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Related Concept Videos

The Proteasome01:13

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
Hyperglycemia01:29

Hyperglycemia

Hyperglycemia is an abnormally high blood glucose level. It is diagnosed by fasting glucose ≥126 mg/dL, 2-hour oral glucose tolerance test (or OGTT) ≥200 mg/dL, random glucose ≥200 mg/dL with symptoms, or HbA1c ≥6.5%. However, HbA1c results may be unreliable in certain conditions, such as anemia or hemoglobinopathies, and the diagnosis should be confirmed unless classic symptoms are present. Postprandial hyperglycemia is typically considered significant when glucose levels exceed 180 mg/dL two...
Hypoglycemia and Glucagon01:15

Hypoglycemia and Glucagon

Without prolonged fasting, healthy individuals maintain blood glucose levels above 3.5 mM due to a well-adapted neuroendocrine counterregulatory system that effectively prevents acute hypoglycemia, a potentially life-threatening condition. The primary clinical scenarios for hypoglycemia encompass diabetes treatment, inappropriate production of endogenous insulin or insulin-like substances by tumors, and the use of glucose-lowering agents in non-diabetic individuals. Notably, hypoglycemia in the...
Proteoglycans01:05

Proteoglycans

Glycans, a class of complex heterogeneous molecules, can be covalently attached to proteins to form glycosylated proteins that regulate various physiological and pathological processes. Glycosylated proteins or glycoproteins comprise N-linked and O-linked oligosaccharides. O-glycosylation is the most common type of protein glycosylation. Here, glycans attach to the oxygen atom of the hydroxyl groups of Serine or Threonine residues. O-linked glycosylation occurs later in protein processing,...

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Mitochondrial Preparation from Microglia for Glycan Analysis
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Hyperglycemia impairs proteasome function by methylglyoxal.

Markus A Queisser1, Dachun Yao, Sven Geisler

  • 1School of Medicine, Institute of Biochemistry, Justus-Liebig-University, Giessen, Germany.

Diabetes
|December 17, 2009
PubMed
Summary
This summary is machine-generated.

High blood sugar in diabetes causes methylglyoxal (MGO) to damage the proteasome, a key protein recycler. This study shows MGO impairs proteasome function, linking hyperglycemia to cellular dysfunction.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Diabetic Complications

Background:

  • The ubiquitin-proteasome system (UPS) degrades damaged intracellular proteins.
  • Diabetes-induced hyperglycemia elevates methylglyoxal (MGO), a reactive dicarbonyl compound.
  • MGO modifies proteins, forming advanced glycation end products (AGEs) and altering cellular functions.

Purpose of the Study:

  • To investigate the impact of MGO-derived AGE formation on proteasome activity.
  • To examine proteasome modification and function in vitro and in vivo under diabetic conditions.

Main Methods:

  • Proteasome subunit modification analyzed by mass spectrometry, immunoprecipitation, and Western blots.
  • Proteasome activity assessed using fluorogenic substrates.
  • Experimental models included endothelial cells and various mouse models of diabetes and glyoxalase 1 knockdown.

Main Results:

  • In vitro MGO incubation led to adduct formation on 20S proteasome subunits.
  • Cultured cells showed reduced chymotrypsin-like proteasome activity and decreased 19S regulatory proteins.
  • Diabetic mice models exhibited reduced proteasome activity and increased MGO modification of the 20S-beta2 subunit.

Conclusions:

  • Hyperglycemia-induced MGO covalently modifies the 20S proteasome, decreasing its activity.
  • MGO modification reduces the polyubiquitin receptor 19S-S5a.
  • This establishes a novel link between hyperglycemia and impaired cellular function via proteasome dysfunction.