ArticleThe Journal of biological chemistry2009
Heme regulatory motifs in heme oxygenase-2 form a thiol/disulfide redox switch that responds to the cellular redox state.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 73 citations in OpenAlex.
- Heme and CO metabolism by the canonical human heme oxygenases.Journal of inorganic biochemistry · 2026Review
- Heme Regulatory Motif of Heme Oxygenase-2 Is Involved in the Interaction with NADPH-Cytochrome P450 Reductase and Regulates Enzymatic Activity.International journal of molecular sciences · 2025Article
- Redox Regulation of KAntioxidants & redox signaling · 2024Review
- Article
- Heme delivery to heme oxygenase-2 involves glyceraldehyde-3-phosphate dehydrogenase.Biological chemistry · 2022Article
- Review
- Regulation of protein function and degradation by heme, heme responsive motifs, and CO.Critical reviews in biochemistry and molecular biology · 2022Review
- Role of Reductive versus Oxidative Stress in Tumor Progression and Anticancer Drug Resistance.Cells · 2021Review
- Heme oxygenase-2 is post-translationally regulated by heme occupancy in the catalytic site.The Journal of biological chemistry · 2020Article
- Discovery of a heme-binding domain in a neuronal voltage-gated potassium channel.The Journal of biological chemistry · 2020Article
- The heme-regulatory motifs of heme oxygenase-2 contribute to the transfer of heme to the catalytic site for degradation.The Journal of biological chemistry · 2020Article
- Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways.Antioxidants (Basel, Switzerland) · 2019Review
- Dynamic and structural differences between heme oxygenase-1 and -2 are due to differences in their C-terminal regions.The Journal of biological chemistry · 2019Article
- Redox Regulation of Heme Oxygenase-2 and the Transcription Factor, Rev-Erb, Through Heme Regulatory Motifs.Antioxidants & redox signaling · 2018Review
- Gas Signaling Molecules and Mitochondrial Potassium Channels.International journal of molecular sciences · 2018Review
- Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology.Oxidative medicine and cellular longevity · 2018Review
- Heme Oxygenase-2 Localizes to Mitochondria and Regulates Hypoxic Responses in Hepatocytes.Oxidative medicine and cellular longevity · 2018Article
- Deletion of the hemopexin or heme oxygenase-2 gene aggravates brain injury following stroma-free hemoglobin-induced intracerebral hemorrhage.Journal of neuroinflammation · 2016Article
- Comparison of the Mechanisms of Heme Hydroxylation by Heme Oxygenases-1 and -2: Kinetic and Cryoreduction Studies.Biochemistry · 2016Article
- A reactive oxygen species activation mechanism contributes to JS-K-induced apoptosis in human bladder cancer cells.Scientific reports · 2015Article
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Authors and funding
6 authors at 1 institution in 1 country.
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Abstract
Heme oxygenase (HO) catalyzes the rate-limiting step in heme catabolism to generate CO, biliverdin, and free iron. Two isoforms of HO have been identified in mammals: inducible HO-1 and constitutively expressed HO-2. HO-1 and HO-2 share similar physical and kinetic properties but have different physiological roles and tissue distributions. Unlike HO-1, which lacks cysteine residues, HO-2 contains three Cys-Pro signatures, known as heme regulatory motifs (HRMs), which are known to control processes related to iron and oxidative metabolism in organisms from bacteria to humans. In HO-2, the C-terminal HRMs constitute a thiol/disulfide redox switch that regulates affinity of the enzyme for heme (Yi, L., and Ragsdale, S. W. (2007) J. Biol. Chem. 282, 20156-21067). Here, we demonstrate that the thiol/disulfide switch in human HO-2 is physiologically relevant. Its redox potential was measured to be -200 mV, which is near the ambient intracellular redox potential. We expressed HO-2 in bacterial and human cells and measured the redox state of the C-terminal HRMs in growing cells by thiol-trapping experiments using the isotope-coded affinity tag technique. Under normal growth conditions, the HRMs are 60-70% reduced, whereas oxidative stress conditions convert most (86-89%) of the HRMs to the disulfide state. Treatment with reductants converts the HRMs largely (81-87%) to the reduced dithiol state. Thus, the thiol/disulfide switch in HO-2 responds to cellular oxidative stress and reductive conditions, representing a paradigm for how HRMs can integrate heme homeostasis with CO signaling and redox regulation of cellular metabolism.
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