Heme Oxygenase: Figures
Figure 1. Primary structures of human heme oxygenase
Crystal structure of human heme oxygenase 1 (HO-1) in complex with heme. The cartoon shows one copy of HO-1 complexed to one copy of protoporphyrin IX containing Fe (Heme) and one copy of sulfate ion (PDB 1n45) 60.
Figure 2. Primary structures of human heme oxygenase
Overall structure of homodimeric HO-1. The cartoon shows two copies of HO-1 complexed to two copies of protoporphyrin IX containing Fe (Heme) and one copy of sulfate ion (PDB 1n45) 60.
Figure 3. Primary structures of human heme oxygenases
The cartoon shows the domain architecture and critical amino acids in human HO-1 and HO-2. The conserved histidine in the catalytic domain (His25 in HO-1 and His45 in HO-2) serves as the proximal heme ligand. Within the catalytic core, the conserved His132 in HO-1 as well as His151 in HO-2 are required for heme oxidation. Black boxes in HO-2 indicate the heme regulatory motifs (HRMs). The C-terminal transmembrane segment (TMS) is highlighted in grey. Image was reproduced, with permission, from Muñoz-Sánchez and Chanez-Cardenas (2014) 150.
Figure 4. Oxidation of heme to biliverdin.
Heme oxygenases (HO-1, HO-2) catalyze the NADPH- and O2-dependent degradation of heme to biliverdin IXα, carbon monoxide (CO), and ferrous iron (Fe2+). The reaction requires the co-enzyme cytochrome p450 reductase (CPR). Afterwards, biliverdin is enzymatically converted to bilirubin by biliverdin reductase. Both molecules serve as important anti-oxidants able to scavenge reactive oxygen species (ROS). CO functions as crucial second messenger implicated in several signal transduction pathways leading to the production of anti-inflammatory cytokines, up-regulation of anti-apoptotic effectors, and inhibition of thrombosis. Activation of HO-1 also up-regulates Fe2+-mediated ferritin expression which competitively inhibits Fe2+, thus detoxifying its pro-oxidant activity. Image was reproduced, with permission, from Chiang et al. (2018) 311.
Figure 5. Canonical and non-canonical functions of heme oxygenases (HOs) and their metabolites.
Image was reproduced from Vanella et al. (2016) 17. License at https://creativecommons.org/licenses/by/3.0/
Figure 6. The Nrf-1/Keap-1 pathway.
Under non-stress conditions, Nrf-2 is held in an inactive state in the cytoplasm in complex with the Kelch-like ECH-associated protein 1 (Keap-1) which blocks the nuclear translocation and determines the targeted ubiquitination of Nrf-2 by the cullin 3-based E3 ubiquitin ligase complex, thus identifying Nrf-2 for proteasomal degradation. Stress-induced phosphorylation and activation of Keap-1 facilitates the release and translocation of Nrf-2 to the nucleus, where it forms heterodimers with small Maf proteins followed by its binding to StRE/ARE sequences and the induction of gene transcription. The heme binding protein BTB and CNC homolog 1 (Bach-1) was recently identified as a transcriptional repressor of HMOX1. Under non-stress conditions, Bach-1 associates with small Maf proteins to form heterodimers that bind to the StRE/ARE sequences and thus competes with Nrf-2 for binding to StRE/AREs (not shown). Oxidative stress or increasing heme concentrations induce conformational re-arrangements of Bach-1 that displace Bach-1 from StRE/ARE sequences and enable its proteasomal degradation so that Nrf-2 can associate with Maf and bind to StRE/AREs within the regulatory sequences of cell defense genes. Image was reproduced from Jaramillo et al. (2013) 634. License at https://creativecommons.org/licenses/by-nc/3.0/
Figure 7. Proposed sequence of the heme oxygenase (HO) reaction.
HO catalyzes the cleavage of heme at the α-methene bridge carbon leading to the generation of biliverdin IXα, CO, and ferrous (Fe2+) iron. The HO reaction involves three serial mono-oxygenation cycles, each of which requiring one molecule of O2 . The overall reaction necessitates seven electrons, provided most likely by NADPH:cytochrome p450 reductase, for the reduction of the heme iron. Biliverdin IXα, released from the HO reaction, is enzymatically reduced by NAD(P)H:biliverdin reductase to form bilirubin IXα. For details, see text.
Figure 8. Role of HO-1 in ferroptosis.
For details, see text. Image was reproduced from Chiang et al. (2018) 311. License at https://creativecommons.org/licenses/by/4.0/
Fig. 9. Signaling pathways mediated by carbon monoxide (CO).
The scheme illustrates the pleiotropic effects of CO and the putative signaling networks involved. For details, see text.