The role of mass spectrometry in the study of non-enzymatic protein glycation in diabetes

Lapolla, Annunziata; Fedele, Domenico; Traldi, Pietro

doi:10.1002/1098-2787(2000)19:5<279::aid-mas3>3.0.co;2-g

Cited by 43 publications

(22 citation statements)

References 73 publications

(49 reference statements)

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“…For all of these experiments, the instrument was set at linear mode to increase the mass range and sensitivity. To ensure mass accuracy, an external calibration was performed prior to each sample spot, and a calibration check was performed after each sample to ensure that the calibration had not shifted (see supplemental material) (43,44).…”

Section: Methodsmentioning

confidence: 99%

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Culbertson

Vassilenko

Morrison

et al. 2003

Journal of Biological Chemistry

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The inhibition of post-Amadori advanced glycation end product (AGE) formation by three different classes of AGE inhibitors, carbonyl group traps, chelators, and radical-trapping antioxidants, challenge the current paradigms that: 1) AGE inhibitors will not increase the formation of any AGE product, 2) transition metal ions are required for oxidative formation of AGE, and 3) screening AGE inhibitors only in systems containing transition metal ions represents a valid estimate of potential in vivo mechanisms. This work also introduces a novel multifunctional AGE inhibitor, 6-dimethylaminopyridoxamine (dmaPM), designed to function as a combined carbonyl trap, metal ion chelator, and radicaltrapping antioxidant. Other AGE inhibitors including pyridoxamine, aminoguanidine, o-phenylenediamine, dipyridoxylamine, and diethylenetriaminepentaacetic acid were also examined. The results during uninterrupted and interrupted ribose glycations show: 1) an unexpected increase in the yield of pentosidine in the presence of radical-trapping phenolic antioxidants such as Trolox and dmaPM, 2) significant formation of N ⑀ -carboxymethyllysine (CML) in the presence of strong chelators and phenolic antioxidants, which implies that there must be nonradical routes to CML, 3) prevention of intermolecular cross-links with radical-trapping inhibitors, and 4) that dmaPM shows excellent inhibition of AGE. Glucose glycations reveal the expected inhibition of pentosidine and CML with all compounds tested, but in a buffer free of trace metal ions the yield of CML in the presence of radical-trapping antioxidants was between the metal ion-free and metal ion-containing controls. Protein molecular weight analyses support the conclusion that Amadori decomposition pathways are constrained in the presence of metal ion chelators and radical traps.Nonenzymatic protein glycation by reducing sugars, such as glucose or ribose, is a complicated cascade of condensations, rearrangements, fragmentations, and oxidative modifications that lead to a plethora of compounds collectively called advanced glycation end products (AGEs) 1 (1). AGE products slowly build up and contribute to the age-dependent chemical modification of long-lived tissue proteins. Once formed, AGE products may prevent normal protein function and recognition or stimulate potentially detrimental interactions in signaling pathways (2, 3). Glycation reactions are believed to have a significant role in the progression of diabetic complications largely because of elevated levels of glucose. Indeed, the formation of AGE has been increasingly implicated in pathogenesis of diabetic complications, atherosclerosis, and Alzheimer's disease (4 -6). Inhibitors that act to reduce AGE formation may prove useful for limiting nonenzymatic protein modification associated in the pathology of these and other chronic agerelated diseases. The reaction of amino compounds, such as lysine, with reducing sugars is known as the Maillard reaction (7, 8). The "classical" or Hodge pathway begins with reversible formation of...

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Section: Methodsmentioning

confidence: 99%

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Culbertson

Vassilenko

Morrison

et al. 2003

Journal of Biological Chemistry

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“…In the case of glycoproteins, multiple modified sites are usually present, and each glycoprotein exhibits a different set of glycoforms. MALDI-TOF-MS has been effectively employed in the analysis of glycoproteins (Papac et al, 1998;Lapolla, Fedele, & Traldi, 2000). The group of Traldi and Lapolla (Lapolla, Fedele, & Traldi, 2000) has applied mass spectrometry techniques to the study of advanced protein glycation end-products.…”

Section: Oligosaccharides and Glycoconjugatesmentioning

confidence: 99%

“…MALDI-TOF-MS has been effectively employed in the analysis of glycoproteins (Papac et al, 1998;Lapolla, Fedele, & Traldi, 2000). The group of Traldi and Lapolla (Lapolla, Fedele, & Traldi, 2000) has applied mass spectrometry techniques to the study of advanced protein glycation end-products. The MALDI-PSD technique has been widely employed for the study of the structure of oligosaccharides and glycoconjugates.…”

Section: Oligosaccharides and Glycoconjugatesmentioning

confidence: 99%

Development of new methodologies for the mass spectrometry study of bioorganic macromolecules

Cristoni

Bernardi

2003

Mass Spectrometry Reviews

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I. Introduction 370 II. Techniques That Are Usually Employed in the Study of Bioorganic Macromolecules 371 A. Proteins and Peptides 371 B. Oligonucleotides 374 C. Oligosaccharides and Glycoconjugates 375 D. Various Complexes (DNA–Protein, Antigen–Antibody, Macromolecules–Metals) 377 III. Common Problems and Developments in the Analysis of Bioorganic Macromolecules by Mass Spectrometry 377 A. Ionization Source Problems and Developments 377 1. Sensitivity 377 2. Problems with Buffers 379 3. Multicharge Effect 381 B. Mass Analyzer Problems and Developments 381 1. Linear Dynamic Range 381 2. Tandem Mass Spectrometry 382 3. Sensitivity 382 4. Resolution 383 5. Mass Accuracy 383 IV. New Promising Technologies 384 A. Interfaces and Ionization Sources 384 1. Improvements in the Coupling of Liquid‐Phase Separation Systems to Mass Spectrometry 384 2. AP‐MALDI 384 3. Deprotonant Agents 385 4. Sonic Spray Ionization 388 5. APCI without Corona Discharge 391 B. Mass Analyzers 393 1. Linear Quadrupole Ion Trap 394 2. TOF Analyzers with New Detectors 395 3. Multiple Mass Analyzers 396 V. Software for Data Treatment 397 VI. Conclusions and Future Developments 399 Acknowledgments 400 References 400 In recent years, mass spectrometry has been increasingly used for the analysis of various macromolecules of biological, biomedical, and biochemical interest. This increase has been made possible by two key developments: the advent of electrospray ionization (ESI) and matrix‐assisted laser desorption ionization (MALDI) sources. The two new techniques produce a significant increase in mass range and in sensitivity that led to the development of new applications and of new analyzer designs, software, and robotics. This review, apart from the description of the status of mass spectrometry in the analysis of bioorganic macromolecules, is mainly devoted to the illustration of the more recent promising techniques and on their possible future evolution. © 2003 Wiley Periodicals, Inc., Mass Spec Rev 22:369–406, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mas.10062

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“…Further rearrangement and cleavage of this fructosamine can lead to other modifications, known as advanced glycation end products (AGEs). Figure 1 provides a summary of such products, as identified in previous work with HSA and other glycated proteins [6,[9][10][11][12][13][14][15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

“…This study examined such modifications by using in vitro glycated HSA, which has proposed to be a good model for glycated HSA in serum and plasma [18,19]. The extent to which HSA can be glycated in vitro can range from minimal levels (<10 mol modification sites per mol protein) to high levels (30-40 mol modification sites per mol protein) [9,10], with previous studies indicating that minimally glycated HSA is the better model for individuals with well-controlled diabetics [11,17].…”

Section: Introductionmentioning

confidence: 99%

Characterization of glycation adducts on human serum albumin by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

Cerny

Clarke³

et al. 2007

Clinica Chimica Acta

107

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Background-Non-enzymatic glycation of human serum albumin (HSA) is associated with the long-term complications of diabetes. We examined the structure and location of modifications on minimally glycated HSA and considered their possible impact on the binding of drugs to this protein.Methods-Minimally glycated and normal HSA (used as a control) were digested with trypsin, Glu-C or Lys-C, followed by fractionation of the resulting peptides and their analysis by matrixassisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) to determine the structures and locations of glycation adducts.Results-Several specific lysine and arginine residues were identified as modification sites in minimally glycated HSA. Residues K12, K51, K199, K205, K439 and K538 were found to be modified through the formation of fructosyl-lysine, while the modification of K159 and K286 involved the formation of pyrraline, N ε -carboxymethyl-lysine respectively. Lysine K378 was found to give N ε -carboxyethyl-lysine in some forms of glycated HSA but fructosyl-lysine in other forms. Residues R160 and R472 produced a modification based on N ε -(5-hydro-4-imidazolon-2-yl) ornithine. Lysine R222 was modified to produce argpyrimidine, N ε -[5-(2,3,4-trihydroxybutyl)-5-hydro-4-imidazolon-2-yl]ornithine or tetrahydropyrimidine.Conclusions-With the exception of K12, K199, K378, K439 and K525, all of the observed sites of modification for minimally glycated HSA were new to this current study. The fact that many of these glycation-related modifications are located at or near known drug binding sites on HSA explains why some differences have been previously noted in the binding of certain drugs to normal vs glycated HSA.

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The role of mass spectrometry in the study of non-enzymatic protein glycation in diabetes

Cited by 43 publications

References 73 publications

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Development of new methodologies for the mass spectrometry study of bioorganic macromolecules

Characterization of glycation adducts on human serum albumin by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

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