Heme Oxygenase-2 Is a Hemoprotein and Binds Heme through Heme Regulatory Motifs That Are Not Involved in Heme Catalysis

McCoubrey, William K.; Huang, Tao; Maines, Mahin D.

doi:10.1074/jbc.272.19.12568

Cited by 171 publications

(182 citation statements)

References 57 publications

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“…These characteristics of the Hmox2 gene, the presence of the consensus sequence of oxygen sensor elements and the highaffinity heme-binding motifs in HO-2 are consistent with its role as a major gene regulator in the cell. 31 Thus, there is good rationale for not perturbing the HO-2 system while trying to control the HO-1 system.…”

Section: Discussionmentioning

confidence: 99%

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In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins

et al. 2011

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Objective: Neonatal jaundice results from an increased bilirubin production and decreased hepatic bilirubin conjugation and excretion. Severe hyperbilirubinemia is currently treated with phototherapy or exchange transfusion; however, its prevention by inhibiting bilirubin formation is a more logical strategy. Heme oxygenase (HO), with inducible (HO-1) and constitutive (HO-2) isoenzymes, is the rate-limiting enzyme in heme catabolism, producing equimolar amounts of bilirubin and carbon monoxide (CO). Metalloporphyrins (Mps) are heme derivatives that competitively inhibit HO and thereby suppress hyperbilirubinemia. No systematic studies have been reported evaluating whether the HO isoenzymes are inhibited differentially by various Mps. Identification of Mps that selectively inhibit the inducible HO-1 without affecting the 'housekeeping' HO-2 isoenzyme might be desirable in the clinical setting of hemolytic disease, in which the Hmox1 gene is greatly induced. Although bilirubin production is due to the activity of both HO-1 and HO-2, the inhibition of HO-1 with a relative sparing of HO-2 activity might provide the most selective approach for the treatment of hemolytic disease.Study Design: We determined for the deutero-, proto-, meso-and bisglycol porphyrins with zinc, tin and chromium as central atoms, respectively, the concentration needed for 50% inhibition (I 50 ) of HO-1 and HO-2 activities in rat spleen and brain tissue.Result: For a given Mp, HO-1 activity was less inhibited than that of HO-2. The order of inhibitor potency of each Mp was nearly identical for both isoenzymes. Tin mesoporphyrin was the most potent inhibitor for both isoenzymes. HO-2 selectivity was greatest for tin protoporphyrin. Conversely, the Zn compounds were least inhibitory toward HO-2. No Mp preferentially inhibited HO-1. Conclusion:Mps that produce a less inhibitory effect on HO-2, while limiting the response of the inducible HO-1, such as ZnPP, may be a useful clinical tool.

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Section: Discussionmentioning

confidence: 99%

“…The 'heme pocket' recognizes the porphyrin ring of the Mps, but not the chelated metal. 31 Therefore, various synthetic Mps can bind to prevent access to the pocket by the natural substrate, heme.…”

Section: Discussionmentioning

confidence: 99%

In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins

et al. 2011

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“…npg Ultimately, heme is degraded. In mammals, two heme oxygenase (HO) enzymes, HO-1 and HO-2, have been identified, confirmed and characterized [123,151,152]. A third gene, HO-3, appears to be a pseudogene derived from HO-2 [153].…”

Section: The Oxidant Potential Of Heme Is Neutralized By Multiple Hemmentioning

confidence: 99%

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

2006

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“…In the predicted primary structure of HO-2 [5], two copies of the HRM also can be identified. HRM bind heme through the cysteine residue [19]. The presence of a single copy of HRM confers heme-dependent transcriptional activity to HAP1 [13].…”

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Isolation and Characterization of a cDNA from the Rat Brain that Encodes Hemoprotein Heme Oxygenase‐3

McCoubrey¹,

Huang²,

Maines³

1997

European Journal of Biochemistry

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773

469

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Two isozymes of heme oxygenase (HO), HO-1 or HSP32 and the constitutive form HO-2, have been characterized to date. We report the discovery of a third protein species and refer to it as HO-3. HO-3 is the product of a single transcript of ~2 . 4 kb and can encode a protein of =33 kDa. The HO-3 transcript is found in the spleen, liver, thymus, prostate, heart, kidney, brain and testis and is the product of a singlecopy gene. The predicted amino acid structure of HO-3 differs from both HO-1 (HSP32) and HO-2 but is closely related to HO-2 (~9 0 % ) .Escherichia coli expressed and purified HO-3 protein does not cross react with polyclonal antibodies to either rat HO-1 or HO-2, is a poor heme catalyst, and displays hemoprotein spectral characteristics. The predicted protein has two heme regulatory motifs that may be involved in heme binding. These motifs and the hemoprotein nature of HO-3 suggest a potential regulatory role for the protein in cellular processes which are heme-dependent.

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Heme Oxygenase-2 Is a Hemoprotein and Binds Heme through Heme Regulatory Motifs That Are Not Involved in Heme Catalysis

Abstract: The heme oxygenase (HO) system degrades heme to biliverdin and CO and releases chelated iron.

Cited by 171 publications

References 57 publications

In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins

In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

Isolation and Characterization of a cDNA from the Rat Brain that Encodes Hemoprotein Heme Oxygenase‐3

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