Why preferentially interacts with its codon AUG (Mellersh,

Why methionine as the initiating amino acid?

Production of methionine
in the supposed prebiotic chemistry conditions, present no particular
challenges (Kim and
Benner, 2018) . Methionine could be initially incorporated into the primordial
RNA-dependent world as a cofactor because, among others, of its involvement in
methyltransferase activities although spontaneous emergence of S-Adenosylmethionine
in the RNA world is very conceivable (Laurino and Tawfik, 2017) .
In addition, thiol-rich
peptides can play various catalytic roles (Vallée et al., 2017) and compounds with sulfur and thioesters must have played a crucial role in
the origin of amino acid activation and peptide bond synthesis (Jakubowski, 2016) . Furthermore, methionine preferentially interacts
with its codon AUG (Mellersh,
1993) . Therefore,
several studies, not all mentioned here, suggest that methionine and its thiolated
precursor and derivative
molecules would have rapidly interacted with RNAs and play critical roles in
the RNA world to the RNA/protein world transition.

On the other hand,
if one extrapolates data from current biological systems to proto-cell world,
various data suggest that it should be very advantageous to initiate the
synthesis of proteins with a methionine. For many proteins, the identity of
the first residue that remains after removal of the NH2-terminal
methionine residue has a profound influence on half-life. This is called the N-end rule. Even if it has
differences according to the type of proteins and the organisms, methionine is
one of the few amino acids that can significantly increase the half-life of
proteins (Varshavsky, 1995) . In current organisms, the rapid removal
of initial methionine allows an increased protein turnover that is an adaptive
mechanism, but in the distant past, it could be very advantageous for the
proteins (or only peptides) to remain functional for very long periods and thus
to retain the initiating amino acid. This could also be correlated to the relatively
high biologic half-life of methionine. Moreover, the metabolic cost of methionine synthesis is
highest among the amino acids (Kaleta et al., 2013) ; so, initiating synthesis by this amino acid almost ensuring
that the risk of deficiencies in other amino acids and energy intermediaries
was low.

Already in the RNA
world, the interactions with methionine could have to be numerous, moreover,
the advantage that would be obtained by the integration of this amino acid as
the first residue during the synthesis of the proteins is such that a codon
start coding for this amino acid (or a modified version as N-formylmethionine) might
have appeared very early in the course of evolution. In prebiotic conditions,
selection largely depended on the stability of the molecules. The cloverleaf
tRNAs and the rRNAs (constituting the proto-PTC and moreover being able to
derive from tRNA fusion) are very stable molecules (Megel et al.,
2015) . A mRNA in the form of ss-tRNA or a combination of several
of these last molecules would have been weakly fragile. In the supposedly conditions
of the prebiotic world, methionine could be protected from degradation by, in
part, interacting with the RNA, and under standard conditions of life, it
proved to be a relatively stable molecule and which moreover can stabilize the
proteins when it is the first incorporated residue and also the second. The
origin of codons of initiation attributed to methionine is thus very old and their presences at the
first stages of the RNA/protein world and in some proto-tRNAs can not be

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