Oxidative Stress and Covalent Modification of Protein with Bioactive Aldehydes

Abstract

The term "oxidative stress" links the production of reactive oxygen species to a variety of metabolic outcomes, including insulin resistance, immune dysfunction, and inflammation. Antioxidant defense systems down-regulated due to disease and/or aging result in oxidatively modified DNA, carbohydrates, proteins, and lipids. Increased production of hydroxyl radical leads to the formation of lipid hydroperoxides that produce a family of ␣,␤-unsaturated aldehydes. Such reactive aldehydes are subject to Michael addition reactions with the side chains of lysine, histidine, and cysteine residues, referred to as "protein carbonylation." Although not widely appreciated, reactive lipids can accumulate to high levels in cells, resulting in extensive protein modification leading to either loss or gain of function. The use of mass spectrometric methods to identify the site and extent of protein carbonylation on a proteome-wide scale has expanded our view of how oxidative stress can regulate cellular processes.

Hydroxynonenal, a lipid peroxidation end product, stimulates uncoupling protein activity in Acanthamoeba castellanii mitochondria; the sensitivity of the inducible activity to purine nucleotides depends on the membranous ubiquinone redox state

“…However, the covalent modification of UCP cannot be excluded because HNE is a highly reactive aldehyde that modifies the functional groups of proteins (Grimsrud et al 2008). HNE forms stable adducts with proteins so this kind of interaction with UCP would not be reversible, but specific HNE adducts of UCPs have not been detected thus far.…”

“…4-Hydroxy-2-nonenal (HNE), a reactive unsaturated aldehyde, is the most abundant end product of lipid peroxidation resulting from the production of mitochondrial superoxide. At a high concentration, HNE can be toxic because it covalently modifies and inactivates biopolymers (Grimsrud et al 2008). In animal mitochondria, the products of lipid peroxidation that arise from ROS, such as HNE and the structurally related compounds trans-retinoic acid, trans-retinal and other 2-alkenals, specifically induce the uncoupling of mitochondria through the uncoupling proteins UCP2 and UCP3 (Rial et al 1999;Echtay et al 2003).…”

X‐ray crystallographic analysis of adipocyte fatty acid binding protein (aP2) modified with 4‐hydroxy‐2‐nonenal

“…As such residues are frequently used in catalysis, alkylation reactions typically result in enzyme inactivation followed by targeted degradation leading to overall net loss of function. 8 Grimsrud et al recently discovered in murine adipose tissue that the adipocyte fatty acid binding protein (AFABP also known as aP2) is the soluble protein most highly modified by 4-HNE. 9 Approximately 6-8% of the AFABP in adipose tissue of obese mice is covalently modified on Cys117 by 4-HNE and results in decreased affinity of the protein for fatty acids.…”

Influence of semicarbazide on the peroxidation processes and Lewis carcinoma growth in mice

“…Це пояснюється тим, що семікарбазид взаємодіє з усіма альдегідами, в тому числі і малоновим діальдегідом як синергетиком. Тобто семікарбазид є сильним антиоксидантом, який блокує вільні радикали і захищає клітини від ушкодження, порушень, зумовлених оксидатив-ним стресом, та від формальдегіду -речовини, яка може спричинити мутації [4,5]. З іншого боку, препарат ефективно пригнічує активність ензиму SSAO (semicarbazide-sensitive amine oxidase).…”