Dataset Information

New insights into intracellular locations and functions of heme oxygenase-1.

ABSTRACT: Heme oxygenase-1 (HMOX1) plays a critical role in the protection of cells, and the inducible enzyme is implicated in a spectrum of human diseases. The increasing prevalence of cardiovascular and metabolic morbidities, for which current treatment approaches are not optimal, emphasizes the necessity to better understand key players such as HMOX1 that may be therapeutic targets.HMOX1 is a dynamic protein that can undergo post-translational and structural modifications which modulate HMOX1 function. Moreover, trafficking from the endoplasmic reticulum to other cellular compartments, including the nucleus, highlights that HMOX1 may play roles other than the catabolism of heme.The ability of HMOX1 to be induced by a variety of stressors, in an equally wide variety of tissues and cell types, represents an obstacle for the therapeutic exploitation of the enzyme. Any capacity to modulate HMOX1 in cardiovascular and metabolic diseases should be tempered with an appreciation that HMOX1 may have an impact on cancer. Moreover, the potential for heme catabolism end products, such as carbon monoxide, to amplify the HMOX1 stress response should be considered.A more complete understanding of HMOX1 modifications and the properties that they impart is necessary. Delineating these parameters will provide a clearer picture of the opportunities to modulate HMOX1 in human disease.

SUBMITTER: Dunn LL

PROVIDER: S-EPMC3961787 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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New insights into intracellular locations and functions of heme oxygenase-1.

Dunn Louise L LL Midwinter Robyn G RG Ni Jun J Hamid Hafizah A HA Parish Christopher R CR Stocker Roland R

Antioxidants & redox signaling 20140228 11

<h4>Significance</h4>Heme oxygenase-1 (HMOX1) plays a critical role in the protection of cells, and the inducible enzyme is implicated in a spectrum of human diseases. The increasing prevalence of cardiovascular and metabolic morbidities, for which current treatment approaches are not optimal, emphasizes the necessity to better understand key players such as HMOX1 that may be therapeutic targets.<h4>Recent advances</h4>HMOX1 is a dynamic protein that can undergo post-translational and structural ...[more]

PMID: 24180287

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Project description:Stress-inducible heme oxygenase-1 (HO-1) catalyzes the oxidative cleavage of heme yielding biliverdin, ferrous iron, and carbon monoxide (CO). Heme oxygenase activity has been attributed to antioxidant defense via the redox cycling system of biliverdin and bilirubin. There is increasing evidence that CO is a gaseous signaling molecule and plays a role in the regulation of energy metabolism. Inhibitory effects of CO on the respiratory chain are well established, but the implication of such a process on the cellular stress response is not well understood. By means of extracellular flux analyses and isotopic tracing, we studied the effects of CO, either released from the CO donor CORM-401 or endogenously produced by heme oxygenases, on the respiratory chain and glucose metabolism. CORM-401 was thereby used as a tool to mimic endogenous CO production by heme oxygenases. In the long term (>60 min), CORM-401-derived CO exposure inhibited mitochondrial respiration, which was compensated by increased glycolysis accompanied by a loss of the ATP production rate and an increase in proton leakage. This effect pattern was likewise observed after endogenous CO production by heme oxygenases. However, in the present setting, these effects were only observed when sufficient substrate for heme oxygenases (hemin) was provided. Modulation of the HO-1 protein level was less important. The long-term influence of CO on glucose metabolism via glycolysis was preceded by a short-term response (<30 min) of the cells to CO. Stable isotope-labeling experiments and metabolic flux analysis revealed a short-term shift of glucose consumption from glycolysis to the pentose phosphate pathway (PPP) along with an increase in reactive oxygen species (ROS) generation. Overall, we suggest that signaling by endogenous CO stimulates the rapid formation of reduction equivalents (NADPH) via the PPP, and plays an additional role in antioxidant defense, e.g., via feed-forward stimulation of the bilirubin/biliverdin redox cycling system.

Project description:M18 aspartyl aminopeptidases (DAPs) are well characterized in microbes and animals with likely functions in peptide processing and vesicle trafficking. In contrast, there is a dearth of knowledge on plant aminopeptidases with a preference for proteins and peptides with N-terminal acidic residues. During evolution of the Plantae, there was an expansion and diversification of the M18 DAPs. After divergence of the ancestral green algae from red and glaucophyte algae, a duplication yielded the DAP1 and DAP2 lineages. Subsequently DAP1 genes were lost in chlorophyte algae. A duplication of DAP2-related genes occurred early in green plant evolution. DAP2 genes were retained in land plants and picoeukaryotic algae and lost in green algae. In contrast, DAP2-like genes persisted in picoeukaryotic and green algae, while this lineage was lost in land plants. Consistent with this evolutionary path, Arabidopsis thaliana has two DAP gene lineages (AtDAP1 and AtDAP2). Similar to animal and yeast DAPs, AtDAP1 is localized to the cytosol or vacuole; while AtDAP2 harbors an N-terminal transit peptide and is chloroplast localized. His6-DAP1 and His6-DAP2 expressed in Escherichia coli were enzymatically active and dodecameric with masses exceeding 600 kDa. His6-DAP1 and His6-DAP2 preferentially hydrolyzed Asp-p-nitroanilide and Glu-p-nitroanilide. AtDAPs are highly conserved metallopeptidases activated by MnCl2 and inhibited by ZnCl2 and divalent ion chelators. The protease inhibitor PMSF inhibited and DTT stimulated both His6-DAP1 and His6-DAP2 activities suggesting a role for thiols in the AtDAP catalytic mechanism. The enzymes had distinct pH and temperature optima, as well as distinct kinetic parameters. Both enzymes had high catalytic efficiencies (kcat/Km) exceeding 1.0 x 107 M-1 sec-1. Using established molecular chaperone assays, AtDAP1 and AtDAP2 prevented thermal denaturation. AtDAP1 also prevented protein aggregation and promoted protein refolding. Collectively, these data indicate that plant DAPs have a complex evolutionary history and have evolved new biochemical features that may enable their role in vivo.

Dataset Information

New insights into intracellular locations and functions of heme oxygenase-1.

Publications

New insights into intracellular locations and functions of heme oxygenase-1.

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