Detoxification of aldehydes by histidine-containing dipeptides: From chemistry to clinical implications

Abstract

Aldehydes are generated by oxidized lipids and carbohydrates at increased levels under conditions of metabolic imbalance and oxidative stress during atherosclerosis, myocardial and cerebral ischemia, diabetes, neurodegenerative diseases and trauma. In most tissues, aldehydes are detoxified by oxidoreductases that catalyze the oxidation or the reduction of aldehydes or enzymatic and nonenzymatic conjugation with low molecular weight thiols and amines, such as glutathione and histidine dipeptides. Histidine dipeptides are present in micromolar to millimolar range in the tissues of vertebrates, where they are involved in a variety of physiological functions such as pH buffering, metal chelation, oxidant and aldehyde scavenging. Histidine dipeptides such as carnosine form Michael adducts with lipid-derived unsaturated aldehydes, and react with carbohydrate-derived oxo- and hydroxy- aldehydes forming products of unknown structure. Although these peptides react with electrophilic molecules at lower rate than glutathione, they can protect glutathione from modification by oxidant and they may be important for aldehyde quenching in glutathione-depleted cells or extracellular space where glutathione is scarce. Consistent with in vitro findings, treatment with carnosine has been shown to diminish ischemic injury, improve glucose control, ameliorate the development of complications in animal models of diabetes and obesity, promote wound healing and decrease atherosclerosis. The protective effects of carnosine have been linked to its anti-oxidant properties, it ability to promote glycolysis, detoxify reactive aldehydes and enhance histamine levels. Thus, treatment with carnosine and related histidine dipeptides may be a promising strategy for the prevention and treatment of diseases associated with high carbonyl load.

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

“…Carnosine, a dipeptide consisting of beta-alanine and L-histidine, is an endogenous brain constituent. Carnosine is highly reactive with aldehydes (Xie et al, 2013), forming covalent adducts that are metabolized by aldose reductase (Baba et al, 2013). Carnosine might be neuroprotective (Bellia et al, 2011).…”

Regulation of amino acid and nucleotide metabolism by crustacean hyperglycemic hormone in the muscle and hepatopancreas of the crayfishProcambarus clarkii

“…3) [45]. Carnosine has been shown to be able to, among others, scavenge and detoxify reactive oxygen species and reactive aldehyde derived from lipid peroxidation [45, 46]. Thus, elevated levels of β-alanine, histidine, and anserine suggest that degradation (to β-alanine and histidine) and conversion (to anserine) from carnosine were enhanced under silenced CHH gene expression and imply that CHH has protective roles for the muscle cells by increasing carnosine levels via combination of β-alanine and histidine and conversion from anserine.…”

Investigação de potenciais biomarcadores redox - um enfoque em aldeídos e seus produtos

“…Mesmo glutationilados estes aldeídos sofrem redução ou oxidação (Xie et al, 2013), suprimindo a reação reversa. Assim como outros conjugados de GSH, esses adutos são transportados ativamente por proteínas de emergente interesse clínico (Awasthi et al, 2009;Hillgren et al, 2013).…”

“…Conforme demostrado por Esterbauer a reação com aldeidos é um processo espontâneo (Esterbauer, Schaur e Zollner, 1991 Porquanto, aldeídos glutationilados estão sujeitos a reduções -mediadas por aldoceto redutases da família 1C -e a oxidações -por ação de aldeído desidrogenases - (Burczynski et al, 2001;Alary, Gueraud e Cravedi, 2003;Xie et al, 2013), evitando que a formação do aduto sirva para translocar o aldeído na célula.…”