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First codon of a messenger RNA translated by a ribosome

The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and archaea and a N formylmethionine (fMet) in bacteria, mitochondria and plastids. The start codon is often preceded by a 5' untranslated region (5' UTR). In prokaryotes this includes the ribosome binding site.

In all three domains of life, the start codon is decoded by a special "initiation" transfer RNA different from the tRNAs used for elongation. There are important structural differences between an initiating tRNA and an elongating one, with distinguish features serving to satisfy the constraints of the translation system. In bacteria and organelles, an acceptor stem C1:A72 mismatch guide formylation, which directs recruitment by the 30S ribosome into the P site; so called "3GC" base pairs allow assembly into the 70S ribosome. In eukaryotes and archaea, the T stem prevents the elongation factors from binding, while eIF2 specifically recognizes the attached methionine and a A1:U72 basepair. In any case, the natural initiating tRNA only codes for methionine.

Alternate start codons (non AUG) are very rare in eukaryotic genomes: a wide range of mechanisms work to guarantee the relative fidelity of AUG initiation. However, naturally occurring non AUG start codons have been reported for some cellular mRNAs. Seven out of the nine possible single nucleotide substitutions at the AUG start codon of dihydrofolate reductase are functional as translation start sites in mammalian cells.

Bacteria do not generally have the wide range of translation factors monitoring start codon fidelity. GUG and UUG are the main, even "canonical", alternate start codons. and one or two others (e. g., an AUU and possibly a CUG). Well known coding regions that do not have AUG initiation codons are those of lacI (GUG) and lacA (UUG) in the E. coli lac operon. Two more recent studies have independently shown that 17 or more non AUG start codons may initiate translation in E. coli.

Mitochondrial genomes use alternate start codons more significantly (AUA and AUG in humans). Many such examples, with codons, systematic range, and citations, are given in the NCBI list of translation tables.

Archaea, which are prokaryotes with a translation machinery similar to but simpler than that of eukaryotes, allow initiation at UUG and GUG. However, it is believed that most translated uORFs only have a mild inhibitory effect on downstream translation because most uORF starts are leaky (i. e. don't initiate translation or because ribosomes terminating after translation of short ORFs are often capable of reinitiating). Mammalian cells can initiate translation with leucine using a specific leucyl tRNA that decodes the codon CUG. This mechanism is independent of eIF2. No secondary structure similar to that of an IRES is needed.

Engineered initiator tRNA (tRNA, changed from a MetY tRNA) have been used to initiate translation at the amber stop codon UAG in E. coli. Initiation with this tRNA not only inserts the traditional formylmethionine, but also formylglutamine, as glutamyl tRNA synthase also recognizes the new tRNA. (Recall from above that the bacterial translation initiation system does not specifically check for methionine, only the formyl modification).