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Glutamate production and Ionotropic Glutamate Receptors

presented by:Dr. Dariush Ghulami

2015university of Tehran, Iran

2 1908, Japanese chemist Kikunae Ikeda

in 1909 the first monosodium glutamate was produced commercially

3Amino Acids (2000-2010) – Global Market Analysis (Historic, Current & Future) in US$ Billion

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9Global market amino acids, 2004

Global market amino acids, 2014Food industry: 65%Feed Additives: 30%Pharmaceutical: 5%

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Commercial production of MSG is the largest and biggest industries world over.

Commercial Production:

Glutamic acid > lysine > methionine > threonine > Aspartic acid

11Methods of Commercial Production of Amino Acids

extraction from natural sources,

chemical synthesis,

fermentation,

enzymatic catalysis

12Chemical Synthesis

The advantage and disadvantage of a chemical synthesis

13Glutamic Acid by Chemical Synthesis

Resolution of Racemic Glutamic Acid

14Fermentation Methods

Have been developed only for the preparation of (S )-lysine and (S )-glutamic acid

The carbon sources for these syntheses are cane or beet molasses, or a starch hydrolysate.

Ammonia is the source of nitrogen,

oxygen is provided by passing compressed air into the fermenting mixture.

15Metabolic pathway

16Important applications of glutamate

Amino acid fertilizer production

Reduce high blood pressure

Amino Acids in Cosmetology

Amino Acids and Environment

Amino Acid Supplements

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Glutamate as a CNS neurotransmitter

18Glutamate

Neurotransmitter at 75-80% of CNS synapses

Synthesized within the brain from Glucose (via KREBS cycle/α-ketoglutarate)

Glutamine (from glial cells)

Actions terminated by uptake through excitatory amino acid transporters (EAATs) in neurons and astrocytes

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NH2 – CH – CH2 – CH2 - COOH

COOH

Glutamate Synthesis

Glutamate

α-ketoglutarate

Glutamine (from glia)

transaminases

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Glutamate Receptor Subtypes

22Ionotropic glutamate receptors

23Ionotropic glutamate receptors: ligand gated channels

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Pharmacology of NMDA receptors

NMDA receptor25

NMDA receptor channel is blocked by phencyclidine (PCP)

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27Calcium (Ca++) permeability of AMPA vs NMDA receptors

RNA editing of GluR subunits

Properties of NMDA Receptor

Blocked at resting membrane potential (coincidence detector)

Requires glycine binding

Permeable to Ca++ as well as Na

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NMDA receptors in long term potentiation

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32NMDA receptors involvement in disease

seizure disorders Alzheimer's disease schizophrenia disease Brain ischemia

33schizophrenia disease

Necrosis Apoptosis

35 References:

1. Maria S., Elena K., and Herman W. 2005. D-Serine Is the Dominant Endogenous Coagonist for NMDA Receptor Neurotoxicity in Organotypic Hippocampal Slices. The Journal of Neuroscience.

2. Wim V., Wim R. and James R. 2000. AMPA Receptor Calcium Permeability, GluR2 Expression, and Selective Motoneuron Vulnerability. The Journal of Neuroscience.

3. Brian S. Meldrum. 2012. Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology. The Journal of Neuroscience.

4. Stephen F., Lonnie P., Chris J., Frank S., Katie M., Kevin K., Kasper B., Hongjie Y., Scott J., and Ray D. 2010. Glutamate Receptor Ion Channels: Structure, Regulation, and Function. Pharmacol. Rev.

5. Derek B. Ionotropic Glutamate Receptors & CNS Disorders. 2009. CNS Neurol Disord Drug Targets.

6. Christian L. and Robert C. 2012. NMDA Receptor -Dependent Long-Term Potentiation and Long-Term Depression (LTP /LTD). Cold Spring Harb Perspect Biol.

7. Susumu T. 2010. Regulation of Ionotropic Glutamate Receptors by Their Auxiliary Subunits. Physiology.

8. Addison A. 2012. The Monosodium Glutamate Story: The Commercial Production of MSG and Other Amino Acids

9. http://web.stanford.edu/group/hopes/cgi-bin/wordpress/2011/06/about-glutamate-toxicity/

10. K. Huthmacher., Wolfgang Leuchtenberger., K. Drauz,. 2005. Biotechnological production of amino acids and derivatives: current status and prospects, Appl Microbiol Biotechnol.

11. A. Burkovski, 2003. Ammonium assimilation and nitrogen control in Corynebacterium glutamicum and its relatives: An example for new regulatory mechanisms in actinomycetes. FEMS Microbiol. Rev.

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Thanks for your attention

37Strecker aminoacid synthesis

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43NMDA receptor uses glycine as a co-agonist

44APP and LTP in Alzheimer disease

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52Regulation Of AMPAR Trafficking

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http://en.wikipedia.org/wiki/Ca2%2B/calmodulin-dependent_protein_kinase

http://en.wikipedia.org/wiki/Phencyclidine

http://en.wikipedia.org/wiki/Long-term_potentiation

http://en.wikipedia.org/wiki/AMPA_receptor

http://en.wikipedia.org/wiki/NMDA_receptor