Heme oxygenation and the widening paradigm of heme degradation

Abstract

Heme degradation through the action of heme oxygenase (HO) is unusual in that it utilizes heme as both a substrate and cofactor for its own degradation. HO catalyzes the oxygen-dependent degradation of heme to biliverdin with the release of CO and "free" iron. The characterization of HO enzymes from humans to bacteria reveals a similar overall structural fold that contributes to the unique reaction manifold. The heme oxygenases share a similar heme-dependent activation of O2 to the ferric hydroperoxide as that of the cytochrome P450s and peroxidases. However, whereas the P450s promote cleavage of the ferric hydroperoxide OO bond to the oxoferryl species the HOs stabilize the ferric hydroperoxide promoting hydroxylation at the heme edge. The alternate reaction pathway in HO is achieved through the conformational flexibility and extensive hydrogen bond network within the heme binding site priming the heme for hydroxylation. Until recently it was believed that all heme degrading enzymes converted heme to biliverdin and iron, with the release of carbon monoxide (CO). However, the recent discovery of the bacterial IsdG-like heme degrading proteins of Staphylococcus aureus, Bacillus anthracis and Mycobacterium tuberculosis has expanded the reaction manifold of heme oxidation. Characterization of the heme degradation products in the IsdG-like reaction suggests a mechanism distinct from the classical HOs. In the following review we will discuss the structure-function of the canonical HOs as it relates to the emerging alternate reaction manifold of the IsdG-like proteins.

Keywords: Biliverdin; Coupled oxidation; Heme degradation; Heme oxygenase; Mycobilin; Staphylobilin; Verdoheme.