On the mechanism of the chemical and enzymic oxygenations of alpha-oxyprotohemin IX to Fe.biliverdin IX alpha.

Sano, Seiyo; Sano, Toyo; Morishima, Isao; Shiro, Y.; Maeda, Yutaka

doi:10.1073/pnas.83.3.531

Cited by 90 publications

(101 citation statements)

References 29 publications

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“…Regioselectivity-When free heme is oxidized by ascorbate in an aerobic environment, all four of the heme meso carbons are oxidized with equal frequency (58). The oxidation of heme by HO-1 can also be driven with ascorbate without cytochrome P450 reductase, but the reaction only results in the oxidation of the heme ␣-mesocarbon, just as in the reaction performed in the presence of the reductase (59).…”

Section: Discussionmentioning

confidence: 99%

Comparison of Apo- and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2

Bianchetti

Ragsdale

et al. 2007

Journal of Biological Chemistry

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Heme oxygenase (HO) catalyzes the first step in the heme degradation pathway. The crystal structures of apo-and heme-bound truncated human HO-2 reveal a primarily ␣-helical architecture similar to that of human HO-1 and other known HOs. Proper orientation of heme in HO-2 is required for the regioselective oxidation of the ␣-mesocarbon. This is accomplished by interactions within the heme binding pocket, which is made up of two helices. The iron coordinating residue, His 45 , resides on the proximal helix. The distal helix contains highly conserved glycine residues that allow the helix to flex and interact with the bound heme. Tyr 154 , Lys 199 , and Arg 203 orient the heme through direct interactions with the heme propionates. The rearrangements of side chains in heme-bound HO-2 compared with apoHO-2 further elucidate HO-2 heme interactions. Heme oxygenase (HO)2 catalyzes the degradation of heme to free iron, carbon monoxide, and biliverdin in the presence of NADPH-dependent cytochrome P450 reductase. Seven electrons are transferred, and three molecules of oxygen are consumed in the degradation of one molecule of heme to biliverdin (Fig. 1). Subsequently, biliverdin reductase reduces biliverdin to bilirubin (1). Present in both bacteria and eukaryotes, HO is the only known enzyme that can degrade heme. HO not only plays a critical role in heme and iron homeostasis, but the products of heme degradation have important physiological functions (1, 2). Iron is the essential catalytic center for heme and many nonheme metalloenzymes and has crucial effects on cytoprotection (3, 4). Although CO is toxic at levels above ϳ500 ppm, it also is a signaling molecule (5, 6). CO has anti-apoptotic, antiinflammation, and anti-proliferation properties (7-9). Bilirubin is an antioxidant that is involved in resistance to oxidative stress (10, 11).Two HO isoforms have been reported in mammalian cells, heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2) (12). The mammalian HO-1 and HO-2 exhibit similar catalytic activities and share 55% identity and 76% similarity in humans (13,14). Another isoform, HO-3, was recently reported in rat; however, no activity was detected for this isoform, and it is considered a pseudogene (15). Plants contain several HOs, including one named HO-2, but these lack the C-terminal membranespanning region seen in mammalian HOs and are more closely related to the bacterial and insect HO-1 than to the mammalian HO-2 (13, 16).Although they are both membrane-bound proteins and their catalytic activities are similar, HO-1 and HO-2 are expressed in discrete tissues and exhibit very different patterns of expression (17). Although human HO-1 is an inducible protein whose expression is up-regulated by heat shock and oxidative stress conditions, HO-2 is constitutively expressed (17-22). HO-1 has been found in most tissues, with particularly high expression levels in liver and spleen; however, HO-2 is mainly found in the brain, testes, and carotid body (23-26).HO-1 and HO-2 exhibit two regions of sequence divergence: o...

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Section: Discussionmentioning

confidence: 99%

Comparison of Apo- and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2

Bianchetti

Ragsdale

et al. 2007

Journal of Biological Chemistry

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“…Moreover, an EPR signal of X observed at g ∼ 4.3 (Fig. 2F) suggests a highly rhombic environment for iron, as observed for ferric-biliverdin complexes of HO (29) and myoglobin (26). One may speculate that the rhombic signal arises from free iron released upon unexpected decomposition of X during the EPR measurement, especially because the spectra of X and the ferric iron-deferoxamine complex closely resemble each other (Fig.…”

Section: Firstmentioning

confidence: 97%

Unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation

Matsui

Nambu

Goulding

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

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Bacterial pathogens must acquire host iron for survival and colonization. Because free iron is restricted in the host, numerous pathogens have evolved to overcome this limitation by using a family of monooxygenases that mediate the oxidative cleavage of heme into biliverdin, carbon monoxide, and iron. However, the etiological agent of tuberculosis, Mycobacterium tuberculosis, accomplishes this task without generating carbon monoxide, which potentially induces its latent state. Here we show that this unusual heme degradation reaction proceeds through sequential mono- and dioxygenation events within the single active center of MhuD, a mechanism unparalleled in enzyme catalysis. A key intermediate of the MhuD reaction is found to be meso-hydroxyheme, which reacts with O2 at an unusual position to completely suppress its monooxygenation but to allow ring cleavage through dioxygenation. This mechanistic change, possibly due to heavy steric deformation of hydroxyheme, rationally explains the unique heme catabolites of MhuD. Coexistence of mechanistically distinct functions is a previously unidentified strategy to expand the physiological outcome of enzymes, and may be applied to engineer unique biocatalysts.

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“…This process of "coupled oxidation" is non-regiospecific so that random oxidation occurs at all four meso carbons to give a mixture of the corresponding IX␣, IX␤, IX␥, and IX␦ biliverdin isomers (12,13). In contrast, the hHO-1-catalyzed reaction regiospecifically oxidizes the ␣-meso carbon.…”

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confidence: 99%

Isoporphyrin Intermediate in Heme Oxygenase Catalysis

Evans

Niemevz

Buldain

et al. 2008

Journal of Biological Chemistry

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Human heme oxygenase-1 (hHO-1) catalyzes the O 2 -and NADPH-dependent oxidation of heme to biliverdin, CO, and free iron. The first step involves regiospecific insertion of an oxygen atom at the ␣-meso carbon by a ferric hydroperoxide and is predicted to proceed via an isoporphyrin -cation intermediate. Here we report spectroscopic detection of a transient intermediate during oxidation by hHO-1 of ␣-meso-phenylheme-IX, ␣-meso-(p-methylphenyl)-mesoheme-III, and ␣-meso-(p-tri-

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On the mechanism of the chemical and enzymic oxygenations of alpha-oxyprotohemin IX to Fe.biliverdin IX alpha.

Cited by 90 publications

References 29 publications

Comparison of Apo- and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2

Comparison of Apo- and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2

Unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation

Isoporphyrin Intermediate in Heme Oxygenase Catalysis

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