Enhanced reactivity of Lys182 explains the limited efficacy of biogenic amines in preventing the inactivation of glucose-6-phosphate dehydrogenase by methylglyoxal

Flores-Morales, Patricio; Diema, Claudio; Vilaseca, Marta; Estelrich, Joan; Luque, F. Javier; Gutiérrez‐Oliva, Soledad; Toro–Labbé, Alejandro; Silva, Eduardo

doi:10.1016/j.bmc.2011.01.044

Cited by 6 publications

(5 citation statements)

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“…This type of reaction would also explain the low yield of carbonyls observed after oxidation of this enzyme. Consistent with this hypothesis, it has been reported that some of the Lys residues on G6PD exhibit an anomalously high reactivity toward carbonyl groups, which is likely to reflect a shift in the p K a of the amine function of some of the Lys residues (resulting in a greater yield of the more powerful nucleophilic RNH 2 form) due to the local environment of some of these residues in the enzyme …”

Section: Discussionmentioning

confidence: 65%

“…Consistent with this hypothesis, it has been reported that some of the Lys residues on G6PD exhibit an anomalously high reactivity toward carbonyl groups, which is likely to reflect a shift in the pK a of the amine function of some of the Lys residues (resulting in a greater yield of the more powerful nucleophilic RNH 2 form) due to the local environment of some of these residues in the enzyme. 58 Overall, these studies using defined doses of wellcharacterized peroxyl radicals have provided important information on the mechanisms of aggregation and fragmentation of three well-characterized proteins. The data obtained indicate that oxidation of Trp and Tyr residues may be of particular importance with this relatively selective but widely encountered type of reactive oxidant in biological systems.…”

Section: Discussionmentioning

confidence: 99%

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Chemical Modification of Lysozyme, Glucose 6-Phosphate Dehydrogenase, and Bovine Eye Lens Proteins Induced by Peroxyl Radicals: Role of Oxidizable Amino Acid Residues

Arenas

López-Alarcón

Kogan

et al. 2013

Chem. Res. Toxicol.

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Chemical and structural alterations to lysozyme (LYSO), glucose 6-phosphate dehydrogenase (G6PD), and bovine eye lens proteins (BLP) promoted by peroxyl radicals generated by the thermal decomposition of 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH) under aerobic conditions were investigated. SDS-PAGE analysis of the AAPH-treated proteins revealed the occurrence of protein aggregation, cross-linking, and fragmentation; BLP, which are naturally organized in globular assemblies, were the most affected proteins. Transmission electron microscopy (TEM) analysis of BLP shows the formation of complex protein aggregates after treatment with AAPH. These structural modifications were accompanied by the formation of protein carbonyl groups and protein hydroperoxides. The yield of carbonyls was lower than that for protein hydroperoxide generation and was unrelated to protein fragmentation. The oxidized proteins were also characterized by significant oxidation of Met, Trp, and Tyr (but not other) residues, and low levels of dityrosine. As the dityrosine yield is too low to account for the observed cross-linking, we propose that aggregation is associated with tryptophan oxidation and Trp-derived cross-links. It is also proposed that Trp oxidation products play a fundamental role in nonrandom fragmentation and carbonyl group formation particularly for LYSO and G6PD. These data point to a complex mechanism of peroxyl-radical mediated modification of proteins with monomeric (LYSO), dimeric (G6PD), and multimeric (BLP) structural organization, which not only results in oxidation of protein side chains but also gives rise to radical-mediated protein cross-links and fragmentation, with Trp species being critical intermediates.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Chemical Modification of Lysozyme, Glucose 6-Phosphate Dehydrogenase, and Bovine Eye Lens Proteins Induced by Peroxyl Radicals: Role of Oxidizable Amino Acid Residues

Arenas

López-Alarcón

Kogan

et al. 2013

Chem. Res. Toxicol.

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“…Because arginine is among the most abundant residues within protein functional sites, − many proteins can potentially benefit from this functional protection by alkyl-PMs. Although lysine residues react with MGO more slowly compared with arginine residues, those at the active sites of enzymes, such as Lys 182 of glucose-6-phosphate dehydrogenase, may have lower p K a and consequently enhanced reactivity toward MGO . As biogenic amines were found to be ineffective in preventing the inactivation of glucose-6-phosphate dehydrogenase by MGO, alkyl-PMs may be able to compete favorably with reactive lysyl residues for the adduction of 1,2-dicarbonyl.…”

Section: Results and Discussionmentioning

confidence: 99%

5′-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls

Amarnath

Avance

et al. 2015

Chem. Res. Toxicol.

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Pyridoxamine (PM) is a prospective drug for treatment of diabetic complications. In order to make zwitterionic PM more lipophilic and improve its tissue distribution, PM derivatives containing medium length alkyl groups on the hydroxymethyl side-chain were prepared. The synthesis of these alkylpyridoxamines (alkyl-PMs) starting from pyridoxine offers high yields and is amenable to bulk preparations. Interestingly, alkyl-PMs were found to react with methylglyoxal (MGO), a major toxic product of glucose metabolism and autoxidation, several orders of magnitude faster than PM. This suggests the formation of non-ionic pyrido-1,3-oxazine as the key step in the reaction of PM with MGO. Since the primary target of MGO in proteins is the guanidine side-chain of arginine, alkyl-PMs were shown to be more effective than PM in reducing modification of N-α-benzoylarginine by MGO. Alkyl-PMs in the presence of MGO also protected the enzymatic activity of lysozyme that contains several arginine residues next to its active site. Alkyl-PMs can be expected to trap MGO and other toxic 1,2-carbonyl compounds more effectively than PM, especially in lipophilic tissue environments, thus protecting macromolecules from functional damage. This suggests potential therapeutic uses for alkyl-PMs in diabetes and other diseases characterized by the elevated levels of toxic dicarbonyl compounds.

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“…Because of the molecular heterogeneity and the reduced mass increase expected for the resulting products (with respect to the mass value of the intact component), only in few cases AGEs formation was verified by direct protein ESI or MALDI MS measurements (Humeny et al, ; Meltretter et al, ; Flores‐Morales et al, ; Pampati, Suravajjala, & Dain, ); instruments with high resolution and high accuracy were generally used to this purpose. Thus, studies on model peptides were normally preferred (Krause et al, ; Kitamura et al, ; Mittelmaier & Pischetsrieder, ).…”

Section: Proteomic Analysis Of Protein Advanced Glycation End‐productsmentioning

confidence: 99%

“…Rarely, dihydroxyimidazolidine derivatives (G‐DH, MG‐DH, and 3DG‐DH) were also observed to occur at Arg residues, as deduced by the corresponding species showing a mass shift of +58, +72, and +162 Da, respectively (Brock et al, ; Lima, Moloney, & Ames, ). On the other hand, NaBH 4 ‐based reductive stabilization of the products generated following protein treatment with MGO allowed to prove the competitive reaction of this α‐dicarbonyl compound with Lys residues, assigning the resulting Schiff base to specific lysines (Flores‐Morales et al, ).…”

Section: Proteomic Analysis Of Protein Advanced Glycation End‐productsmentioning

confidence: 99%

Non‐enzymatic glycation and glycoxidation protein products in foods and diseases: An interconnected, complex scenario fully open to innovative proteomic studies

Arena

Salzano

Renzone

et al. 2013

Mass Spectrometry Reviews

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The Maillard reaction includes a complex network of processes affecting food and biopharmaceutical products; it also occurs in living organisms and has been strictly related to cell aging, to the pathogenesis of several (chronic) diseases, such as diabetes, uremia, cataract, liver cirrhosis and various neurodegenerative pathologies, as well as to peritoneal dialysis treatment. Dozens of compounds are involved in this process, among which a number of protein-adducted derivatives that have been simplistically defined as early, intermediate and advanced glycation end-products. In the last decade, various bottom-up proteomic approaches have been successfully used for the identification of glycation/glycoxidation protein targets as well as for the characterization of the corresponding adducts, including assignment of the modified amino acids. This article provides an updated overview of the mass spectrometry-based procedures developed to this purpose, emphasizing their partial limits with respect to current proteomic approaches for the analysis of other post-translational modifications. These limitations are mainly related to the concomitant sheer diversity, chemical complexity, and variable abundance of the various derivatives to be characterized. Some challenges to scientists are finally proposed for future proteomic investigations to solve main drawbacks in this research field.

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Enhanced reactivity of Lys182 explains the limited efficacy of biogenic amines in preventing the inactivation of glucose-6-phosphate dehydrogenase by methylglyoxal

Cited by 6 publications

References 63 publications

Chemical Modification of Lysozyme, Glucose 6-Phosphate Dehydrogenase, and Bovine Eye Lens Proteins Induced by Peroxyl Radicals: Role of Oxidizable Amino Acid Residues

Chemical Modification of Lysozyme, Glucose 6-Phosphate Dehydrogenase, and Bovine Eye Lens Proteins Induced by Peroxyl Radicals: Role of Oxidizable Amino Acid Residues

5′-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls

Non‐enzymatic glycation and glycoxidation protein products in foods and diseases: An interconnected, complex scenario fully open to innovative proteomic studies

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