Polypeptide chain initiation eukaryotes

Goss, D. J., Parkhurst, L. J., Mehta, H. B., Woodley, C. L., and Wahba, A.J. (1984). Studies on the role of eukaryotic nucleotide exchange factor in polypeptide chain initiation. 

For most polypeptide chains initiation begins with one of the three initiation codons, most commonly the methionine codon AUG. When properly placed in an mRNA chain, GUG may also serve as a bacterial initiation codon. In such cases, it codes for methionine rather than for valine. Occasionally UUG, AUU, ACG, and perhaps other codons can initiate translation 288/289 This is less frequent in eukaryotes than in bacteria. The sequence of bases preceding the initiation codon must also be important for recognition of the "start" signal. 

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. 

Siekierka, J., Mauser, L., and Ochoa, S., 1982, Mechanism of polypeptide chain initiation in eukaryotes and its control by phosphorylation of the a subunit of initiation factor 2, Proc. Natl. Acad. Sci. USA 79 2537. 

B. Datta, M.K. Ray, D. Chakrabarti, D.E. Wylie and N.K. Gupta, J. Biol Chem., 1989, 264, 20620-20624, Glycosylation of eukaryotic peptide chain initiation factor 2 (eIF-2)-associated 67-kDa polypeptide (p ) and its possible role in the inhibition of elF-2 kinase-catalyzed phosphorylation of the eIF-2 a-subunit. 

The pathway of protein synthesis translates the three-letter alphabet of nucleotide sequences on mRNA into the twenty-letter alphabet of amino acids that constitute proteins. The mRNA is translated from its 5 -end to its 3 -end, producing a protein synthesized from its amino-terminal end to its carboxyl-terminal end. Prokaryotic mRNAs often have several coding regions, that is, they are polycistronic (see p. 420). Each coding region has its own initiation codon and produces a separate species of polypeptide. In contrast, each eukaryotic mRNA codes for only one polypeptide chain, that is, it is monocistronic. The process of translation is divided into three separate steps initiation, elongation, and termination. The polypeptide chains produced may be modified by posttranslational modification. Eukaryotic protein synthesis resembles that of prokaryotes in most details. [Note Individual differences are mentioned in the text.]... 

In E. coli polypeptide chains are always initiated with the amino acid N-formylmethionine. Some bacteria can apparently live without the ability to formylate methionyl-tRNA,290 but most eubacteria as well as mitochondria and chloroplasts use formyl-methionine for initiation. In a few cases, both among bacteria and eukaryotes, initiation can sometimes occur with other amino acids 291 The first step is the alignment of the proper initiation codon correctly on... 

The molecular mechanism of translation in eukaryotes is very similar to that in bacteria. The activation of amino acids and attachment to tRNAs and the steps of initiation, elongation, and termination of polypeptide chains are essentially the same in overall terms. The small and large ribosomal subunits of bacteria and eukaryotes are equivalent with respect to their roles in initiation and elongation of chains. 

The codon AUG has two functions. It corresponds to the amino acid methionine when AUG occurs within a coding sequence in the mRNA, i.e., within a polypeptide chain. It also serves as a signal to initiate polypeptide synthesis—with methionine for eukaryotic cells but with N-formylmethionine for prokaryotic cells. How the protein-synthesizing system distinguishes an initiating AUG from an internal AUG is discussed below. The codon GUG also has both functions, but it is only rarely used in initiation. Once initiation has occurred at an AUG codon, the reading frame is established and the subsequent codons are translated in order. 

Eukaryotic initiator tRNA molecules differ from the prokaryotic initiator molecule in several ways. The most striking difference is that whereas eukaryotic organisms produce both a normal tRNA and an initiator tRNA, which is also charged with methionine, the methionine does not undergo formylation. In eukaryotes, the first amino acid in a growing polypeptide chain is Met and not fMet. The codon for both kinds of tRNA molecules in eukaryotes is AUG, just as for prokaryotes. 

Synthesis of all polypeptide chains In prokaryotic and eukaryotic cells begins with the amino acid methionine. In most mRNAs, the start (initiator) codon specifying this amino-terminal methionine is AUG. In a few bacterial mRNAs, GUG is used as the initiator codon, and CUG occasionally is used as an initiator codon for methionine in eukaryotes. The three codons UAA, UGA, and UAG do not specify amino acids but constitute stop (termination) codons that mark the carboxyl terminus of polypeptide chains in almost all cells. The sequence of codons that runs from a specific... 

The previous sections have introduced the major participants in protein synthesis—mRNA, aminoacylated tRNAs, and ribosomes containing large and small rRNAs. We now take a detailed look at how these components are brought together to carry out the biochemical events leading to formation of polypeptide chains on ribosomes. Similar to transcription, the complex process of translation can be divided into three stages—initiation, elongation, and termination—which we consider in order. We focus our description on translation in eukaryotic cells, but the mechanism of translation is fundamentally the same in all cells. 

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