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Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal.

Petrova KV, Millsap AD, Stec DF, Rizzo CJ - Chem. Res. Toxicol. (2014)

Bottom Line: We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1).Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized.The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry and Biochemistry, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University , Nashville, Tennessee 37235, United States.

ABSTRACT
Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA-protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side chains. However, the chemical nature of the methylglyoxal induced DPC have not been determined. We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1). The cross-link was identified by mass spectrometry and the structure confirmed by comparison to a synthetic sample. Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized. The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

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Model cross-links formed by methylglyoxaland related 1,2-dicarbonyls.
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fig9: Model cross-links formed by methylglyoxaland related 1,2-dicarbonyls.

Mentions: Reactiveelectrophiles other than methylglyoxal are formed fromthe degradation of carbohydrates, which can also modify proteins andDNA. It was observed that amines can accelerate the modification ofDNA and in some cases be incorporated into the product. For example,the reaction of guanosine with glucose in the presence of n-propylamine resulted in amide cross-links related to 1 (Figure 9).87 Analogous products were observed when d-ribose was used.The work provided the first insight into the structure of DPCs derivedfrom Maillard products. Subsequently, cross-link 1 wasobserved from the reaction of Ac-Lys, dGuo, and either dihydroxyacetoneor glyceraldehyde.88 It is possible thatmethylglyoxal is the reactive bis-electrophile in these examples orthat perhaps other electrophilicMaillard products are capable of forming the same cross-link. A relatedglyoxal cross-link between Lys side chains has also been characterizedin vitro from the reaction of glyoxal with bovine serum albumin (BSA)and human lens proteins.25 Interestingly,the yield of this cross-link for the in vitro reactions increasedat lower glyoxal concentrations.


Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal.

Petrova KV, Millsap AD, Stec DF, Rizzo CJ - Chem. Res. Toxicol. (2014)

Model cross-links formed by methylglyoxaland related 1,2-dicarbonyls.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4060920&req=5

fig9: Model cross-links formed by methylglyoxaland related 1,2-dicarbonyls.
Mentions: Reactiveelectrophiles other than methylglyoxal are formed fromthe degradation of carbohydrates, which can also modify proteins andDNA. It was observed that amines can accelerate the modification ofDNA and in some cases be incorporated into the product. For example,the reaction of guanosine with glucose in the presence of n-propylamine resulted in amide cross-links related to 1 (Figure 9).87 Analogous products were observed when d-ribose was used.The work provided the first insight into the structure of DPCs derivedfrom Maillard products. Subsequently, cross-link 1 wasobserved from the reaction of Ac-Lys, dGuo, and either dihydroxyacetoneor glyceraldehyde.88 It is possible thatmethylglyoxal is the reactive bis-electrophile in these examples orthat perhaps other electrophilicMaillard products are capable of forming the same cross-link. A relatedglyoxal cross-link between Lys side chains has also been characterizedin vitro from the reaction of glyoxal with bovine serum albumin (BSA)and human lens proteins.25 Interestingly,the yield of this cross-link for the in vitro reactions increasedat lower glyoxal concentrations.

Bottom Line: We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1).Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized.The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry and Biochemistry, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University , Nashville, Tennessee 37235, United States.

ABSTRACT
Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA-protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side chains. However, the chemical nature of the methylglyoxal induced DPC have not been determined. We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1). The cross-link was identified by mass spectrometry and the structure confirmed by comparison to a synthetic sample. Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized. The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

Show MeSH