes a ferredoxin reductase that would complete the oxygenase system, but is not essential for rhizopine catabolism. We propose a rhizopine catabolic model whereby MocB transports rhizopine into the cell and MocDE and MocF (or a similar protein elsewhere in the genome), under the regulation of MocR, act in concert to form a ferredoxin oxygenase system that demethylates 3-O-MSI to form scyllo-inosamine (SI). MocA, an NAD(H)-dependent dehydrogenase, and MocC continue the catabolic process. Compounds formed then enter the inositol catabolic pathway.

Amino Acid Sequence↗
PubMed2000

The role of heme oxygenase in neuropathic and incisional pain.

UNLABELLED: Heme oxygenase (HO) catalyzes the formation of free iron, biliverdin, and the second messenger molecule carbon monoxide from heme. We document a role for HO in both neuropathic and incisional pain models. For our neuropathic model, the L5 and L6 nerve roots of rats were ligated unilaterally resulting in mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paws. Both changes were dose-dependently reversed by systemic administration of the HO inhibitor tin protoporphyrin (Sn-P). Likewise, a 1-cm incision made in one hind paw resulted in mechanical allodynia and thermal hyperalgesia, again reversible by using Sn-P. The 50% effective doses for Sn-P ranged from 4.0 to 6.8 micromol/kg depending on the model and nociceptive stimulus. We also observed that the blood-brain barrier impermeable HO inhibitor zinc protoporphyrin had little analgesic activity in these models when injected systemically. Using an enzymatic assay, we observed increased HO activity in lumbar spinal cord tissue from either nerve root ligated or incised animals as compared with tissue from sham-operated animals. Taken together, we interpret our results to indicate that an increase in spinal cord HO activity at least partially underlies the allodynia and hyperalgesia seen in rat models of neuropathic and incisional pain. IMPLICATIONS: Central nervous system heme oxygenase likely plays a role in nociceptive signaling in both neuropathic and incisional models of pain. Therefore, inhibitors of heme oxygenase activity may be viable analgesics in these settings.

Analgesics↗
PubMed2000

Interaction of amyloid precursor proteins and heme oxygenase.

Amyloid precursor protein generates the beta-amyloid peptide and is a member of a multigene family that contains at least two other gene products, known as amyloid precursor-like proteins. Heme oxygenase is an enzyme whose products are antioxidant and neuroprotective. The authors report that amyloid precursor protein and amyloid precursor-like protein bind to heme oxygenase to inhibit its enzymatic activity. Our findings suggest that decreased neuroprotection caused by amyloid precursor protein-heme oxygenase interactions influences neurotoxicity in Alzheimer disease.

Alzheimer Disease↗
PubMed1999

Differential expression pattern of heme oxygenase-1/heat shock protein 32 and nitric oxide synthase-II and their impact on liver injury in a rat model of hemorrhage and resuscitation.

OBJECTIVE: To investigate the role of the vasodilator systems heme oxygenase-1/heat shock protein 32 (HO-1/HSP32) and nitric oxide synthase-II (NOS-II), generating carbon monoxide and nitric oxide respectively, as modulators of liver injury in an experimental model of reversible hemorrhagic shock. DESIGN: Prospective controlled laboratory study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 250-350 g. INTERVENTIONS: Animals were anesthetized and assigned to a hemorrhagic shock (mean arterial pressure, 35-40 mmHg for 60 mins) or a sham protocol. On the basis of the time course of gene expression, HO-1/HSP32 or NOS-II was blocked 5 hrs after onset of resuscitation. To assess the role of the antioxidative properties of the heme oxygenase (HO) pathway in additional experiments, Trolox, a potent antioxidant, was administered at the time of blockade of HO. Liver injury was assessed morphometrically and by plasma alpha-glutathione-S-transferase (alpha-GST) release 11 hours after onset of resuscitation. MEASUREMENTS AND MAIN RESULTS: Hemorrhage and resuscitation increased HO-1/HSP32 messenger RNA and protein primarily in parenchymal cells, and a faint induction of NOS-II, restricted to nonparenchymal cells, was observed. Inhibition of the HO pathway with tin protoporphyrin-IX (SnPP-IX) increased the incidence of pericentral necrosis (intact acini: shock/vehicle 68.8%; shock/SnPP-IX 42.6%) and alpha-GST levels (sham 94+/-24 microg/L; shock/vehicle 377+/-139 microg/L; shock/SnPP-IX 1708+/-833 microg/L), whereas blockade of NOS-II with S-methylisothiourea did not affect liver injury. Coadministration of Trolox failed to attenuate the aggravation of necrosis associated with blockade of HO, whereas alpha-GST levels were reduced (intact acini: shock/vehicle/Trolox 82.1%, shock/SnPP-IX/Trolox 42.7%; alpha-GST: shock/vehicle/Trolox 202+/-55 microg/L; shock/SnPP-IX/Trolox 236+/-61 microg/L). CONCLUSIONS: These data suggest that HO-1/HSP32, but not the alternative cyclic guanosine monophosphate-generating enzyme NOS-II, is induced after hemorrhage and resuscitation and protects against hepatocellular injury. Both metabolites generated by the heme oxygenase pathway, e.g., carbon monoxide (a vasodilator) and biliverdin (an antioxidant) seem to contribute to the salutary effects of induction of HO-1/HSP32.

Analysis of Variance↗
PubMed2001

The role of haem oxygenase in renal vascular reactivity in normotensive and hypertensive rats.

OBJECTIVE: To evaluate the contribution of the haem oxygenase-carbon monoxide (CO) system to renal vascular tone in normotensive Wistar rats and in the stroke-prone spontaneously hypertensive rats (SHR-SPs). METHODS: An isolated perfused rat kidney preparation was used in which perfusion pressure/phenylephrine dose-vasoconstrictor responses were generated. Haemin was given 24 h previously, to induce haem oxygenase-1 (HO-1), and L-NAME (N-omega-nitro-L-arginine methyl ester) was given to block nitric oxide (NO) production. RESULTS: Haemin pretreatment attenuated the phenylephrine-induced rise in perfusion pressure (P < 0.05) but L-NAME had no effect on the magnitude of the renal vasoconstrictor responses to phenylephrine. This suggested that the effect of haemin incubation on renovascular responses did not involve NO production. Pretreatment of the rats with the haem oxygenase inhibitor, tin protoporphyrin IX (SnPP-IX) had no effect on either the basal tone or the phenylephrine-induced contractions in the renal vasculature. By contrast, the renovascular responses to phenylephrine in haemin-treated animals were restored following the coadministration of SnPP-IX. Haemin administration in the SHR-SPs caused a significantly greater reduction in the renovascular responses to phenylephrine compared to those in the normotensive animals (P < 0.05). CONCLUSIONS: Following induction of HO-1, the HO-CO system plays an important role in the regulation of renal responses to an adrenergically induced vasoconstrictor challenge. Moreover, the renal vascular bed of hypertensive animals exhibited a greater propensity to upregulate the HO-CO system, which may provide an important counteractive role against the elevation of blood pressure in hypertension.

Animals↗
PubMed2003

Different faces of the heme-heme oxygenase system in inflammation.

The heme-heme oxygenase system has recently been recognized to possess important regulatory properties. It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection, apoptosis, and inflammation. Heme functions as a double-edged sword. In moderate quantities and bound to protein, it forms an essential element for various biological processes, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. The effect of this free heme on the vascular system is determined by extracellular factors, such as hemoglobin/heme-binding proteins, haptoglobin, albumin, and hemopexin, and intracellular factors, including heme oxygenases and ferritin. Heme oxygenase (HO) enzyme activity results in the degradation of heme and the production of iron, carbon monoxide, and biliverdin. All these heme-degradation products are potentially toxic, but may also provide strong cytoprotection, depending on the generated amounts and the microenvironment. Pre-induction of HO activity has been demonstrated to ameliorate inflammation and mediate potent resistance to oxidative injury. A better understanding of the complex heme-heme

Animals↗
PubMed1995

Substrate diversity and expression of the 2,4,5-trichlorophenoxyacetic acid oxygenase from Burkholderia cepacia AC1100.

Burkholderia cepacia AC1100 uses the chlorinated aromatic compound 2,4,5-trichlorophenoxyacetic acid as a sole source of carbon and energy. The genes encoding the proteins involved in the first step (tftA and tftB [previously designated tftA1 and tftA2, respectively]) have been cloned and sequenced. The oxygenase, TftAB, is capable of converting not only 2,4,5-trichlorophenoxyacetic acid to 2,4,5-trichlorophenol but also a wide range of chlorinated aromatic phenoxyacetates to their corresponding phenolic derivatives, as shown by whole-cell and cell-free assays. The rate of substrate utilization by TftAB depends upon the extent of chlorination of the substrate, the positions of the chlorines, and the phenoxy group. These results indicate a mechanistic similarity between TftAB and the 2,4-dichlorophenoxyacetic acid/alpha-ketoglutarate-dependent dioxygenase, TfdA, from Alcaligenes eutrophus JMP134. The promoter of the oxygenase genes was localized by promoter-probe analysis, and the transcriptional start site was identified by primer extension. The beta-galactosidase activity of the construct containing the promoter region cloned upstream of the beta-galactosidase gene in the promoter-probe vector pKRZ-1 showed that this construct is constitutively expressed in Escherichia coli and in AC1100. The -35 and -10 regions of the oxygenase genes show significant sequence identity to typical Escherichia coli sigma 70 promoters.

Base Sequence↗
PubMed2005

Diversity of oxygenase genes from methane- and ammonia-oxidizing bacteria in the Eastern Snake River Plain aquifer.

PCR amplification, restriction fragment length polymorphism, and phylogenetic analysis of oxygenase genes were used for the characterization of in situ methane- and ammonia-oxidizing bacteria from free-living and attached communities in the Eastern Snake River Plain aquifer. The following three methane monooxygenase (MMO) PCR primer sets were used: A189-A682, which amplifies an internal region of both the pmoA gene of the MMO particulate form and the amoA gene of ammonia monooxygenase; A189-mb661, which specifically targets the pmoA gene; and mmoXA-mmoXB, which amplifies the mmoX gene of the MMO soluble form (sMMO). Whole-genome amplification (WGA) was used to amplify metagenomic DNA from each community to assess its applicability for generating unbiased metagenomic template DNA. The majority of sequences in each archive were related to oxygenases of type II-like methanotrophs of the genus Methylocystis. A small subset of type I sequences found only in free-living communities possessed oxygenase genes that grouped nearest to Methylobacter and Methylomonas spp. Sequences similar to that of the amoA gene associated with ammonia-oxidizing bacteria (AOB) most closely matched a sequence from the uncultured bacterium BS870 but showed no substantial alignment to known cultured AOB. Based on these functional gene analyses, bacteria related to the type II methanotroph Methylocystis sp. were found to dominate both free-living and attached communities. Metagenomic DNA amplified by WGA showed characteristics similar to those of unamplified samples. Overall, numerous sMMO-like gene sequences that have been previously associated with high rates of trichloroethylene cometabolism were observed in both free-living and attached communities in this basaltic aquifer.

Ammonia↗