Heme oxygenase

Heme oxygenase
crystal structures of ferrous and ferrous-no forms of verdoheme in a complex with human heme oxygenase-1: catalytic implications for heme cleavage
Identifiers
Symbol	Heme_oxygenase
Pfam	PF01126
Pfam clan	CL0230
InterPro	IPR016053
PROSITE	PDOC00512
SCOP	1qq8
SUPERFAMILY	1qq8
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Heme oxygenase or haem oxygenase (HO) is an enzyme that catalyzes the degradation of heme. This produces biliverdin, ferrous iron, and carbon monoxide.^[1][2] There is limited evidence that levels of heme oxygenase are positive predictors of metabolic disease, insulin resistance, and metaflammation.^[3]

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:^[4]

Heme b³⁺ + O
2 + NADPH + H+
→ α-meso-hydroxyheme³⁺ + NADP+
+ H
2O

α-meso-hydroxyheme³⁺ + H+
+ O
2 → verdoheme⁴⁺ + CO + H2O

verdoheme⁴⁺ + 7/2 NADPH + O
2+ 3/2 H+
 → biliverdin + Fe²⁺ + 7/2 NADP+
+ H
2O

The sum of these reactions is:

Heme b³⁺ + 3O
2 + 9/2 NADPH + 7/2 H+
 → biliverdin + Fe²⁺ + CO + 9/2 NADP+
+ 3H
2O

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

Heme b  Biliverdin

This reaction can occur in virtually every cell; the classic example is the formation of a bruise, which goes through different colors as it gradually heals: red heme to green biliverdin to yellow bilirubin. Under normal physiological conditions, the activity of heme oxygenase is highest in the spleen, where old erythrocytes are sequestrated and destroyed. In terms of molecular mechanisms, the enzyme facilitates the intramolecular hydroxylation of one meso carbon centre in the heme.^[5]

Isoforms

Three isoforms of heme oxygenase are known. Heme oxygenase 1 (HO-1) is an inducible isoform in response to stress such as oxidative stress, hypoxia, heavy metals, cytokines, etc. Heme oxygenase 2 (HO-2) is a constitutive isoform that is expressed under homeostatic conditions. Both HO-1 and HO-2 are ubiquitously expressed and catalytically active. HO-1 is encoded by the HMOX1 gene and HO-2 by HMOX2.

A third heme oxygenase (HO-3) is not catalytically active, but is thought to work in oxygen sensing.

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. Carbon monoxide released from the reaction of free heme in the bloodstream of someone with the sickle-cell trait is believed to lessen the effects of cerebral malaria.^[6]

References

External links

• Heme Oxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)
• EC 1.14.99.3