Heme oxygenase-1 affects cytochrome P450 function through the formation of heteromeric complexes: Interactions between CYP1A2 and heme oxygenase-1
| Autor: | J. Patrick Connick, George F. Cawley, Wayne L. Backes, James R. Reed |
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| Rok vydání: | 2021 |
| Předmět: |
EROD
7-ethoxyresorufin deethylation 0301 basic medicine NADPH-cytochrome P450 reductase cytochrome P450 CYP1A2 Heme Reductase Biochemistry structure-function Protein–protein interaction protein-protein interaction DLPC L-α-dilauroyl-sn-glycero-3-phosphocholine chemistry.chemical_compound 03 medical and health sciences Cytochrome P-450 CYP1A2 Humans membrane protein BRET bioluminescence resonance energy transfer Molecular Biology GFP green fluorescent protein chemistry.chemical_classification bioluminescence resonance energy transfer (BRET) 030102 biochemistry & molecular biology biology Chemistry Endoplasmic reticulum Cytochrome P450 Cell Biology Metabolism heme oxygenase 7-ER 7-ethoxyresorufin electron transfer HO-1 Heme oxygenase 1 Heme oxygenase HEK293 Cells 030104 developmental biology Enzyme Energy Transfer Membrane protein biology.protein Biophysics Xenobiotic Heme Oxygenase-1 POR NADPH-cytochrome P450 reductase Protein Binding Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra120.015911 |
| Popis: | Heme oxygenase 1 (HO-1) and the cytochromes P450 (P450s) are endoplasmic reticulum-bound enzymes that rely on the same protein, NADPH-cytochrome P450 reductase (POR), to provide the electrons necessary for substrate metabolism. Although the HO-1 and P450 systems are interconnected due to their common electron donor, they generally have been studied separately. As the expression of both HO-1 and P450s are affected by xenobiotic exposure, changes in HO-1 expression can potentially affect P450 function, and conversely, changes in P450 expression can influence HO-1. The goal of this study was to examine interactions between the P450 and HO-1 systems. Using bioluminescence resonance energy transfer (BRET), HO-1 formed HO-1•P450 complexes with CYP1A2, CYP1A1, and CYP2D6, but not all P450s. Studies then focused on the HO-1/CYP1A2 interaction. CYP1A2 formed a physical complex with HO-1 that was stable in the presence of POR. As expected, both HO-1 and CYP1A2 formed BRET-detectable complexes with POR. Whereas the POR•CYP1A2 complex was readily disrupted by the addition of HO-1, the POR•HO-1 complex was not significantly affected by the addition of CYP1A2. Interestingly, enzyme activities did not follow this pattern. Whereas BRET data suggested substantial inhibition of CYP1A2-mediated 7-ethoxyresorufin deethylation in the presence of HO-1, its activity was actually stimulated at subsaturating POR. In contrast, HO-1-mediated heme metabolism was inhibited at subsaturating POR. These results indicate that HO-1 and CYP1A2 form a stable complex and have mutual effects on the catalytic behavior of both proteins that cannot be explained by simple competition for POR. |
| Databáze: | OpenAIRE |
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