Isolation of S-(carboxymethyl)cystein from urine

Ubuka, Toshihiko; Kodama, Hiroyuki; Mizuhara, Shunzi

doi:10.1016/0304-4165(67)90100-6

Cited by 24 publications

(3 citation statements)

References 9 publications

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“…CMC formation has also been detected on reaction of glucose with proteins. Literature data is consistent with the formation of this species in vivo, with higher levels of CMC detected in the urine of patients suffering from diabetes and hypertension than in healthy people (34), and elevated levels of CMC detected in the muscle proteins of rats with diabetes compared to controls (35,36). Preliminary experiments (Zeng and Davies, unpublished data) have shown that CMC can also be detected in human plasma, confirming that this material is produced in vivo.…”

Section: Discussionsupporting

confidence: 75%

Evidence for the Formation of Adducts andS-(Carboxymethyl)cysteine on Reaction of α-Dicarbonyl Compounds with Thiol Groups on Amino Acids, Peptides, and Proteins

Zeng

Davies

2005

Chem. Res. Toxicol.

138

110

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Nonenzymatic covalent adduction of glucose, or aldehydes derived from glucose or oxidation reactions, to proteins (glycation) has been proposed as a key factor in the vascular complications of diabetes. In conditions of chronic glucose elevation, alpha-dicarbonyl compounds, including glyoxal and methylglyoxal, are also present at elevated levels. These carbonyls react rapidly with nucleophilic groups on Lys and Arg side chains and the N-terminal amino group, to give poorly defined products, often called advanced glycation endproducts. These are present at elevated levels in tissue samples from people with diabetes and have been linked with disease development. As the thiol group of Cys is a powerful nucleophile, we hypothesized that adduction should occur rapidly and efficiently at Cys residues. It is shown here that Cys residues react with dicarbonyl compounds to give thiol-aldehyde adducts, which have been detected by electrospray ionization mass spectrometry. This process is accompanied by loss of the thiol group and formation of stable products. In the case of glyoxal, these reactions give S-(carboxymethyl)cysteine. The percentage conversion of thiol lost to product is substrate-dependent and < or = 32%. S-(Carboxymethyl)cysteine has been quantified by HPLC on thiol-containing, protected amino acids, peptides, and proteins, after exposure to glyoxal. The yield of this product has been shown to increase in a time- and dose-dependent manner with higher glyoxal concentrations and to also be formed on extended incubation of serum albumin with glucose. This novel, stable, advanced glycation endproduct is a potential marker of glycation.

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Section: Discussionsupporting

confidence: 75%

Evidence for the Formation of Adducts andS-(Carboxymethyl)cysteine on Reaction of α-Dicarbonyl Compounds with Thiol Groups on Amino Acids, Peptides, and Proteins

Zeng

Davies

2005

Chem. Res. Toxicol.

138

110

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“…Little attention has been paid to date on the role of thiol glycation in the development of diabetic complications. CMC formed from the reaction of glyoxal or glycolaldehyde with a thiol group on a protein is the first, and only, sulfhydryl AGE identified to date in vivo (38,39) and in vitro (16), though the presence of elevated levels of CMC, compared to controls, in the urine of patients suffering from diabetes and hypertension has been long established (40). The mechanism of CMC formation has not been fully elucidated, though it has been proposed that the initial thiohemiacetal adduct formed by addition of the Cys residue to glyoxal undergoes an intramolecular Cannizzaro rearrangement to give CMC (38).…”

Section: Discussionmentioning

confidence: 99%

Protein and Low Molecular Mass Thiols as Targets and Inhibitors of Glycation Reactions

Zeng

Davies

2006

Chem. Res. Toxicol.

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Protein glycation has been implicated in the aging process as well as the complications of diabetes (retinopathy, neuropathy, nephropathy, and atherosclerosis). The nitrogen substituents of Lys, Arg, and His residues and the N-terminus of proteins are known to be readily glycated. As the thiol group of Cys is a powerful nucleophile, we hypothesized that Cys residues should also be targets of glycation and that low molecular mass thiols may act as protective agents. In this study the role of thiol glycation, induced by dicarbonyls, in protein cross-link formation and damage prevention is examined. It is shown that incubation of creatine kinase with glyoxal results in protein cross-link formation, with this occurring concurrently with loss of thiol groups, enzyme inactivation, and formation of S-carboxymethylcysteine, a product of glyoxal adduction to Cys residues. Cross-links have also been detected between N-acetylcysteine and the Lys-rich protein histone H1, demonstrating the formation of thiol-glyoxal-amine cross-links. Mass spectrometry has been used to characterize some of these cross-links as 2-(alkylthio)acetamides. A range of low molecular mass thiols have been shown to inhibit dicarbonyl adduction to, and cross-linking of, the thiol-free protein lysozyme, consistent with these thiols being alternative (sacrificial) targets of glycation. Some of these thiols are more efficient modulators of glycation than established glycation inhibitors such as aminoguanidine. These data demonstrate that thiols are facile targets of glycation and that low molecular mass thiols are potent glycation inhibitors. These data may aid the design of therapeutic agents for the treatment of the complications of diabetes.

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“…The glutathione-isovaleric acid conjugate is probably catabolized to isovalthine by the same enzymes that catabolize the glutathione conjugates of mercapturic acid precursors (Kuwaki, 1965). Other cysteine derivatives isolated or detected include S-(p-carboxyn-propy1)-L-cysteine (also known as P-isobuteine) and S-(P-carboxyethyl)-L-cysteine present in normal child urine (Ohmori, Shimomura, Azumi, and Mizuhara, 1965), and S-(carboxymethy1)cysteine present in some animal tissues and in the urine of hypertensive and diabetic patients (Ubuka, Kodama, and Mizuhara, 1967). These derivatives may arise from a mechanism similar to that described above for isovalthine (54) or may be enzymically synthesized from the corresponding Lypunsaturated compound and glutathione by glutathione S-alkenetransf erases.…”

mentioning

confidence: 99%

The Role of Glutathione and Glutathione S‐Transferases in Mercapturic Acid Biosynthesis

Boyland¹,

Chasseaud²

1969

Advances in Enzymology - And Related Areas of Molecular Biology

332

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Isolation of S-(carboxymethyl)cystein from urine

Cited by 24 publications

References 9 publications

Evidence for the Formation of Adducts andS-(Carboxymethyl)cysteine on Reaction of α-Dicarbonyl Compounds with Thiol Groups on Amino Acids, Peptides, and Proteins

Evidence for the Formation of Adducts andS-(Carboxymethyl)cysteine on Reaction of α-Dicarbonyl Compounds with Thiol Groups on Amino Acids, Peptides, and Proteins

Protein and Low Molecular Mass Thiols as Targets and Inhibitors of Glycation Reactions

The Role of Glutathione and Glutathione S‐Transferases in Mercapturic Acid Biosynthesis

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