Principles of Biochemistry Volume 3 - A. Lehninger 1985

Molecular mechanisms of genetic information transfer
Protein synthesis and its regulation
The initiating amino acid in prokaryotes is N-formylmethionine, and in eukaryotes, methionine

In E. coli and all other prokaryotes, the initial N-terminal amino acid residue is always N-formylmethionine (Fig. 29-10). It enters the METABOLISM/35.html">Protein Biosynthesis process as N-formylmethionyl-tRNA (designated as fMet-tRNA^fMet), which is formed through two consecutive reactions. First, Methionine is attached by methionyl-tRNA synthetase to a specialized initiating methionine tRNA, tRNA^fMet:

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In the second reaction, the formyl group is transferred by a specific transformylase from the donor N-formyltetrahydrofolate (Section 10.10) to the amino group of the methionine residue:

Fig. 29-10. N-formylmethionine as the initiating amino acid in all prokaryotes. The N-formyl group is shown in red.

The transformylase is unable to formylate free methionine. There are two types of tRNA specific for methionine: tRNA^Met and tRNA^fMet. Both of these tRNAs can accept methionine in the activation reaction, but methionine can acquire a formyl group and serve as the initiating amino acid only when attached to tRNA^fMet. The other tRNA, Met-tRNA^Met, is used to insert methionine into internal positions of the polypeptide chain. Blocking the amino group of methionine with an N-formyl residue prevents this amino acid from being incorporated into internal sites of the chain, while simultaneously allowing fMet-tRNA^fMet to bind to a specific initiation site on the ribosome where neither Met-tRNA^Met nor any other aminoacyl-tRNA can bind.

As for Eukaryotic Cells, all Polypeptides synthesized by their extra-mitochondrial Ribosomes begin with a methionine residue delivered by a special initiating methionyl-tRNA. However, polypeptides synthesized in the Cell/35.html">Mitochondria and Chloroplasts of eukaryotic cells, much like those in Bacteria, begin with N-formylmethionine. This and other striking similarities between the protein-synthesizing machinery of mitochondria and chloroplasts on the one hand, and bacteria on the other, strongly support the view (Sections 2.8 and 17.18) that mitochondria and chloroplasts evolved from bacteria during the Cytology/cytology/16.html">Early stages of Introduction/5.html">Eukaryotic Cell evolution. It should be noted, however, that in several other respects, the Transcription and Translation mechanisms of bacteria and mitochondria show significant differences.

One puzzle still remains unanswered. Since there is only a single known codon for methionine, namely (5')AUG(3'), the question arises: how is this single codon used to encode both the initial N-formylmethionine residue (or methionine in eukaryotes) and the methionine residues destined for internal positions of polypeptide chains? The answer to this question will be provided later, after we examine the initiation phase of Protein Synthesis; but first, we must examine The Structure of ribosomes.