Physics:Reactive carbonyl species
Reactive carbonyl species (RCS) are molecules with highly reactive carbonyl groups, and often known for their damaging effects on proteins, nucleic acids, and lipids. They are often generated as metabolic products. Important RCSs include 3-deoxyglucosone, glyoxal, and methylglyoxal. RCSs react with amines and thiol groups leading to advanced glycation endproducts (AGEs). AGE's are indicators of diabetes.[1]
Reactive aldehyde species (RASP),[2] such as malondialdehyde and 4-hydroxynonenal, are a subset of RCS that are implicated in a variety of human diseases.[3]
RCSs are involved in many important reactions, including here lipid peroxidation and carbohydrate reduction. Their interaction with specific proteins by forming covalent adducts is critical in understanding the RCSs role in diabetes and cardiovascular diseases.
Overview of Reactive Carbonyl Species Generation
Reactive carbonyl species (RCS) are molecules that can be derived both exogenously and endogenously. Exogenously RCSs can enter the cell through the exposure and products of industrial pollutants, food additives, and even cigarette smoke. This includes molecules such as glyoxal, formaldehyde, and acrolein. Endogenously, RCS is a byproduct of biochemical enzymatic and nonenzymatic reactions, such as lipid and amino acid oxidation. [4]
In lipid peroxidation, it is the breakdown of the polyunsaturated fatty acids’ free radical chain that synthesizes many RCS molecules, such as malondialdehyde (MDA), which is a highly reactive molecule that marks oxidative stress. Low-density lipoproteins can be covalently modified by RCS, which results in their oxidized form. The modified LDL can be recognized by scavenger receptors and lead to the formation of foam cells.[5]
RCSs are involved in the reduction of carbohydrates. For example, carbohydrates, such as MGO and 3-DG are noted as side products of some enzymatic pathways, such as glycolysis. Methylglyoxal (MGO) is a highly reactive compound falling under the reactive carbonyl species category. Glycolysis results in production of MGO. As part of a reaction of the triosephosphate isomerase enzyme, enediol phosphate can decompose in Pi (inorganic phosphate) and MGO.[4]
RCS Reactions with Proteins
Through Schiff base formations and Michael addition reactions, carbonyl containing compounds form covalent adducts with proteins. The RCS carbonyl electrophile targets a nucleophilic group present in amino acid residues. In the case of Schiff base reactions, the reaction occurs between the carbonyl and the primary amine group through a dehydration reaction. This results in secondary reactions that proceed in producing further arrangements, structures, to cross-link proteins and form complex structures. In Michael addition, the α,β-unsaturated RCS carbonyl group reacts with nucleophilic thiol sulfur, amino, and imidazole nitrogen. These reactions result in the stable covalent adducts that have a role in protein stability, structure, and function. On different kinds of RCS and proteins, these modifications' specificity differs greatly. Factors that are accounted for are the carbon chain length, degree of unsaturation, polarity, solubility, and reactivity of target amino acid residues.[6]
Disease Relevance - Cardiovascular Disease & Neurotoxicity
RCS's role as highly reactive intermediates results in damaging and disrupting normal cellular function as researched in diseases such as diabetes, cardiovascular disease, and neurodegeneration. Hearts from control and diabetic rats were used to assess the relative amount of adducts formed by RCS with key calcium-handling proteins in heart muscle, such as RyR2 and SERCA2a. These proteins are key to proper heart function. From the RCS tested, MGO, GO, 4-HNE, and MDA, RyR2 had 2x more MGO and GO adducts. SERCA2a had 2x more MGO adducts. No 4-HNE or MDA adducts were detected. The findings suggest that MGO and GO are part of the RCS that contribute to key modification in diabetic conditions’ cardiac proteins.[7]
Conjugated α,β-unsaturated carbonyl RCS adduct formation mechanism has been linked to neurotoxicity. RCS form covalent adducts with neuronal proteins. This depends on the reactivity of the RCS electrophile to the thiol groups found in neurons. Type-2 alkenes, classified as soft electrophiles, undergo Michael addition reactions with the thiol group of cysteine residues in proteins. When the cysteine residues are modified due to RCS activity, there is a disruption of the normal cellular function. Cysteine residues are found in ion channels and synaptic proteins. Their modification can result in disruptions of the synaptic signaling and neurotransmitter release. These disturbances are directly related to the development of neurotoxicity.[8]
See also
References
- ↑ Bellier, Justine; Nokin, Marie-Julie; Lardé, Eva; Karoyan, Philippe; Peulen, Olivier; Castronovo, Vincent; Bellahcène, Akeila (2019). "Methylglyoxal, a Potent Inducer of AGEs, Connects Between Diabetes and Cancer". Diabetes Research and Clinical Practice 148: 200–211. doi:10.1016/j.diabres.2019.01.002. PMID 30664892.
- ↑ Mandell, Kenneth J.; Clark, David; Chu, David S.; Foster, C. Stephen; Sheppard, John; Brady, Todd C. (2020). "Randomized Phase 2 Trial of Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious Anterior Uveitis: Model for Corticosteroid Replacement". Journal of Ocular Pharmacology and Therapeutics 36 (10): 732–739. doi:10.1089/jop.2020.0056. ISSN 1557-7732. PMID 32955967.
- ↑ Ayala, Antonio; Muñoz, Mario F.; Argüelles, Sandro (2014). "Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal". Oxidative Medicine and Cellular Longevity 2014. doi:10.1155/2014/360438. ISSN 1942-0994. PMID 24999379.
- ↑ 4.0 4.1 Semchyshyn, Halyna M. (2014). "Reactive Carbonyl Species In Vivo : Generation and Dual Biological Effects" (in en). The Scientific World Journal 2014: 1–10. doi:10.1155/2014/417842. ISSN 2356-6140. PMID 24634611.
- ↑ Nègre-Salvayre, Anne; Salvayre, Robert (2024-02-14). "Reactive Carbonyl Species and Protein Lipoxidation in Atherogenesis" (in en). Antioxidants 13 (2): 232. doi:10.3390/antiox13020232. ISSN 2076-3921. PMID 38397830.
- ↑ Mano, Jun’ichi; Biswas, Md. Sanaullah; Sugimoto, Koichi (2019-09-30). "Reactive Carbonyl Species: A Missing Link in ROS Signaling" (in en). Plants 8 (10): 391. doi:10.3390/plants8100391. ISSN 2223-7747. PMID 31575078. Bibcode: 2019Plnts...8..391M.
- ↑ Tian, Chengju; Alomar, Fadhel; Moore, Caronda J.; Shao, Chun Hong; Kutty, Shelby; Singh, Jaipaul; Bidasee, Keshore R. (2014). "Reactive carbonyl species and their roles in sarcoplasmic reticulum Ca2+ cycling defect in the diabetic heart" (in en). Heart Failure Reviews 19 (1): 101–112. doi:10.1007/s10741-013-9384-9. ISSN 1382-4147. PMID 23430128.
- ↑ LoPachin, Richard M.; Barber, David S.; Gavin, Terrence (2008). "Molecular Mechanisms of the Conjugated α,β-Unsaturated Carbonyl Derivatives: Relevance to Neurotoxicity and Neurodegenerative Diseases" (in en). Toxicological Sciences 104 (2): 235–249. doi:10.1093/toxsci/kfm301. ISSN 1096-6080. PMID 18083715. PMC 2734294. https://academic.oup.com/toxsci/article/1651009/Molecular.
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