Abstract
The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.
Highlights
Heme oxygenase (HO) is an enzyme that was originally described in 1969 that catalyzes the oxidation of the heme group to form biliverdin, an intermediated step to form bilirubin through the NADPH-dependent biliverdin reductase [1]
A series of natural compounds based on a statistical/computational approach were identified as new HO-1 inhibitors from three databases: Marine natural products (MNPs), ZINC natural products (ZNPs), and super natural II (SN2), providing an in silico proposal of imidazole-like compounds [75]
Oxidant and pro-inflammatory environments enhance the transcription of HO-1, and an increase of heme improves Heme oxygenase 2 (HO-2) activity [11,152]
Summary
Heme oxygenase (HO) is an enzyme that was originally described in 1969 that catalyzes the oxidation of the heme group to form biliverdin, an intermediated step to form bilirubin through the NADPH-dependent biliverdin reductase [1]. Studies referring to the distribution of the HO system have shown that HO-1 is expressed ubiquitously, being predominantly found in the liver and spleen [8]. This isoform works as an inducible protein, upregulated by different stimuli, such as heavy metals, growth factors, cytokines, and heme, among others [8,9]. HO-2 is constitutively expressed at high levels in the brain, testes, or endothelial cells [8,9], while HO3HO-3 has been observed onlyonly in rat at lower levels than. HO-1 and how inhibitors beneficial due to their immunomodulatory activity.activity
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