Journal article
Characterization of Catecholaldehyde Adducts with Carnosine and L-Cysteine Reveals Their Potential as Biomarkers of Catecholaminergic Stress
Chemical research in toxicology, Vol.34(10), pp.2184-2193
10/18/2021
DOI: 10.1021/acs.chemrestox.1c00153
PMCID: PMC8527522
PMID: 34506109
Appears in UI Libraries Support Open Access
Abstract
Monoamine oxidase (MAO) catalyzes the oxidative deamination of dopamine and norepinephrine to produce 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), respectively. Both of these aldehydes are potently cytotoxic and have been implicated in pathogenesis of neurodegenerative and cardiometabolic disorders. Previous work has demonstrated that both the catechol and aldehyde moieties of DOPAL are reactive and cytotoxic via their propensity to cause macromolecular cross-linking. With certain amines, DOPAL likely reacts via a Schiff base before oxidative activation of the catechol and rearrangement to a stable indole product. Our current work expands on this reactivity and includes the less-studied DOPEGAL. Although we confirmed that antioxidants mediated DOPAL's reactivity with carnosine and N-acetyl-L-lysine, antioxidants had no effect on reactivity with L-cysteine. Therefore, we propose a non-oxidative mechanism where, following Schiff base formation, the thiol of L-cysteine reacts to form a thiazolidine. Similarly, we demonstrate that DOPEGAL forms a putative thiazolidine conjugate with L-cysteine. We identified and characterized both L-cysteine conjugates via HPLC-MS and additionally identified a DOPEGAL adduct with carnosine, which is likely an Amadori product. Furthermore, we were able to demonstrate that these conjugates are produced in biological systems via MAO after treatment of the cell lysate with norepinephrine or dopamine along with the corresponding nucleophiles (i.e., L-cysteine and carnosine). As it has been established that metabolic and oxidative stress leads to increased MAO activity and accumulation of DOPAL and DOPEGAL, it is conceivable that conjugation of these aldehydes to carnosine or L-cysteine is a newly identified detoxification pathway. Furthermore, the ability to characterize these adducts via analytical techniques reveals their potential for use as biomarkers of dopamine or norepinephrine metabolic disruption.
Details
- Title: Subtitle
- Characterization of Catecholaldehyde Adducts with Carnosine and L-Cysteine Reveals Their Potential as Biomarkers of Catecholaminergic Stress
- Creators
- Rachel A Crawford - University of IowaEttore Gilardoni - University of IowaT. Blake Monroe - University of IowaLuca Regazzoni - University of MilanEthan J Anderson - University of IowaJonathan A Doorn - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.34(10), pp.2184-2193
- DOI
- 10.1021/acs.chemrestox.1c00153
- PMID
- 34506109
- PMCID
- PMC8527522
- NLM abbreviation
- Chem Res Toxicol
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Publisher
- American Chemical Society
- Number of pages
- 10
- Grant note
- T32GM067795 / University of Iowa Pharmacological Sciences Training Program P30ES005605 / University of Iowa Environmental Health Sciences Research Center University of Iowa 20SFRN35200003 / American Heart Association; American Heart Association R01HL122863; R21AG057006; R01 ES029035 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 10/18/2021
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Medicinal and Natural Products Chemistry; Health, Sport, and Human Physiology
- Record Identifier
- 9984230429102771
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