Thestart codon is the firstcodon of amessenger RNA (mRNA) transcript translated by aribosome. The start codon always codes formethionine ineukaryotes andarchaea and aN-formylmethionine(fMet) in bacteria,mitochondria andplastids.

The start codon is often preceded by a 5' untranslated region (5' UTR). Inprokaryotes this includes theribosome 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.^[1] In eukaryotes and archaea, the T stem prevents theelongation factors from binding, whileeIF2 specifically recognizes the attached methionine and a A1:U72 basepair.^[2]

In any case, the natural initiating tRNA only codes for methionine.^[3] Knowledge of the key recognizing features has allowed researchers to construct alternative initiating tRNAs that code for different amino acids; see below.

Alternative start codons are different from the standard AUG codon and are found in bothprokaryotes (bacteria and archaea) andeukaryotes. Alternate start codons are still translated as Met when they are at the start of a protein (even if the codon encodes a different amino acid otherwise). This is because a separate tRNA is used for initiation.^[3]

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.^[4] However, naturally occurring non-AUG start codons have been reported for some cellular mRNAs.^[5] Seven out of the nine possible single-nucleotide substitutions at the AUG start codon ofdihydrofolate reductase are functional as translation start sites in mammalian cells.^[6]

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.^[4] GUG in particular is important to controlling the replication of plasmids.^[4]

E. coli uses 83% AUG (3542/4284), 14% (612) GUG, 3% (103) UUG^[7] and one or two others (e.g., an AUU and possibly a CUG).^[8][9]

Well-known coding regions that do not have AUG initiation codons are those oflacI (GUG)^[10][11] andlacA (UUG)^[12] in theE. colilac operon. Two more recent studies have independently shown that 17 or more non-AUG start codons may initiate translation inE. coli.^[13][14]

Mitochondrial genomes use alternate start codons more significantly (AUA and AUG in humans).^[15] Many such examples, with codons, systematic range, and citations, are given in the NCBIlist of translation tables.^[16]

Archaea, which are prokaryotes with a translation machinery similar to but simpler than that of eukaryotes, allow initiation at UUG and GUG.^[4]

These are "alternative" start codons in the sense that they are upstream of the regular start codons and thus could be used as alternative start codons. More than half of all humanmRNAs have at least one AUG codon upstream (uAUG) of their annotated translation initiation starts (TIS) (58% in the current versions of the humanRefSeq sequence). Their potential use as TISs could result in translation of so-called upstreamOpen Reading Frames (uORFs). uORF translation usually results in the synthesis of short polypeptides, some of which have been shown to be functional, e.g., in ASNSD1,MIEF1,MKKS, and SLC35A4.^[17] 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).^[17]

^A Possiblestart codons in NCBI table 1. AUG is most common.^[19] The two other start codons listed by table 1 (GUG and UUG) are rare in eukaryotes.^[20] Prokaryotes have less strigent start codon requirements; they are described byNCBI table 11.

^{B^^^} The historical basis for designating thestop codons as amber, ochre and opal is described in an autobiography by Sydney Brenner^[21] and in a historical article by Bob Edgar.^[22]

Translation started by aninternal ribosome entry site (IRES), which bypasses a number of regular eukaryotic initiation systems, can have a non-methinone start with GCU or CAA codons.^[23]

Mammalian cells can initiate translation withleucine 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. It proceeds by ribosomal scanning, and aKozak context enhances initiation efficiency.^[24][25][26]

Engineered initiator tRNA (tRNA^fMet
_CUA, changed from a MetY tRNA^fMet
_CAU) have been used to initiate translation at theamber stop codon UAG inE. coli. Initiation with this tRNA not only inserts the traditionalformylmethionine, but also formylglutamine, as glutamyl-tRNA synthase also recognizes the new tRNA.^[27] (Recall from above that the bacterial translation initiation system does not specifically check for methionine, only the formyl modification).^[1] One study has shown that the amber initiator tRNA does not initiate translation to any measurable degree from genomically-encoded UAG codons, only plasmid-borne reporters with strong upstreamShine-Dalgarno sites.^[28]

This sectionis missing information about new progress mentioned in introduction ofdoi:10.3389/fchem.2021.772648 (Ngo et al., 2013 might be worth a special mention). Please expand the section to include this information. Further details may exist on thetalk page.(December 2023)

• Central dogma of molecular biology
• Codon
• Messenger RNA
• Missense mRNA
• Stop codon
• Transfer RNA
• Translation

• The Genetic Codes. Compiled by Andrzej (Anjay) Elzanowski and Jim Ostell, National Center for Biotechnology Information (NCBI), Bethesda, Maryland, US[1]

• DNA
• Molecular genetics

• Articles with short description
• Short description is different from Wikidata
• Articles to be expanded from December 2023