Heme oxygenase or haem oxygenase is an enzyme that catalyzes the degradation of heme. This produces biliverdin, ferrous iron, and carbon monoxide. HO was first described in the late 1960s when Raimo Tenhunen demonstrated an enzymatic reaction for heme catabolism. HO is the premier source for endogenous carbon monoxide production. Indeed, monitored small doses of CO are being studied for therapeutic benefits.
Heme oxygenase
Heme oxygenase is a heme-containing member of the heat shock protein 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, ferrousiron, and carbon monoxide. Though present throughout the body, HO has significant activity in the spleen in the degradation of hemoglobin during erythrocyte recycling, 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 and ineffective erythropoiesis in bone marrow. HO enzymes are degraded via ubiquitination. In humans three isoforms of heme oxygenase are known.
Heme oxygenase 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
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 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 phylogenetic 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. The human microbiome contributes to endogenous carbon monoxide production in humans.
Reaction
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: The sum of these reactions is: If the iron is initially in the +2 state, the reaction could be: 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: heme to biliverdin to bilirubin. In terms of molecular mechanisms, the enzyme facilitates the intramolecular hydroxylation of one meso carbon centre in the heme.
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
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 level in a non-smoker is between 0.2% and 0.85% 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.
