Methylglyoxal Diseases

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Methylglyoxal Diseases

• March 24/09
• Ishtiaque Choudhury (ishtiaque.choudhury_at_utoronto.
  ca)
• Jaspreet Chahal (jaspreet.chahal_at_utoronto.ca)
• Sachi Sharma (sachi.sharma_at_utoronto.ca)
• Mihir Patel (mr.patel_at_utoronto.ca)

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Presentation Outline

• Background Information
• - What is Methylglyoxal
• - How is it generated and its MOA in the body
• Types of Methylglyoxal diseases
• - Methylglyoxal and its role in Diabetes
• Bodys Defense Mechanisms
• Treatment Options
• Methylglyoxals Potential use in Cancer Treatment
• Class Question

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So, what exactly IS Methylglyoxal?

• Methylglyoxal has two carbonyl groups, making it
  a dicarbonyl compound
• Both an aldehyde and a ketone
• Highly cytotoxic

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and how is it generated?

• Methylglyoxal is formed as a side-product of
  several metabolic pathways, it is an
  intermediate of
• Threonine catabolism via Amine Oxide
• Acetone metabolism via CYP2E1
• Glycolysis via Methylglyoxal Synthase

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What can it do?

• The deleterious effects of methylglyoxal includes
  increasing mitochondrial ROS arising from high
  cellular glucose levels
• Furthermore, methylglyoxal can deplete
  glutathione reserves, thus making the cell more
  vulnerable to oxidative damage
• Methylglyoxal can also cause direct inhibition of
  proteins e.g. Na/K/ATPase pump
• Methylglyoxal may also interact with DNA

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Types of Methylglyoxal diseases

• Elevated methylglyoxal levels may lead to these
  disease states
• Atherosclerosis
• Asthma
• Arthritis
• Alzheimer's disease
• Diabetes
• Nephropathy
• Neuropathy
• Retinopathy

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Methylglyoxal and Diabetes

• In hyperglycemic conditions, intracellular
  alpha-ketoaldehydes, such as methylglyoxal, are
  an essential source of intracellular advanced
  glycation endproducts, or AGEs.
• The abnormal accumulation of methylglyoxal is
  related to the development of diabetic
  complications in various tissues and organs

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Methylglyoxal and Diabetes

• Studies have suggested that an increase in
  intracellular methylglyoxal AGEs inhibits
  insulin signalling
• This inhibition can induce insulin resistance at
  the level of metabolic responses in skeletal
  muscle

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How do we get rid of it?

• The bodys methylglyoxal-detoxification mechanism
  is known as the glyoxalase system
• Glyoxalase I II, and catalytic levels of GSH
• Methylglyoxal reacts with glutathione forming a
  hemithioacetal. This is converted into
  S-D-lactoyl-glutathione by glyoxalase I and then
  further metabolised into D-lactate by glyoxalase
  II

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Figure 2 Glyoxalase pathway
hemithioacetal
S-D-lactoyl-glutathione
Biochemical Society Transactions
www.biochemsoctrans.org Biochem. Soc.
Trans. (2003) 31, 1409-1412
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Are there any treatment options?

• There are multiple theoretical pharmacological
  interventions.
• Antidiabetic drugs metformin aminoguanidine
  inhibit MG formation
• Pyridoxamine vitamin B6 traps ROS
• Dietary modifications

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Is Methylglyoxal useful at all?

• Researchers are investigating methylglyoxal use
  during cancer therapy
• Methylglyoxal is capable of inducing apoptosis in
  prostatic cancer PC-3 cells, due primarily to a
  blocking of the cell cycle progression (G1
  arrest) and glycolytic pathway
• Therefore, MG could be a potent apoptosis
  inducer, which may have a potential for prostate
  cancer treatment

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Summary

• Methylglyoxal has two carbonyl groups, making it
  a dicarbonyl compound and it is highly cytotoxic
• It is formed as a side-product of several
  metabolic pathways
• Threonine catabolism via Amine Oxide
• Acetone metabolism via CYP2E1
• Glycolysis via Methylglyoxal Synthase
• It is involved in the formation of Advanced
  Glycation End Products (AGEs) and is one of the
  more significant AGEs-forming agents
• These AGEs are implicated in the progression of
  disease states such as diabetes
• The body removes Methyglyoxal by the Glyoxalase
  detoxification system
• There are multiple theoretical pharmacological
  interventions.
• - Antidiabetic drugs metformin,aminoguanidine
  trap MG.
• - Pyridoxamine, a vitamin B6, traps MG
• - Addition of anti-oxidants to enhance
  anti-oxidant defense
• - Dietary modifications

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References

• Inoue Y and Kimura A. 1995. Methylglyoxal and
  regulation of its metabolism in microorganisms.
  Advanced Microbiological Physiology 37177227.
• Kalapos M. 2008. The tandem of free radicals and
  methylglyoxal. Chemico-Biological Interactions
  171(3)251-271.
• Ray S and Ray M. 1983. Formation of methylglyoxal
  from aminoacetone by amine oxidase from goat
  plasma. Journal of Biological Chemistry
  258(6)34613462.
• Thornalley PJ. 2003. Glyoxalase I--structure,
  function and a critical role in the enzymatic
  defence against glycation. Biochemical Society
  Transcations 31(6)13431348.

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Who wants to be a biochemist?

• Which of these enzymes is NOT involved in
  methylglyoxal synthesis?
• A) Amine Oxidase
• B) Glyoxylase II
• C) CYP2E1
• D) Methylglyoxal Synthase