Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls

Abstract

Extensive research has shown that increased production of reactive oxygen species (ROS) results in tissue injury under a variety of pathological conditions and chronic degenerative diseases. While ROS are highly reactive and can incite significant injury, polyunsaturated lipids in membranes and lipoproteins are their main targets. ROS-triggered lipid peroxidation reactions generate a range of reactive carbonyl species (RCS), and these RCS spread and amplify ROS-related injury. Several RCS generated in oxidizing lipids, such as 4-hydroxy trans-2-nonenal (HNE), 4-oxo-2-(E)-nonenal (ONE), acrolein, malondialdehyde (MDA) and phospholipid aldehydes have been shown to be produced under conditions of oxidative stress and contribute to tissue injury and dysfunction by depleting glutathione and other reductants leading to the modification of proteins, lipids, and DNA. To prevent tissue injury, these RCS are metabolized by several oxidoreductases, including members of the aldo-keto reductase (AKR) superfamily, aldehyde dehydrogenases (ALDHs), and alcohol dehydrogenases (ADHs). Metabolism via these enzymes results in RCS inactivation and detoxification, although under some conditions, it can also lead to the generation of signaling molecules that trigger adaptive responses. Metabolic transformation and detoxification of RCS by oxidoreductases prevent indiscriminate ROS toxicity, while at the same time, preserving ROS signaling. A better understanding of RCS metabolism by oxidoreductases could lead to the development of novel therapeutic interventions to decrease oxidative injury in several disease states and to enhance resistance to ROS-induced toxicity.

Cross-talk between lipid and protein carbonylation in a dynamic cardiomyocyte model of mild nitroxidative stress

“…Electrophilic oxoLPPs are metabolized via different reactions catalysed by aldo-keto reductases (reduction), aldehyde dehydrogenase/cytochrome P450 (oxidation) and glutathione S-transferase (conjugation with GSH) [26], [61]. Carbonylated proteins can be degraded by the proteasome (mostly by 20S proteasome in ATP and ubiquitin independent manner) and the mitochondrial Lon-protease [62].…”

Biogenic Aldehydes as Therapeutic Targets for Cardiovascular Disease

“…These enzymes include aldehyde dehydrogenase, aldose reductase, carbonyl reductase, aldehyde reductase, and enzymes in the glutathione-dependent family [16]. However, this network of enzymes can be overwhelmed during periods of acute ( e.g ., ischemia, sepsis) and chronic cardio-metabolic stress ( e.g ., hypertension, diabetes) [2 • ].…”

Aldose reductase (AKR1B) deficiency promotes phagocytosis in bone marrow derived mouse macrophages

“…Aldose reductase (AKR1B) is a multifunctional aldo-keto reductase that catalyzes the reduction of aldehydes ranging from glucose to lipid peroxidation products such as 4-hydroxy-trans-2-nonenal (HNE) and acrolein [5]. Although the primary function of AR is to regulate cellular osmolality by catalyzing the reduction of glucose to sorbitol [6, 7], several studies suggest that AR plays an important role in inflammation [8].…”