scholarly journals Mapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Simone Di Sanzo ◽  
Katrin Spengler ◽  
Anja Leheis ◽  
Joanna M. Kirkpatrick ◽  
Theresa L. Rändler ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Specific Protein ◽  
Protein Glycation ◽  
Advanced Glycation ◽  
Protein Targets ◽  
Glycation End Products ◽  
End Products ◽  
Functional Consequences ◽  
Cell Cycle Perturbation ◽  
And Function

AbstractPosttranslational mechanisms play a key role in modifying the abundance and function of cellular proteins. Among these, modification by advanced glycation end products has been shown to accumulate during aging and age-associated diseases but specific protein targets and functional consequences remain largely unexplored. Here, we devise a proteomic strategy to identify sites of carboxymethyllysine modification, one of the most abundant advanced glycation end products. We identify over 1000 sites of protein carboxymethylation in mouse and primary human cells treated with the glycating agent glyoxal. By using quantitative proteomics, we find that protein glycation triggers a proteotoxic response and indirectly affects the protein degradation machinery. In primary endothelial cells, we show that glyoxal induces cell cycle perturbation and that carboxymethyllysine modification reduces acetylation of tubulins and impairs microtubule dynamics. Our data demonstrate the relevance of carboxymethyllysine modification for cellular function and pinpoint specific protein networks that might become compromised during aging.

scholarly journals Mapping sites of carboxymethyllysine modification on proteins reveals its consequences for proteostasis and cell proliferation

2020 ◽  
Author(s):  
Simone Di Sanzo ◽  
Katrin Spengler ◽  
Anja Leheis ◽  
Joanna M. Kirkpatrick ◽  
Theresa L. Rändler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Specific Protein ◽  
Microtubule Dynamics ◽  
26S Proteasome ◽  
Protein Glycation ◽  
List Type ◽  
Protein Targets ◽  
Functional Consequences ◽  
Cell Cycle Perturbation ◽  
And Function

SummaryPosttranslational mechanisms play a key role in modifying the abundance and function of cellular proteins. Among these, modification by advanced glycation end products (AGEs) has been shown to accumulate during aging and age-associated diseases but specific protein targets and functional consequences remain largely unexplored. Here, we devised a proteomic strategy to identify specific sites of carboxymethyllysine (CML) modification, one of the most abundant AGEs. We identified over 1000 sites of CML modification in mouse and primary human cells treated with the glycating agent glyoxal. By using quantitative proteomics, we found that protein glycation triggers a proteotoxic response and directly affects the protein degradation machinery. We show that glyoxal induces cell cycle perturbation in primary endothelial cells and that CML modification reduces acetylation of tubulins and impairs microtubule dynamics. Our data demonstrate the relevance of AGE modification for cellular function and pinpoint specific protein networks that might become compromised during aging.HighlightsA peptide enrichment strategy allows mapping of CML modification in cells and tissuesCML modification competes with ubiquitination or acetylation of lysinesGlyoxal treatment destabilizes the 26S proteasomeGlyoxal arrests cell cycle and impairs microtubule dynamics via altering the tubulin code

Protein glycation in vivo: functional and structural effects on yeast enolase

2008 ◽  
Vol 416 (3) ◽  
pp. 317-326 ◽  
Author(s):  
Ricardo A. Gomes ◽  
Luís M. A. Oliveira ◽  
Mariana Silva ◽  
Carla Ascenso ◽  
Alexandre Quintas ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Specific Protein ◽  
Protein Glycation ◽  
Advanced Glycation ◽  
Structure And Stability ◽  
Glycation End Products ◽  
End Products ◽  
Activity Loss

Protein glycation is involved in structure and stability changes that impair protein functionality, which is associated with several human diseases, such as diabetes and amyloidotic neuropathies (Alzheimer's disease, Parkinson's disease and Andrade's syndrome). To understand the relationship of protein glycation with protein dysfunction, unfolding and β-fibre formation, numerous studies have been carried out in vitro. All of these previous experiments were conducted in non-physiological or pseudo-physiological conditions that bear little to no resemblance to what may happen in a living cell. In vivo, glycation occurs in a crowded and organized environment, where proteins are exposed to a steady-state of glycation agents, namely methylglyoxal, whereas in vitro, a bolus of a suitable glycation agent is added to diluted protein samples. In the present study, yeast was shown to be an ideal model to investigate glycation in vivo since it shows different glycation phenotypes and presents specific protein glycation targets. A comparison between in vivo glycated enolase and purified enolase glycated in vitro revealed marked differences. All effects regarding structure and stability changes were enhanced when the protein was glycated in vitro. The same applies to enzyme activity loss, dimer dissociation and unfolding. However, the major difference lies in the nature and location of specific advanced glycation end-products. In vivo, glycation appears to be a specific process, where the same residues are consistently modified in the same way, whereas in vitro several residues are modified with different advanced glycation end-products.

scholarly journals Advanced Glycation End Products and Oxidative Stress in a Hyperglycaemic Environment

2021 ◽  
Author(s):  
Akio Nakamura ◽  
Ritsuko Kawahrada
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Advanced Glycation End Products ◽  
Reactive Oxygen ◽  
Protein Glycation ◽  
Oxygen Species ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
And Oxidative Stress

Protein glycation is the random, nonenzymatic reaction of sugar and protein induced by diabetes and ageing; this process is quite different from glycosylation mediated by the enzymatic reactions catalysed by glycosyltransferases. Schiff bases form advanced glycation end products (AGEs) via intermediates, such as Amadori compounds. Although these AGEs form various molecular species, only a few of their structures have been determined. AGEs bind to different AGE receptors on the cell membrane and transmit signals to the cell. Signal transduction via the receptor of AGEs produces reactive oxygen species in cells, and oxidative stress is responsible for the onset of diabetic complications. This chapter introduces the molecular mechanisms of disease onset due to oxidative stress, including reactive oxygen species, caused by AGEs generated by protein glycation in a hyperglycaemic environment.

scholarly journals The Modern Western Diet Rich in Advanced Glycation End-Products (AGEs): An Overview of Its Impact on Obesity and Early Progression of Renal Pathology

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1748 ◽  
Author(s):  
Arianna Bettiga ◽  
Francesco Fiorio ◽  
Federico Di Marco ◽  
Francesco Trevisani ◽  
Annalisa Romani ◽  
...  
Keyword(s):  
Chronic Diseases ◽  
Advanced Glycation End Products ◽  
Cell Function ◽  
Advanced Glycation ◽  
Covalent Bonds ◽  
Physiological Processes ◽  
Glycation End Products ◽  
End Products ◽  
And Function

Advanced glycation end-products (AGEs) are an assorted group of molecules formed through covalent bonds between a reduced sugar and a free amino group of proteins, lipids, and nucleic acids. Glycation alters their structure and function, leading to impaired cell function. They can be originated by physiological processes, when not counterbalanced by detoxification mechanisms, or derive from exogenous sources such as food, cigarette smoke, and air pollution. Their accumulation increases inflammation and oxidative stress through the activation of various mechanisms mainly triggered by binding to their receptors (RAGE). So far, the pathogenic role of AGEs has been evidenced in inflammatory and chronic diseases such as chronic kidney disease, cardiovascular disease, and diabetic nephropathy. This review focuses on the AGE-induced kidney damage, by describing the molecular players involved and investigating its link to the excess of body weight and visceral fat, hallmarks of obesity. Research regarding interventions to reduce AGE accumulation has been of great interest and a nutraceutical approach that would help fighting chronic diseases could be a very useful tool for patients’ everyday lives.

Advanced Glycation End Products Modulate the Maturation and Function of Peripheral Blood Dendritic Cells

Diabetes ◽  
2004 ◽  
Vol 53 (6) ◽  
pp. 1452-1458 ◽  
Author(s):  
C. L. Price ◽  
P. S. Sharp ◽  
M. E. North ◽  
S. J. Rainbow ◽  
S. C. Knight
Keyword(s):  
Dendritic Cells ◽  
Advanced Glycation End Products ◽  
Peripheral Blood ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
And Function

scholarly journals Autophagy Inhibits the Accumulation of Advanced Glycation End Products by Promoting Lysosomal Biogenesis and Function in the Kidney Proximal Tubules

Diabetes ◽  
2017 ◽  
Vol 66 (5) ◽  
pp. 1359-1372 ◽  
Author(s):  
Atsushi Takahashi ◽  
Yoshitsugu Takabatake ◽  
Tomonori Kimura ◽  
Ikuko Maejima ◽  
Tomoko Namba ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Proximal Tubules ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
And Function ◽  
Kidney Proximal Tubules

scholarly journals How Does Pyridoxamine Inhibit the Formation of Advanced Glycation End Products? The Role of Its Primary Antioxidant Activity

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 344 ◽  
Author(s):  
Rafael Ramis ◽  
Joaquín Ortega-Castro ◽  
Carmen Caballero ◽  
Rodrigo Casasnovas ◽  
Antonia Cerrillo ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Advanced Glycation End Products ◽  
Rate Constants ◽  
Protein Glycation ◽  
Diffusion Limit ◽  
Advanced Glycation ◽  
Hydrogen Atoms ◽  
Glycation End Products ◽  
End Products ◽  
Primary Antioxidant

Pyridoxamine, one of the natural forms of vitamin B6, is known to be an effective inhibitor of the formation of advanced glycation end products (AGEs), which are closely related to various human diseases. Pyridoxamine forms stable complexes with metal ions that catalyze the oxidative reactions taking place in the advanced stages of the protein glycation cascade. It also reacts with reactive carbonyl compounds generated as byproducts of protein glycation, thereby preventing further protein damage. We applied Density Functional Theory to study the primary antioxidant activity of pyridoxamine towards three oxygen-centered radicals (•OOH, •OOCH3 and •OCH3) to find out whether this activity may also play a crucial role in the context of protein glycation inhibition. Our results show that, at physiological pH, pyridoxamine can trap the •OCH3 radical, in both aqueous and lipidic media, with rate constants in the diffusion limit (>1.0 × 108 M - 1 s - 1 ). The quickest pathways involve the transfer of the hydrogen atoms from the protonated pyridine nitrogen, the protonated amino group or the phenolic group. Its reactivity towards •OOH and •OOCH3 is smaller, but pyridoxamine can still scavenge them with moderate rate constants in aqueous media. Since reactive oxygen species are also involved in the formation of AGEs, these results highlight that the antioxidant capacity of pyridoxamine is also relevant to explain its inhibitory role on the glycation process.

scholarly journals Advanced glycation end products (AGEs), protein aggregation and their cross talk: new insight in tumorigenesis

Glycobiology ◽  
2019 ◽  
Vol 30 (1) ◽  
pp. 2-18
Author(s):  
Ejazul Haque ◽  
Mohd Kamil ◽  
Adria Hasan ◽  
Safia Irfan ◽  
Saba Sheikh ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Advanced Glycation End Products ◽  
Cross Talk ◽  
Structural Changes ◽  
Current Knowledge ◽  
Normal Function ◽  
Protein Glycation ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

Abstract Protein glycation and protein aggregation are two distinct phenomena being observed in cancer cells as factors promoting cancer cell viability. Protein aggregation is an abnormal interaction between proteins caused as a result of structural changes in them after any mutation or environmental assault. Protein aggregation is usually associated with neurodegenerative diseases like Alzheimer’s and Parkinson’s, but of late, research findings have shown its association with the development of different cancers like lung, breast and ovarian cancer. On the contrary, protein glycation is a cascade of irreversible nonenzymatic reaction of reducing sugar with the amino group of the protein resulting in the modification of protein structure and formation of advanced glycation end products (AGEs). These AGEs are reported to obstruct the normal function of proteins. Lately, it has been reported that protein aggregation occurs as a result of AGEs. This aggregation of protein promotes the transformation of healthy cells to neoplasia leading to tumorigenesis. In this review, we underline the current knowledge of protein aggregation and glycation along with the cross talk between the two, which may eventually lead to the development of cancer.

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