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.

Hydrogen bond donation to the heme distal ligand of Staphylococcus aureus IsdG tunes the electronic structure

“…Although several important discoveries have been made regarding the mechanism of IsdG-catalyzed heme degradation [11,12,22,23], it remained unclear how secondsphere interactions in the enzyme active site might direct an activated oxygen species toward the β-and/or δ-meso carbons of the heme substrate. With the addition of the spectroscopic and computational data presented in this article, a structural picture emerges where the second sphere influences of Asn7 and Trp67 work in concert to organize a transition state that favors oxygenation of the β-and δ-meso carbons.…”

“…In an S = ½ system, the singly-occupied molecular orbital is the primary determinant of the spin density distribution, which has been proposed to be a major contributor to the reactivity of heme degrading enzymes [7,22,23,57]. In the DFT model of N7A IsdG-heme-N 3 , the axial azide ligand acts as a π-donor to the iron center raising the energy of the Fe 3d xz -and 3d yz -based molecular orbitals above the Fe 3d xy -based molecular orbital and the spin density is localized to the iron and azide moieties (Fig.…”

“…There are different electronic and mechanistic implications for the two scenarios where either the α-or β-atom of a distal dioxygen-based ligand acts as a hydrogen bond acceptor [20][21][22][23]. It is important to note that a reactive iron-dioxygen species has not yet been isolated for IsdG, but is likely to exist based upon the observations that molecular oxygen is required for enzymatic turnover [19], and that both azide-and cyanide-inhibited forms of IsdG are inactive ( Figure S1).…”

Marine algae and land plants share conserved phytochrome signaling systems

“…In most cases, these proteins use biliverdin IXα (BV) as chromophore. BV is ubiquitous, owing to the widespread distribution of heme oxygenases used in heme detoxification and degradation (40), excepting obligate anaerobes (7). Bilin-based sensors such as phytochromes are well suited to integrate both light and oxygen signals because bilin biosynthesis is oxygen dependent (18).…”

Decarboxylation involving a ferryl, propionate, and a tyrosyl group in a radical relay yields heme b

“…Their functional versatility is due to the macrocycle's capacity for accommodating a variety of metals at the center and organic functional groups around the periphery. Many well-characterized enzymes that use a metallotetrapyrrole as a substrate, such as heme oxygenase (1,2), heme A synthase (3), or some cytochrome P450s (4), take advantage of its intrinsic reactivity, so that these reactions have an autocatalytic character. Coproheme decarboxylase is a metallotetrapyrrolemodifying enzyme that likewise uses a heme as both substrate and cofactor, catalyzing the oxidative decarboxylation of ferric 2,4,6,7-tetrapropionic acid porphyrin (coproheme) to yield ferric 6,7-dipropionic acid-2,4-divinyl porphyrin (heme b).…”