Detoxification of Carbonyl Compounds by Carbonyl Reductase in Neurodegeneration

Abstract

Oxidative stress in the brain is the major cause of neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's, and Creutzfeldt-Jakob diseases or amyotrophic lateral sclerosis. Under conditions of oxidative stress, the production of highly reactive oxygen species (ROS) overwhelms antioxidant defenses, resulting in the modification of macromolecules and their deposition in neuronal cell tissues. ROS plays an important role in neuronal cell death that they generate reactive aldehydes from membrane lipid peroxidation. Several neuronal diseases are associated with increased accumulation of abnormal protein adducts of reactive aldehydes, which mediate oxidative stress-linked pathological events, including cell growth inhibition and apoptosis induction. Combining findings on neurodegeneration and oxidative stress in Drosophila with studies on the metabolic characteristics of the human enzyme CBR1, it is clear now that CBR1 has a potential physiological role of neuroprotection in humans. Several studies suggest that CBR1 represents a significant pathway for the detoxification of reactive aldehydes derived from lipid peroxidation and that CBR1 in humans is essential for neuronal cell survival and to confer protection against oxidative stress-induced brain degeneration. Recently, it was discovered that HIF1alpha, AP-1, and Nrf2 could all regulate CBR1 at the transcriptional level. Nrf2 is known to regulate the transcription of antioxidant enzymes, and CBR1 functions as an antioxidant enzyme, suggesting that transcriptional regulation of CBR1 is a major contributor to the control of oxidative stress in neurodegeneration.

Kinetic features of carbonyl reductase 1 acting on glutathionylated aldehydes

“…Moreover, as recently reported [44], CBR1 positively affects neuronal cell survival and confers protection against oxidative stress-induced brain degeneration. For all these, as highlighted by Bousova et al [24], the potential of polyphenols (or other naturally occurring molecules) to interfere with CBR1 activity may lead to an alteration of cell homeostasis.…”

Evolution of cellular stress response mechanisms

“…Several phylogenetically highly conserved enzymes, e.g. carbonyl reductases (Forrest & Gonzalez, 2000;Rashid, Haque, & Akbar, 2016), catalyze decarbonylation of diverse cellular molecules other than proteins. However, until recently protein carbonylation was thought to be irreversible and only removable via proteolytic degradation of the affected proteins (Suzuki, Carini, & Butterfield, 2010;Wong, Marcocci, Liu, & Suzuki, 2010).…”

Autophagy as a protective mechanism in oxidative stress

“…Все ýти α-оксальальдегиды -3-деоксиглюкозон, глиоксаль и метилглиоксаль -реагируют с лизиновыми и аргининовыми остатками протеинов, формируя специфические КПНГ. Карбонильные соединения могут восстанавливаться карбонилредуктазами, вместе с тем, однажды сформировавшись, КПНГ остаются стабильными и накапливаются в клетках, связываясь с белками [120].…”