Molecular Basis of Maillard Amide-Advanced Glycation End Product (AGE) Formation in Vivo

Henning, Christian; Smuda, Mareen; Girndt, Matthias; Ulrich, Christof; Glomb, Marcus A.

doi:10.1074/jbc.m111.282442

Cited by 52 publications

(55 citation statements)

References 30 publications

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“…This view is supported by studies at the amino acid level of plasma protein hydrolysates that detected similar global AGE levels in healthy persons (45,57).…”

Section: Discussionsupporting

confidence: 66%

“…Gas phase fractionation of pooled plasma samples was sufficiently sensitive to identify 19 modified sites in 11 plasma proteins. Most common were acetylation and formylation sites among the identified amide-AGEs, which is in accordance with the ratio of free AGE-modified amino acids in healthy and uremic plasma (45). Other modification sources apart from nonenzymatic glycosylation might be enzymatic reactions or acetylating agents (e.g.…”

Section: Discussionmentioning

confidence: 65%

“…We recently reported a two-step procedure to detect AGE-modified residues in plasma samples using specific and sensitive precursor ion scans (43,44). Here, we extended this approach by using gas phase fractionation to detect amide-bound AGEs that have been previously identified in lens homogenate (41) and as free adducts in human plasma and urine and found to be increased in uremic dialysis patients (45). These peptides were relatively quantified in plasma samples obtained from obese type 2 diabetes mellitus (T2DM) patients with good or poor glycemic control and compared with healthy lean and obese persons.…”

mentioning

confidence: 99%

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Plasma Proteins Modified by Advanced Glycation End Products (AGEs) Reveal Site-specific Susceptibilities to Glycemic Control in Patients with Type 2 Diabetes

Greifenhagen

Frolov

Blüher

et al. 2016

Journal of Biological Chemistry

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Protein glycation refers to the reversible reaction between aldoses (or ketoses) and amino groups yielding relatively stable Amadori (or Heyns) products. Consecutive oxidative cleavage reactions of these products or the reaction of amino groups with other reactive substances (e.g. ␣-dicarbonyls) yield advanced glycation end products (AGEs) that can alter the structures and functions of proteins. AGEs have been identified in all organisms, and their contents appear to rise with some diseases, such as diabetes and obesity. Here, we report a pilot study using highly sensitive and specific proteomics approach to identify and quantify AGE modification sites in plasma proteins by reversed phase HPLC mass spectrometry in tryptic plasma digests. In total, 19 AGE modification sites corresponding to 11 proteins were identified in patients with type 2 diabetes mellitus under poor glycemic control. The modification degrees of 15 modification sites did not differ among cohorts of normoglycemic lean or obese and type 2 diabetes mellitus patients under good and poor glycemic control. The contents of two amide-AGEs in human serum albumin and apolipoprotein A-II were significantly higher in patients with poor glycemic control, although the plasma levels of both proteins were similar among all plasma samples. These two modification sites might be useful to predict long term, AGE-related complications in diabetic patients, such as impaired vision, increased arterial stiffness, or decreased kidney function.The reaction between reducing sugars (i.e. aldoses or ketoses) and amines is termed glycation or nonenzymatic glycosylation (1). The initially formed aldimines or ketimines can rearrange forming relatively stable Amadori or Heyns products, respectively. Consecutive rearrangements and oxidations yield advanced glycation end products (AGEs) 3 (2-6), a structurally heterogeneous group of compounds including cross-linked proteins (1). Alternatively, ␣-dicarbonyls generated by Amadori degradation (7,8), saccharide autoxidation (9, 10), lipid peroxidation (11, 12), and enzymatic reactions (13-15) can modify the side chains of lysine and arginine residues (16 -18). Degradation of glucose-derived Amadori products, for example, yields 1-deoxyglucosone (7, 19) and its tautomers, which upon nucleophilic attack by a N ⑀ -amino group of a lysine residue undergo hydrolytic ␤-cleavage yielding amide-AGEs, such as N ⑀ -acetyl-, formyl-, and glycerinyl-lysine ( Fig. 1) (20). Generally, AGEs can alter the structure of proteins contributing to diabetic retinopathy (21, 22), increased arterial stiffness (23, 24), or impaired renal function (25) along with aging and diabetes. Furthermore, receptor binding-induced activation of proinflammatory signaling pathways is associated with the development and progression of atherosclerosis (26) and nephropathy (25).AGEs have been localized in biological tissues by immunohistochemistry (27-29) and quantified with ELISA using monoclonal antibodies recognizing methylglyoxal-derived hydroimidazolone (30), imidazol...

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“…This view is supported by studies at the amino acid level of plasma protein hydrolysates that detected similar global AGE levels in healthy persons (45,57).…”

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 65%

mentioning

confidence: 99%

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Plasma Proteins Modified by Advanced Glycation End Products (AGEs) Reveal Site-specific Susceptibilities to Glycemic Control in Patients with Type 2 Diabetes

Greifenhagen

Frolov

Blüher

et al. 2016

Journal of Biological Chemistry

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“…Interestingly, N-lac-Val, N-lac-Leu, and N-lac-Ile have been identified in the urine of a patient with elevated branched-chain amino acids due to maple syrup urine disease (37). Another lactic acid amide, N 6 -lac-Lys, has been detected in human plasma and was found to be increased in the plasma of hemodialytic patients (38). As opposed to the biosynthesis described here, N 6 -lac-Lys is an amide-advanced glycation end product, formed nonenzymatically through the Maillard reaction (39).…”

Section: Discussionmentioning

confidence: 98%

N -lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids

Jansen

Addie

Merkx³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite technological advances in metabolomics, large parts of the human metabolome are still unexplored. In an untargeted metabolomics screen aiming to identify substrates of the orphan transporter ATP-binding cassette subfamily C member 5 (ABCC5), we identified a class of mammalian metabolites, N-lactoyl-amino acids. Using parallel protein fractionation in conjunction with shotgun proteomics on fractions containing N-lactoyl-Phe-forming activity, we unexpectedly found that a protease, cytosolic nonspecific dipeptidase 2 (CNDP2), catalyzes their formation. N-lactoyl-amino acids are ubiquitous pseudodipeptides of lactic acid and amino acids that are rapidly formed by reverse proteolysis, a process previously considered to be negligible in vivo. The plasma levels of these metabolites strongly correlate with plasma levels of lactate and amino acid, as shown by increased levels after physical exercise and in patients with phenylketonuria who suffer from elevated Phe levels. Our approach to identify unknown metabolites and their biosynthesis has general applicability in the further exploration of the human metabolome.unknown metabolites | untargeted metabolomics | ABCC5 | MRP5 | physical exercise U ntargeted metabolomics aims to provide a comprehensive snapshot of the metabolome and is becoming a mainstream technique to discover biomarkers, to study the effects of interventions, and to discover the function of enzymes (1).Recent technical improvements now make it possible to detect several thousand metabolites in a single untargeted metabolomics analysis, but the identity of these metabolites is initially not known beyond their molecular mass (1). Knowing the chemical identity of metabolites is crucial for the proper interpretation of metabolomic studies, however. Online metabolite databases like METLIN (∼240,000 entries) and the Human Metabolome Database (HMDB; ∼42,000 entries) contain vast numbers of metabolites and are extremely useful to annotate the detected molecular masses (2, 3). These databases cover large parts of the metabolome, but significant gaps remain. Due to poorly characterized and promiscuous enzymes, the human metabolome is much larger than initially anticipated (4). State-of-the-art untargeted metabolomics studies still report up to 40% unidentified, but potentially important, metabolites that can be detected reproducibly (5-8). Nevertheless, unknown metabolites are only rarely characterized because of the extensive work required for de novo structure elucidation (9-11). Here, we describe the characterization of a class of mammalian metabolites that we discovered in an untargeted metabolomic screen aimed to identify substrates of the orphan transporter ATP-binding cassette subfamily C member 5 (ABCC5).ABCC5 is a member of the C-branch of the superfamily of ABC transporters, which use the energy provided by the hydrolysis of ATP to transport substrates across the plasma membrane (12). ABCC5, also known as multidrug resistance-associated protein 5 (MRP5), is ubiquitously expressed, but levels in b...

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“…AGE concentrations in vivo are markedly amplified in diabetes but also in non-diabetic uremia with a significant loss of renal clearance (9). Thus, besides substrate concentration, carbonyl stress, as described by Baynes et al (10), is an alternative explanation for the increase of chemical protein modifications in various diseases.…”

mentioning

confidence: 93%

Extending the Spectrum of α-Dicarbonyl Compounds in Vivo

Henning¹,

Liehr²,

Girndt

et al. 2014

Journal of Biological Chemistry

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114

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Background: ␣-Dicarbonyls are central intermediates in the formation of advanced glycation end products (AGEs). Results: A quantitation method for the complete spectrum relevant in vivo was established. Conclusion: Non-enzymatic chemistry of glucose and L-ascorbic acid as precursors and ␣-dicarbonyl intermediates play an important role in vivo. Significance: Knowledge of plasma levels of ␣-dicarbonyls is crucial to understand the complex pathways of AGE formation in vivo.

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Molecular Basis of Maillard Amide-Advanced Glycation End Product (AGE) Formation in Vivo

Cited by 52 publications

References 30 publications

Plasma Proteins Modified by Advanced Glycation End Products (AGEs) Reveal Site-specific Susceptibilities to Glycemic Control in Patients with Type 2 Diabetes

Plasma Proteins Modified by Advanced Glycation End Products (AGEs) Reveal Site-specific Susceptibilities to Glycemic Control in Patients with Type 2 Diabetes

N -lactoyl-amino acids are ubiquitous metabolites that originate from CNDP2-mediated reverse proteolysis of lactate and amino acids

Extending the Spectrum of α-Dicarbonyl Compounds in Vivo

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