Signaling eukaryotic initiation factor

Fig. 4.3 Mechanism of action of sirolimus. Sirolimus readily diffuses into the cytoplasm of the target cells where it binds to immunophilins (FK506-BP). The sirolimus-immunophilin complex does not inhibit calcineurin activity instead it binds to the mTOR. The sirolimus-immunophilin-mTOR complex stops the cell cycle progression from G1 to S phase. The targets of sirolimus include the eukaryotic initiation factor (eIF-4F), 70-kDa S6 protein kinase (p70S6 K) and several cyclin-dependent kinases (cdk). As a consequence, it blocks downstream signaling pathway initiated after activation of IL-2 receptors, resulting in blockage of T-cell proliferation (see Color Insert)...

CHEN, K.Y., LIU, A.Y.C., Biochemistry and function of hypusine formation on eukaryotic initiation factor 5A. Biol. Signals, 1997,6,105-109. 

Sharp JW, Ross-Inta CM, Hao S, Rudell JB, Gietzen DW. 2006. Co-localization of phosphorylated extracellular signal-related protein kinases 1/2 (ERK 1/2) and phosphorylated eukaryotic initiation factor 2a (eIF2a) in response to a threonine-devoid diet. J Comp Neurol 494 485-494. (Gives A-P dimension and location of APC cells that may be the primary sensory cells for lAA deficiency)... 

A list of key differences between prokaryotes and eukaryotes with respect to protein synthesis is shown in Table 9-1. These include the existence of multiple eukaryotic initiation factors that facilitate the assembly of the riboso-mal protein synthetic machinery, whereas there are only three for prokaryotes. An initiation site on bacterial mRNA consists of the AUG initiation codon preceded with a gap of approximately 10 bases by the Shine-Dalgamo polypurine hexamer, whereas the 5 Cap (a 7-methylguanylate residue in a 5 —>5 triphosphate linkage) acts as an initiation signal in eukaryotes. In prokaryotes, the first or A-terminal amino acid is a formyl-methionine (fMet), but in eukaryotes it is usually a simple methionine. Additionally, the size and nature of the prokaryotic ribosomes are quite different from the eukaryotic ribosomes. 

There are four main canonical response pathways to manage unfolded proteins via unfolded protein response (UPR) signaling and HSP. PKR-related ER kinase (PERK) is one of receptors to detect ER stress at the ER lumen, which normally binds with BIP (GRP78) (Samali and 2010). When unfolded protein binds to BIP and dissociates from BIP/PERK complex, PERK becomes active and phosphorylates eukaryotic initiation factor 2 initiation factor 2a (eIF2) (Samali etal. 2010). Phosphory-... 

High concentrations of hemin inhibit the transport of ALA synthase into the mitochondria, where one of the substrates, succinyl-CoA, is formed. Thus, heme synthesis is inhibited until enough globin is made to react with any heme already formed. Low concentrations, or the absence, of hemin is the signal that globin is not needed this protein (and, therefore, globin) synthesis is inhibited. In the absence of hemin, a protein kinase is activated this phosphorylates an initiation factor of (eukaryotic) protein synthesis, eIF-2, which then inhibits polypeptide chain initiation (Chap. 17) and hence inhibits globin synthesis. 

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