1.14.14.18: heme oxygenase (biliverdin-producing)
This is an abbreviated version!
For detailed information about heme oxygenase (biliverdin-producing), go to the full flat file.
Word Map on EC 1.14.14.18
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1.14.14.18
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monoxide
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cytoprotective
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endothelial
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necrosis
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dismutase
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protoporphyrin
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erythroid
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2-related
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tnf
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bilirubin
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artery
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malondialdehyde
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lipopolysaccharide
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catalase
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hemin
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neuroprotective
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ischemia
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gsh
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lps
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sod
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anti-oxidant
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mapks
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sirna
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caspase-3
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quinone
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pulmonary
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reperfusion
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lps-induced
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hypoxia
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cyclooxygenase-2
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cox-2
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ferritin
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erk
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nf-e2-related
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anti-apoptotic
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cobalt
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myeloperoxidase
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ischemia-reperfusion
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nrf2-mediated
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pro-oxidant
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kelch-like
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nadph:quinone
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factor-2
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lps-stimulated
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2-like
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erythroid-derived
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oxygenases
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delta-aminolevulinic
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sulforaphane
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hyperbilirubinemia
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medicine
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drug development
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analysis
- 1.14.14.18
- monoxide
-
cytoprotective
- endothelial
- necrosis
- dismutase
- protoporphyrin
-
erythroid
-
2-related
- tnf
- bilirubin
- artery
- malondialdehyde
- lipopolysaccharide
- catalase
- hemin
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neuroprotective
- ischemia
- gsh
- lps
- sod
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anti-oxidant
- mapks
- sirna
- caspase-3
- quinone
- pulmonary
-
reperfusion
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lps-induced
- hypoxia
- cyclooxygenase-2
- cox-2
- ferritin
- erk
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nf-e2-related
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anti-apoptotic
- cobalt
- myeloperoxidase
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ischemia-reperfusion
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nrf2-mediated
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pro-oxidant
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kelch-like
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nadph:quinone
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factor-2
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lps-stimulated
-
2-like
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erythroid-derived
- oxygenases
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delta-aminolevulinic
- sulforaphane
- hyperbilirubinemia
- medicine
- drug development
- analysis
Reaction
+ 3 [reduced NADPH-hemoprotein reductase] + 3 O2 = + + + 3 [oxidized NADPH-hemoprotein reductase] + 3 H2O
Synonyms
biliverdin-producing heme oxygenase, ChuS, ChuZ, EC 1.14.99.3, haem oxygenase, heme oxygenase, heme oxygenase 1, heme oxygenase 2, heme oxygenase-1, heme oxygenase-2, HemO, Hmox1, Hmox1a, Hmox1b, Hmox2, Hmox2a, Hmox2b, HmuO, Hmx1, HO, HO-1, HO-2, Ho1, Ho2, Ho3, HO4, HSP32, HugZ, HY1, inducible heme oxygenase-1, More, MsHO1, ORP33 proteins, oxygenase, heme (decyclizing), pbsA1, PigA, proteins, specific or class, ORP33 (oxygen-regulated protein 33,000-mol.-wt.), Syn HO-1, Syn HO-2
ECTree
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General Information
General Information on EC 1.14.14.18 - heme oxygenase (biliverdin-producing)
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evolution
malfunction
metabolism
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isoform HO-1 modulates the function of transcriptional factor Nuclear factor erythroid 2-related factor 2 (Nrf2). In oxidative stress, nuclear isoform HO-1 interacts with Nrf2 and stabilizes it from glycogen synthase kinase 3beta-mediated phosphorylation coupled with ubiquitin-proteasomal degradation, thereby prolonging its accumulation in the nucleus
physiological function
additional information
bacterial HmuO and mammalian heme oxygenases are similar in their reaction mechanisms and structures
evolution
bacterial HmuO and mammalian heme oxygenases are similar in their reaction mechanisms and structures
evolution
HmuO and mammalian heme oxygenases are similar in their reaction mechanisms and structures
evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. In Pseudomonas aeruginosa PAO1, PigA is encoded in a cluster together with proteins involved in iron utilization while BphO is functionally and genetically coupled to the phytochrome BphP
evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. In Pseudomonas fluorescence Pf-5, PigA is encoded in a cluster together with proteins involved in iron utilization while BphO is functionally and genetically coupled to the phytochrome BphP
evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. In Pseudomonas mendocina YMP, PigA is encoded in a cluster together with proteins involved in iron utilization while BphO is functionally and genetically coupled to the phytochrome BphP
evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. In Pseudomonas syringae DC3000, PigA is encoded in a cluster together with proteins involved in iron utilization while BphO is functionally and genetically coupled to the phytochrome BphP
evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. Only one of the two PigA homologues identified in Pseudomonas putida KT2440 is encoded in an iron-associated gene cluster
evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. Only one of the two PigA homologues identified in Pseudomonas putida KT2440 is encoded in an iron-associated gene cluster
evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. In Pseudomonas fluorescence Pf-5, PigA is encoded in a cluster together with proteins involved in iron utilization while BphO is functionally and genetically coupled to the phytochrome BphP
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evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. In Pseudomonas syringae DC3000, PigA is encoded in a cluster together with proteins involved in iron utilization while BphO is functionally and genetically coupled to the phytochrome BphP
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evolution
Pseudomonas aeruginosa KT 2240
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. Only one of the two PigA homologues identified in Pseudomonas putida KT2440 is encoded in an iron-associated gene cluster
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evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. Only one of the two PigA homologues identified in Pseudomonas putida KT2440 is encoded in an iron-associated gene cluster
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evolution
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Pseudomonas strains exhibit four possible enzyme compositions: (I) BphO, (II) PigA, (III) BphO and PigA and (IV) two PigAs. In Pseudomonas mendocina YMP, PigA is encoded in a cluster together with proteins involved in iron utilization while BphO is functionally and genetically coupled to the phytochrome BphP
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mutation of ChuZ abolishes the ability of Campylobacter jejuni to use hemin or hemoglobin as sources of iron
malfunction
mutation of the distal Asp decreases the verdoheme ring opening activity
malfunction
mutation of the distal Asp decreases the verdoheme ring opening activity
malfunction
mutation of the distal Asp decreases the verdoheme ring opening activity
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because HO-1 and NADPH-cytochrome P450 reductase (CPR) are membrane-bound proteins, the presence of membrane hydrophobic milieu (dilauroylphosphatidylcholine or endoplasmic reticulum membrane) may alter the mechanism by which cytosolic biliverdin reductase metabolizes its substrate biliverdin to bilirubin
physiological function
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HO enzyme activity in the human seminal plasma is related to spermatogenesis and sperm-motility processes
physiological function
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HO-1 is a negative regulator of trophoblast motility acting via up-regulation of peroxisome proliferator activated receptor (PPAR) gamma. In wound healing assays, trophoblast migration into the denuded area is diminished upon induction of HO-1
physiological function
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HO-1 is critically involved in macrophage polarization toward an M2 phenotype. HO-1 affects anti-inflammatory and antiapoptotic pathways in macrophages
physiological function
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HO-1-specific T cells isolated from the peripheral blood of cancer patients inhibit cytokine release, proliferation, and cytotoxicity of other immune cells
physiological function
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human patient wiht HO-1-deficiency died in his childhood with clinical manifestations, including growth failure, anemia, tissue iron deposition, lymphoadenopathy, leukocytosis and increased sensitivity to oxidative injury. HO-1 serves to provide cytoprotection against oxidative stress and is necessary in mammals
physiological function
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inducible form of HO-1, biliverdin, and CO possess generalized endogenous anti-inflammatory activities and provide protection against intestinal ischemia/reperfusion injury. Exogenous HO-1 expression, as well as exogenously administered CO and biliverdin, have potent cytoprotective effects on intestinal ischemia/reperfusion injury as well
physiological function
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mice lacking the HO-1 gene frequently die in utero, and the mice that survive to adulthood exhibit growth failure, anemia, chronic inflammation characterized by hepatosplenomegaly, leukocytosis, glomerulonephritis, and histological hepatoportal cellular infiltration. HO-1 serves to provide cytoprotection against oxidative stress and is necessary in mammals
physiological function
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4-hydroxy hexenal stimulates expression of the antioxidant enzyme HO-1 through the activation of Nrf2 in vascular endothelial cells resulting in prevention of oxidative stress-induced cytotoxicity, this may represent a possible mechanism to partly explain the cardioprotective effects of n-3 polyunsaturated fatty acids
physiological function
BrHO1 may play an important role in abiotic stress tolerance of Chinese cabbage. Heme oxygenase is a regulatory enzyme that cleaves heme to biliverdin IXalpha, with the concomitant release of carbon monoxide and the production of free Fe2+
physiological function
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by catalyzing the first step in heme degradation, heme oxygenase plays a vital role in maintaining proper heme homeostasis. Isozymes HO-1 and HO-2, exist that catalyze the same reaction but differ in several notable ways, overview
physiological function
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heme oxygenase-1 signals are involved in preferential inhibition of pro-inflammatory cytokine release by surfactin, produced by Bacillus subtilis, in cells activated with Porphyromonas gingivalis lipopolysaccharide
physiological function
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heme oxygenase-1/CO induces vascular endothelial growth factor expression via p38 kinase-dependent activation of Sp1. CO-induced VEGF promoter activation requires the binding of the Sp1 transcriptional factor to a cis-regulatory sequence located at the VEGF promoter. HO-1/CO induced p38-dependent phosphorylation of Sp1 at Thr453 and Thr739 both in vitro and in vivo
physiological function
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heme oxygenases are widely distributed enzymes involved in the oxidative cleavage of the heme macrocycle that yields the open-chain tetrapyrrole biliverdin IX, CO, and iron
physiological function
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heme oxygenases are widely distributed enzymes involved in the oxidative cleavage of the heme macrocycle that yields the open-chain tetrapyrrole biliverdin IX, CO, and iron
physiological function
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HO-1 together with dichloromethane induces interleukin-10 expression in liver. HO-1, acting through the Nfe2l2, i.e. Nrf2, transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO1 induction after LPS stimulates anti-inflammatory interleukin-10 and interleukin-1 receptor antagonist expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-alpha expression
physiological function
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HugZ is part of the iron acquisition mechanism of Helicobacter pylori, and is required for the adaptive colonization of the pathogen in human hosts. Arg166, which is involved in azide binding, is essential for HugZ enzymatic activity, whereas His245 is not, implying that HugZ has an enzymatic mechanism distinct from other heme oxygenases
physiological function
MsHO1 may play an important role in oxidative responses
physiological function
heme oxygenase has cytoprotective properties and may play a role in several disease states. HO-1 activity is upregulated in response to several therapeutic treatments and is implicated in promoting tumour growth. HO-1-derived CO is associated with angiogenesis, inducing vascular endothelial growth factor synthesis, and stimulating the proliferation of endothelial cells. Role of the HO/CO system in neuronal complications, particularly of HO-1
physiological function
heme oxygenase has cytoprotective properties and may play a role in several disease states. Role of the HO/CO system in neuronal complications, particularly of HO-1
physiological function
heme oxygenase-1 is the limiting enzyme in heme catabolism. Induction of HO-1 expression decreases dramatically NADPH oxidase Nox4 activity in C-20/A4 and HEK-293T-RExTM Nox4 cell lines, mediated by carbon monoxide, the decrease is not accompanied by any change in the expression, the subcellular localization or the maturation of Nox4. Inhibition of the heme synthesis by succinylacetone rather than heme catabolism by HO-1, leads to a confinement of the Nox4/p22phox heterodimer in the endoplasmic reticulum with an absence of redox differential spectrum highlighting an incomplete maturation. HO-1 decreases MMP-1 expression and chondrocytes DNA fragmentation via CO release
physiological function
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role of PigA in iron acquisition, in strains containing no PigA, this function may be fulfilled by BphO
physiological function
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role of PigA in iron acquisition, in strains containing no PigA, this function may be fulfilled by BphO
physiological function
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role of PigA in iron acquisition, in strains containing no PigA, this function may be fulfilled by BphO
physiological function
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role of PigA in iron acquisition, in strains containing no PigA, this function may be fulfilled by BphO
physiological function
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the enzyme enables the organism to use heme as the sole iron source
physiological function
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enzyme overexpression is critical for tumor cell death with an impaired mitochondrial energetics
physiological function
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the enzyme exhibits protective effects on cecal ligation and puncture-induced acute lung injury via regulating cell surface thrombomodulin and activated protein C expression and modulating blood coagulation
physiological function
enzyme interacts and acquires heme from cytoplasmic heme transport protein holo-PhuS. In mutant strains, the absence of bilverdin IXbeta and bilverdinIXdelta leads to a decrease in extracellular levels of hemophore HasA
physiological function
Hmox2 and cytochrome P450 reductase form a dynamic ensemble of complexes that precede formation of the productive electron transfer complex. Specific residues, including Leu201, near the heme face of Hmox2 are affected by the addition of cytochrome P450 reductase. Hmox2 and biliverdin reductase form a very weak complex, and biliverdin reductase binds Hmox2 weakly
physiological function
isoform Hmox2 contains two C-terminal heme regulatory motifs centered at Cys265 and Cys282. The same mechanism of heme hydroxylation to alpha-meso-hydroxyheme is employed by both isoform Hmox1 and Hmox2 and the heme regulatory motifs do not affect the physicochemical properties of the oxy-Fe(II) and HOO-Fe(III) states of Hmox2. Heme oxygenation by Hmox2 occurs solely at the catalytic core and hydroxylation proceeds three times slower and the oxy-Fe(II) state is 100fold less stable in Hmox2 than in Hmox1
physiological function
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overexpression of Brassica oleracea HO1 in transgenic Arabidopsis plants significantly alleviates salinity stress-inhibited seedling growth, accompanied by the reestablishment of reactive oxygen species and ion homeostasis. Protein abundance related to light reactions is greatly suppressed by NaCl stress in wild-type, but is partially recovered in the transgenic strain. HO1 may activate multiple stress-responsive pathways to help Arabidopsis thaliana regain cellular homeostasis during salinity stress
physiological function
pharmacological induction of Hmox1 significantly ameliorates the effects of amyloid-beta1-42 in rat primary hippocampal neurons
physiological function
pharmacological induction or genetic overexpression of Hmox1 significantly ameliorates the effects of amyloid-beta1-42 in SH-SY5Y cells
physiological function
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role of PigA in iron acquisition, in strains containing no PigA, this function may be fulfilled by BphO
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physiological function
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role of PigA in iron acquisition, in strains containing no PigA, this function may be fulfilled by BphO
-
physiological function
-
HO-1 together with dichloromethane induces interleukin-10 expression in liver. HO-1, acting through the Nfe2l2, i.e. Nrf2, transcription factor, links anti-inflammatory cytokine expression to activation of mitochondrial biogenesis. HO1 induction after LPS stimulates anti-inflammatory interleukin-10 and interleukin-1 receptor antagonist expression in mouse liver, human HepG2 cells, and mouse J774.1 macrophages but blunted tumor necrosis factor-alpha expression
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physiological function
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role of PigA in iron acquisition, in strains containing no PigA, this function may be fulfilled by BphO
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in cells, Hmox1 or Nfe2l2 RNA silencing prevents IL-10 and IL-1Ra up-regulation, and HO-1 induction fails post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2-/- mice
additional information
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modulation of HO catalysis by ligands targeting the critical distal pocket structure, overview
additional information
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modulation of HO catalysis by ligands targeting the critical distal pocket structure, overview
additional information
modulation of HO catalysis by ligands targeting the critical distal pocket structure, overview
additional information
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physiological effects of angiotensin II with and without tin mesoporphyrin on renal and aortic HO-1 activity, overview
additional information
QM/MM calculations based on this crystal structure exploring the reaction mechanisms starting from the FeOOH-verdoheme and FeHOOH-verdoheme complexes, which mimic, respectively, the O2- and H2O2-supported degradations. The rate-determining step is the initial O-O bond breaking step, which is either homolytic, for FeHOOH-verdoheme, or coupled to electron and proton transfers, in FeOOH-verdoheme. The FeHOOH-verdoheme complex is more reactive than the FeOOH-verdoheme complex
additional information
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QM/MM calculations based on this crystal structure exploring the reaction mechanisms starting from the FeOOH-verdoheme and FeHOOH-verdoheme complexes, which mimic, respectively, the O2- and H2O2-supported degradations. The rate-determining step is the initial O-O bond breaking step, which is either homolytic, for FeHOOH-verdoheme, or coupled to electron and proton transfers, in FeOOH-verdoheme. The FeHOOH-verdoheme complex is more reactive than the FeOOH-verdoheme complex
additional information
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regulation of isozyme HO-2, overview. Presence of three Cys residues as part of heme-regulatory motifs in HO-2, low-spin Fe(III) heme species are characteristic of thiolate ligation is formed when Cys265 is reduced. Resonance Raman data collected at different temperatures reveal an intriguing temperature dependence of the iron spin state in the heme-HO-2 complex
additional information
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analysis of enzyme-protohemin substrate variant complexes and of enzyme-propionate substrate complexes by NMR, active site structure, overview. The enzyme's C-terminal fragment interacts with the active site of the enzyme. The C-terminal dipeptide Arg208-His209 cleaves spontaneously. Stronger hydrophobic contacts between pyrroles A and B with the enzyme contribute more substantially to the substrate binding free energy than in mammalian HOs, liberating one propionate to stabilize the C-terminus
additional information
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heme is bound in its binding site on the dimer interface by four histidine side-chains through hydrophobic interactions, canonical heme-binding site structure, reaction mechanism and structure-function relationship, overview
additional information
heme oxygenase is an enzyme that catalyzes the regiospecific conversion of heme to biliverdin IXalpha, carbon monoxide, and free Fe(II). Heme degradation by heme oxygenase proceeds through three successive steps of O2 activation. The first step is formation of alpha-meso-hydroxyheme from from heme, second formation of verdoheme from alpha-meso-hydroxyheme, the third step is the ring opening of verdoheme, Only alpha-verdoheme with the O atom in its alpha position, and not beta-, gamma-, or delta-verdoheme, is converted to biliverdin. The third step, like the first, shows regiospecificity, the distal Asp plays an important role in this step, similar to the first. The substrate heme is sandwiched between two helices, termed the proximal and distal helices
additional information
heme oxygenase is an enzyme that catalyzes the regiospecific conversion of heme to biliverdin IXalpha, carbon monoxide, and free Fe(II). Heme degradation by heme oxygenase proceeds through three successive steps of O2 activation. The first step is formation of alpha-meso-hydroxyheme from from heme, second formation of verdoheme from alpha-meso-hydroxyheme, the third step is the ring opening of verdoheme, Only alpha-verdoheme with the O atom in its alpha position, and not beta-, gamma-, or delta-verdoheme, is converted to biliverdin. The third step, like the first, shows regiospecificity, the distal Asp plays an important role in this step, similar to the first. The substrate heme is sandwiched between two helices, termed the proximal and distal helices
additional information
heme oxygenase is an enzyme that catalyzes the regiospecific conversion of heme to biliverdin IXalpha, carbon monoxide, and free Fe(II). Heme degradation by heme oxygenase proceeds through three successive steps of O2 activation. The first step is formation of alpha-meso-hydroxyheme from heme, second formation of verdoheme from alpha-meso-hydroxyheme, the third step is the ring opening of verdoheme. Only alpha-verdoheme with the O atom in its alpha position, and not beta-, gamma-, or delta-verdoheme, is converted to biliverdin. The third step, like the first, shows regiospecificity, the distal Asp plays an important role in this step, similar to the first. The substrate heme is sandwiched between two helices, termed the proximal and distal helices
additional information
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the enzyme shows substrate-protein, specifically pyrrole-I/II-helix-2, peripheral interactions. The enzyme's C-terminus interacts with substrate in solution, interaction of the C-terminus with the active site destabilizes the crystallographic protohemin orientation, which is consistent with optimizing the His207-Asp27 H-bond, active site stress for product release, NMR analysis of wild-type and mutant enzymes, overview. Thermodynamics of substrate orientational isomerism are mapped for substrates with individual vinyl to methyl to hydrogen substitutions and with enzyme C-terminal deletions. Replacing bulky vinyls with hydrogens results in a 180 degree rotation of substrate about the alpha,gamma-meso axis in the active site
additional information
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physiological effects of angiotensin II with and without tin mesoporphyrin on renal and aortic HO-1 activity, overview
-
additional information
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in cells, Hmox1 or Nfe2l2 RNA silencing prevents IL-10 and IL-1Ra up-regulation, and HO-1 induction fails post-LPS in Nfe2l2-silenced cells and post-sepsis in Nfe2l2-/- mice
-