#3 NS 160 Lec AA Sensing & Protein Synthesis

#3 NS 160 Lec AA Sensing & Protein Synthesis - AA...

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Synthesis of protein is stimulated after a meal Mixed meals stimulate skeletal muscle prot. synthesis in fasted animals, however consumption of a protein deficient meal does not elicit this response AA SENSING and Protein Synthesis 1
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Postprandial increases in prot. synthesis cannot be explained by increased AA concentration because: AA SENSING tRNAs are fully charged with their respective AA at the intracellular AA conc. found in fasting conditions Translational initiation but not elongation is accelerated by increased AA levels Removal of the essential AA leucine prevents the effects of AAs on prot. synthesis Norleucine, which cannot be incorporated into proteins, also stimulates protein synthesis and Protein Synthesis 2
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AA SENSING and Protein Synthesis Lodish et al., Molecular cell biology, online edition 3
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Regulation of this complex pathway by AAs occurs primarily (leucine) through the modulation of two steps during the initiation phase of translation AA SENSING and Protein Synthesis Cell signaling technology Inc. 4
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Eukaryotic Initiation Factor 2 (eIF2) is a heterotrimeric GTP binding prot. that mediates the binding of methionyl-tRNAi to the 40 S ribosomal subunit to form the 43 S pre-initiation complex. This complex interacts with the cap binding complex. Following Met-tRNAi engagement with the start codon eIF2 GTP is hydrolyzed to GDP in a process involving the GTPase activator protein eIF5. The guanine nucleotide exchange factor eIF2B recycles eIF2-GDP back to -GTP. Phosphorylation of eIF2 inhibits GEF activity. An eIF2 kinase (GCN2, general control nonderepressible 2) is activated by stress and lack of one or more essential amino acids. AA SENSING and Protein Synthesis Stipanuk, Nutrition Reviews, 2007 5
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eIF4F (consisting of eIF4A, E, and G) binds to the m 7 GTP cap structure of mRNAs and unwinds secondary structure in the 5’UTR of the mRNA following eIF4B binding. Phosphorylation of eIF4B by S6 kinase stimulates its activity. The allows for the recruitment of the 43S complex and translational initiation. eIF4E availability is regulated through modulation of the association with eIF4E binding protein (4E-BP). Phosphorylation of 4E-BP causes dissociation of the complex and increases the available eIF4E. Leucine stimulates the activity of the 4E-BP kinase mTOR (mammalian target of rapamycin) thus enhancing translation. mTOR also activates S6K and is a critical regulator of growth. AA SENSING
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#3 NS 160 Lec AA Sensing & Protein Synthesis - AA...

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