Synthetic Evidence of the Amadori-Type Alkylation of Biogenic Amines by the Neurotoxic Metabolite Dopegal

Abstract

The neurotransmitter metabolite 3,4-dihydroxy-phenylglycolaldehyde (dopegal) damages neurons and the myocardium by protein cross-linking, resulting in conglomerations and cell death. We investigated this process on a synthetic scale, leading to the discovery of an Amadori-type rearrangement of dopegal in the reaction with several amino acids and neuropeptides. This alkylation also occurs with neurotransmitters, suggesting an influence of dopegal on neurochemical processes. The rearrangement occurs readily under physiological conditions.

Characterization of Catecholaldehyde Adducts with Carnosine and l-Cysteine Reveals Their Potential as Biomarkers of Catecholaminergic Stress

“…We were able to identify DOPEGAL adducts with both carnosine (DOPEGAL–carnosine; Figure C) and l -cysteine (DOPEGAL–cys; Figure E). Our findings align with prior reports of an Amadori product for DOPEGAL and carnosine, with an [M + H] + at 377.1469 m / z (theoretical [M + H] + = 377.1445 m / z , accuracy = 6.36 ppm). The structure was further characterized via MS/MS fragmentation analysis, and the putative fragment structures are reported in Figure D.…”

“… 4 , 20 Our group has previously investigated the ability of known nucleophiles, such as the dipeptide carnosine and amino acid l -cysteine, to scavenge DOPAL and DOPEGAL and hence protect cellular proteins from modification. 13 Our previous work showed carnosine and l -cysteine were able to sequester DOPAL in vitro, but information on reactivity of DOPEGAL is very limited 21 due to its commercial unavailability and difficult synthesis. 13 , 19 In this report, we further characterize the reactivity of carnosine and l -cysteine with both DOPAL and DOPEGAL biochemically and in a cellular matrix.…”

“…As previously reported, catecholaldehydes form covalent, stable adducts with protein amines such as lysine and other nucleophilic molecules. , This causes permanent modification of protein structure and function. , Our group has previously investigated the ability of known nucleophiles, such as the dipeptide carnosine and amino acid l -cysteine, to scavenge DOPAL and DOPEGAL and hence protect cellular proteins from modification . Our previous work showed carnosine and l -cysteine were able to sequester DOPAL in vitro, but information on reactivity of DOPEGAL is very limited due to its commercial unavailability and difficult synthesis. , In this report, we further characterize the reactivity of carnosine and l -cysteine with both DOPAL and DOPEGAL biochemically and in a cellular matrix. Adducts of carnosine with DOPEGAL and l -cysteine with DOPEGAL and DOPAL were identified and characterized via mass spectrometry.…”

Non-enzymatic covalent modifications: a new link between metabolism and epigenetics

“…Other types of aldehyde-bearing metabolites (e.g., ascorbic acid, dopegal, formaldehyde, 5-formylcytosine, and isolevuglandins) also form NECMs on proteins via the same Maillard chemistry (Fig. 2D and 2E) (Linetsky et al, 2007;Szende and Tyihák, 2010;May-Zhang et al, 2018;Raiber et al, 2018;Wanner et al, 2020).…”

A Catecholaldehyde Metabolite of Norepinephrine Induces Myofibroblast Activation and Toxicity via the Receptor for Advanced Glycation Endproducts: Mitigating Role of l-Carnosine

“…Due to the reactivity of the electrophilic aldehyde and catechol moieties, DOPEGAL will readily react with nucleophilic species on biomolecules to form adducts. 15 Adducts of biogenic aldehydes derived from oxidized sugars and lipids constitute advanced glycation products (AGEs) and advanced lipoxidation endproducts (ALEs), endogenous agonists of the receptor for advanced glycation endproducts (RAGE). RAGE has been shown to induce hallmarks of myofibroblast differentiation, 16 including rapid fibroblast proliferation 17 and collagen overproduction.…”