Heme oxygenase or haem oxygenase (HO) is an enzyme that catalyzes the degradation of heme. This produces biliverdin, ferrous iron, and carbon monoxide. HO was first described in the late 1960's when Tenhunen demonstrated an enzymatic reaction for heme catabolism. HO is the premier source for endogenous carbon monoxide (CO) production, which is being studied for therapeutic benefits.
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Crystal structures of ferrous and ferrous-no forms of verdoheme in a complex with human heme oxygenase-1: catalytic implications for heme cleavage
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Heme oxygenase is a heme-containing member of the heat shock protein (HSP) family identified as HSP32. HO-1 is a 32kDa enzyme contains 288 amino acid residues. HO is located in the endoplasmic reticulum, though it has also been reported in the mitochondria, cell nucleus, and plasma membrane.
HO catalyzes the degradation of heme to biliverdin/bilirubin, ferrous iron, and carbon monoxide. Though present throughout the body, HO has significant activity in the spleen in the degradation of hemoglobin during erythrocyte recycling (0.8% of the erythrocyte pool per day), which accounts for ~80% of the heme derived endogenous CO production. The remaining 20% of heme derived CO production is largely attributed to hepatic catabolism of hemoproteins (myoglobin, cytochromes, catalase, peroxidases, soluble guanylate cyclase, nitric oxide synthase) and ineffective erythropoiesis in bone marrow. HO enzymes are degraded via ubiquitination. In humans three isoforms of heme oxygenase are known.
Heme oxygenase 1
Heme oxygenase 1 (HO-1) is a stress-induced isoform present throughout the body with highest concentrations in the spleen, liver, and kidneys. HO-1 is a 32kDa enzyme containing 288 amino acid residues which is encoded by the HMOX1 gene. A study has found levels of HO-1 in lung tissue were directly related to infection with Tuberculosis or infection-free areas, and knockout mice were found susceptible, showing the essential role of this enzyme.
Heme oxygenase 2
Heme oxygenase 2 (HO-2) is a constitutive isoform that is expressed under homeostatic conditions in the testes, endothelial cells and the brain. HO-2 is encoded by the HMOX2 gene. HO-2 is 36 kDa and shares 47% similarity with the HO-1 amino acid sequence.
Heme oxygenase 3
A third heme oxygenase (HO-3) is considered to be catalytically inactive and is thought to work in heme sensing or heme binding. HO-3 is 33 kDa with greatest presence in the liver, prostate, and kidneys.
Microbial heme oxygenase
Heme oxygenase is conserved across phylogenic kingdoms. The European Bioinformatics Institute’s InterPro taxonomy database indicates there are 4,347 bacteria species, 552 fungi species, and 6 archaea species expressing a HO-1-like enzymes. Microbial HO homologues use different abbreviation such as HMX1 in Saccharomyces cerevisiae, Hmu O in Corynebacterium diphtheriae, and Chu S in Escherichia coli. A critical role of the prokaryotic HO systems is to facilitate acquisition of nutritional iron from a eukaryotic host. Some HO-like prokaryotic enzymes are inactive or do not liberate CO. Certain strains of Escherichia coli express the non-CO producing Chu W isoform, whilst HO-like enzymes in other microbes have been reported to produce formaldehyde.
Heme oxygenase cleaves the heme ring at the alpha-methene bridge to form either biliverdin or, if the heme is still attached to a globin, verdoglobin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. The reaction comprises three steps, which may be:
- Heme b3+ + O
2 + NADPH + H+
→ α-meso-hydroxyheme3+ + NADP+
- α-meso-hydroxyheme3+ + H+
2 → verdoheme4+ + CO + H2O
- verdoheme4+ + 7/2 NADPH + O
2+ 3/2 H+
→ biliverdin + Fe2+ + 7/2 NADP+
- Heme b3+ + O
The sum of these reactions is:
- Heme b3+ + 3O
2 + 9/2 NADPH + 7/2 H+
→ biliverdin + Fe2+ + CO + 9/2 NADP+
If the iron is initially in the +2 state, the reaction could be:
- Heme b2+ + 3O2 + 4 NADPH + 4 H+ → biliverdin + Fe2+ + CO + 4 NADP+ + 3H2O
This reaction can occur in virtually every cell; the classic example is the formation of a contusion, which forms different chromogens as it gradually heals: (red) heme to (green) biliverdin to (yellow) bilirubin. In terms of molecular mechanisms, the enzyme facilitates the intramolecular hydroxylation of one meso carbon centre in the heme.
HO-1 is induced by countless molecules including heavy metals, statins, paclitaxel, rapamycin, probucol, nitric oxide, sildenafil, carbon monoxide, carbon monoxide-releasing molecules, and porphyrins.
Phytochemical inducers of HO include: curcumin, resveratrol, piceatannol, caffeic acid phenethyl ester, dimethyl fumarate, fumaric acid esters, flavonoids, chalcones, ginkgo biloba, anthrocyanins, phlorotannins, carnosol, rosolic acid, and numerous other natural products.
NRF2 inducers with downstream HO-1 induction include: genistein, 3-hydroxycoumarin, oleanolic acid, isoliquiritigenin, PEITC, diallyl trisulfide, oltipraz, benfotiamine, auranofin, acetaminophen, nimesulide, paraquat, ethoxyquin, diesel exhaust particles, silica, nanotubes, 15‐deoxy‐Δ12,14 prostaglandin J2, nitro-oleic acid, hydrogen peroxide, and succinylacetone.
Roles in physiology
Heme oxygenase expression is induced by oxidative stress, and in animal models increasing this expression seems to be protective. Carbon monoxide released from heme oxygenase reactions can influence vascular tone independently or influence the function of nitric oxide synthase.
Endogenous carbon monoxide
- See also: carbon monoxide-releasing molecules
The first detection of CO in humans was in 1949. Sjöstrand determined that CO originated from the alpha-methene carbon of heme, setting the stage for the molar ratio between hemin degradation and CO production to be established. HO is the main source of endogenous CO production, though other minor contributors have been identified in recent years. CO is formed at a rate of 16.4 µmol/hour in the human body, ~86% originating from heme via heme oxygenase and ~14% from non-heme sources including: photooxidation, lipid peroxidation, and xenobiotics. The average carboxyhemoglobin (CO-Hb) level in a non-smoker is between 0.2% and 0.85% CO-Hb (whereas a smoker may have between 4% and 10% CO-Hb), though geographic location, occupation, health and behavior are contributing variables. Among these, the microbial HO system within the digestive tract is believed to contribute to systemic CO-Hb concentrations.
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