Review
Heme oxygenase and heme degradation☆

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Abstract

The microsomal heme oxygenase system consists of heme oxygenase (HO) and NADPH–cytochrome P450 reductase, and plays a key role in the physiological catabolism of heme which yields biliverdin, carbon monoxide, and iron as the final products. Heme degradation proceeds essentially as a series of autocatalytic oxidation reactions involving heme bound to HO. Large amounts of HO proteins from human and rat can now be prepared in truncated soluble form, and the crystal structures of some HO proteins have been determined. These advances have greatly facilitated the understanding of the mechanisms of individual steps of the HO reaction. HO can be induced in animals by the administration of heme or several other substances; the induction is shown to involve Bach1, a translational repressor. The induced HO is assumed to have cytoprotective effects. An uninducible HO isozyme, HO-2, has been identified, so the authentic HO is now called HO-1. HOs are also widely distributed in invertebrates, higher plants, algae, and bacteria, and function in various ways according to the needs of individual species.

Section snippets

Properties of HO

HO is a simple protein that does not have any of the prosthetic groups necessary for O2 activation [8], [9], [10]. Instead, O2 activation is performed by the substrate heme and its two intermediates, α-meso-hydroxyheme and verdoheme (Scheme 1). HO binds substrate heme at the specific position of its pocket to form heme–enzyme complex. This complex behaves as a kind of heme protein, whose spectrophotometric properties closely resemble those of myoglobin [8], [10], suggesting that histidine is a

Structure of HO

Thus far, the structures of seven HOs have been determined by X ray crystal analysis. These include human [20] and rat [22] HO-1s of mammalian origin, three HOs of bacterial origin, HemO of Neisseria meningitidis[61], HmuO of C. diphtheriae[62], and PigA of Pseudomonas aeruginosa[59], and two HO isoforms of cyanobacterial origin, Syn HO-1 [63] and Syn HO-2 [64]. For crystallization of the mammalian HO-1 (∼33 kDa), the truncated and soluble versions (∼28 kDa) lacking the membrane-binding domain

Biological aspects of HO

The activity of HO-1 in liver and other organs is markedly increased by the administration of hemin or hemoglobin to animals [71], [72], [73]. Induction of HO-1 is now shown to be due to de-repression of the HO-1 gene by heme through direct binding to a translational repressor, Bach1 [74]. HO-1 in rat liver is also increased by a number of non-heme substances such as endotoxin, bromobenzene, hormones, and certain metal ions [75]. Cadmium ion was shown to induce heme oxygenase also by way of the

Acknowledgments

We thank Drs. M. Ikeda-Saito, D.L. Rousseau, S. Takahashi, M. Sato, H, Fujii, Z. Hong, C.T. Migita, J.S. Olson, B.M. Hoffman, X. Zhang, S. Shibahara, K. Fukuyama, G. Palmer, H. Sakamoto, M. Sugishima, and Y. Higashimoto for their collaboration in this study. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of

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    ☆

    Abbreviations: HO, heme oxygenase; CO, carbon monoxide; NO, nitric oxide; HemO, HO of Neisseria meningitidis; HmuO, HO of Corynebacterium diphtheriae; PigA, HO of Pseudomonas aeruginosa.

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