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{{short description|First codon of a messenger RNA translated by a ribosome}}
[[File:Homo sapiens-mtDNA~NC 012920-ATP8+ATP6 Overlap.svg|thumb|right|400px|Start codon (blue circle) of the human mitochondrial DNA ''MT-ATP6'' gene. For each nucleotide triplet (square brackets), the corresponding amino acid is given (one-letter code), either in the +1 [[reading frame]] for ''MT-ATP8'' (in red) or in the +3 frame for ''MT-ATP6'' (in blue). In this genomic region, the two genes [[Overlapping gene|overlap]].]]
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 [[eukaryote]]s and [[archaea]] and a [[N-Formylmethionine|''N''-formylmethionine]] (fMet) in bacteria, [[mitochondria]] and [[plastid]]s.

The start codon is often preceded by a 5' untranslated region ([[5' UTR]]). In [[prokaryotes]] this includes the [[ribosome binding site]].

== Decoding ==
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.<ref name=p28204695>{{cite journal |last1=Shetty |first1=S |last2=Shah |first2=RA |last3=Chembazhi |first3=UV |last4=Sah |first4=S |last5=Varshney |first5=U |title=Two highly conserved features of bacterial initiator tRNAs license them to pass through distinct checkpoints in translation initiation. |journal=Nucleic Acids Research |date=28 February 2017 |volume=45 |issue=4 |pages=2040–2050 |doi=10.1093/nar/gkw854 |pmid=28204695 |pmc=5389676}}</ref> In eukaryotes and archaea, the T stem prevents the [[elongation factor]]s from binding, while [[eIF2]] specifically recognizes the attached methionine and a A1:U72 basepair.<ref>{{cite journal |last1=Kolitz |first1=SE |last2=Lorsch |first2=JR |title=Eukaryotic initiator tRNA: finely tuned and ready for action. |journal=FEBS Letters |date=21 January 2010 |volume=584 |issue=2 |pages=396–404 |doi=10.1016/j.febslet.2009.11.047 |pmid=19925799 |pmc=2795131}}</ref>

In any case, the natural initiating tRNA only codes for methionine.<ref name="Lobanov 2010"/> 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 ==
Alternative start codons are different from the standard AUG codon and are found in both [[prokaryotes]] (bacteria and archaea) and [[eukaryotes]]. 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.<ref name="Lobanov 2010">{{Cite journal |pmid = 20446809 |pmc = 3311535 |year = 2010 |last1 = Lobanov |first1 = A. V. |title = Dual functions of codons in the genetic code |journal = Critical Reviews in Biochemistry and Molecular Biology |volume = 45 |issue = 4 |pages = 257–65 |last2 = Turanov |first2 = A. A. |last3 = Hatfield |first3 = D. L. |last4 = Gladyshev |first4 = V. N. |doi = 10.3109/10409231003786094 }}</ref>

=== Eukaryotes ===
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.<ref name="pmid26779403a">{{cite journal |last1=Asano |first1=K |title=Why is start codon selection so precise in eukaryotes? |journal=Translation (Austin, Tex.) |date=2014 |volume=2 |issue=1 |pages=e28387 |doi=10.4161/trla.28387 |pmid=26779403|pmc=4705826 }}</ref> However, naturally occurring non-AUG start codons have been reported for some cellular mRNAs.<ref name="Ivanov2011">{{Cite journal |last1 = Ivanov |first1 = I. P. |last2 = Firth |first2 = A. E. |last3 = Michel |first3 = A. M. |last4 = Atkins |first4 = J. F. |last5 = Baranov |first5 = P. V. |title = Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences |doi = 10.1093/nar/gkr007 |journal = Nucleic Acids Research |volume = 39 |issue = 10 |pages = 4220–4234 |year = 2011 |pmid = 21266472 |pmc =3105428 |name-list-style = vanc }}</ref> 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.<ref name="Peabody1989">{{Cite journal
 |pmid = 2538469 |year = 1989 |last1 = Peabody |first1 = D. S. |title = Translation initiation at non-AUG triplets in mammalian cells |journal = The Journal of Biological Chemistry |volume = 264 |issue = 9 |pages = 5031–5|doi = 10.1016/S0021-9258(18)83694-8 |doi-access = free }}</ref>

=== Bacteria ===
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.<ref name="pmid26779403a" /> GUG in particular is important to controlling the replication of plasmids.<ref name="pmid26779403a" />

''[[E. coli]]'' uses 83% AUG (3542/4284), 14% (612) GUG, 3% (103) UUG<ref>{{Cite journal|last7 = Collado-Vides |first9 = C. K. |first8 = J. D. |first7 = J.|last10 = Mayhew|title = The Complete Genome Sequence of Escherichia coli K-12 |first17 = Y.|last17 = Shao |first16 = B.|last16 = Mau |first15 = D. J.|last15 = Rose |first14 = M. A.|last14 = Goeden |first13 = H. A.|last13 = Kirkpatrick |first12 = N. W.|last12 = Davis |first11 = J.|journal = Science|last11 = Gregor|doi = 10.1126/science.277.5331.1453 |first10 = G. F.|pmid = 9278503|year = 1997|pages = 1453–1462|volume = 277|issue = 5331 |first6 = M. |first2 = G.|last9 = Rode |first3 = C. A.|last2 = Plunkett g|last4 = Perna |first1 = F. R.|last6 = Riley|last5 = Burland|last1 = Blattner|last8 = Glasner |first5 = V. |first4 = N. T.|last3 = Bloch |doi-access = free}}</ref> and one or two others (e.g., an AUU and possibly a CUG).<ref name="Sequence of a 1.26-kb DNA fragment containing the structural gene for E.coli initiation factor IF3: presence of an AUU initiator codon">{{Cite journal |last1 = Sacerdot |first1 = C. |last2 = Fayat |first2 = G. |last3 = Dessen |first3 = P. |last4 = Springer |first4 = M. |last5 = Plumbridge |first5 = J. A. |last6 = Grunberg-Manago |first6 = M. |last7 = Blanquet |first7 = S. |title = Sequence of a 1.26-kb DNA fragment containing the structural gene for E.coli initiation factor IF3: Presence of an AUU initiator codon |journal = The EMBO Journal |volume = 1 |issue = 3 |pages = 311–315 |year = 1982 |pmid = 6325158 |pmc = 553041 |doi = 10.1002/j.1460-2075.1982.tb01166.x }}</ref><ref name="The Escherichia coli heat shock gene htpY: mutational analysis, cloning, sequencing, and transcriptional regulation.">{{Cite journal |last1 = Missiakas |first1 = D. |last2 = Georgopoulos |first2 = C. |last3 = Raina |first3 = S. |title = The Escherichia coli heat shock gene htpY: Mutational analysis, cloning, sequencing, and transcriptional regulation |journal = Journal of Bacteriology |volume = 175 |issue = 9 |pages = 2613–2624 |year = 1993 |pmid = 8478327 |pmc = 204563 |doi = 10.1128/jb.175.9.2613-2624.1993 }}</ref>

Well-known coding regions that do not have AUG initiation codons are those of ''lacI'' (GUG)<ref>[https://www.ncbi.nlm.nih.gov/nuccore/146575?itemID=6&report=gbwithparts#feature_146575 E.coli lactose operon with lacI, lacZ, lacY and lacA genes GenBank: J01636.1]</ref><ref name="Sequence of the lacI gene.">{{Cite journal |doi = 10.1038/274765a0 |last1 = Farabaugh |first1 = P. J. |title = Sequence of the lacI gene |journal = Nature |volume = 274 |issue = 5673 |pages = 765–769 |year = 1978 |pmid = 355891 |bibcode = 1978Natur.274..765F |s2cid = 4208767 }}</ref> and ''lacA'' (UUG)<ref>[https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=146575&itemID=4&view=gbwithparts#feature_146575 NCBI Sequence Viewer v2.0<!-- Bot generated title -->]</ref> 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''.<ref>{{Cite journal |last1=Hecht |first1=Ariel |last2=Glasgow |first2=Jeff |last3=Jaschke |first3=Paul R. |last4=Bawazer |first4=Lukmaan A. |last5=Munson |first5=Matthew S.|author6-link=Jennifer Cochran |last6=Cochran |first6=Jennifer R. |last7=Endy |first7=Drew |last8=Salit |first8=Marc |title=Measurements of translation initiation from all 64 codons in E. coli |journal=Nucleic Acids Research |volume=45 |issue=7 |pages=3615–3626 |language=en |doi=10.1093/nar/gkx070 |pmid=28334756 |pmc=5397182 |year=2017}}</ref><ref>{{Cite journal |last1=Firnberg |first1=Elad |last2=Labonte |first2=Jason |last3=Gray |first3=Jeffrey |last4=Ostermeir |first4=Marc A. |title=A comprehensive, high-resolution map of a gene's fitness landscape |journal=Molecular Biology and Evolution |volume=31 |issue=6 |pages=1581–1592 |language=en |doi=10.1093/molbev/msu081 |pmid=24567513 |year=2014 |pmc=4032126}}</ref>

=== Mitochondria ===
[[Mitochondrial genome]]s use alternate start codons more significantly (AUA and AUG in humans).<ref name="WatanabeSuzuki2001">{{cite book|last1=Watanabe|first1=Kimitsuna|title=Encyclopedia of Life Sciences|last2=Suzuki|first2=Tsutomu|chapter=Genetic Code and its Variants|year=2001|doi=10.1038/npg.els.0000810|isbn=978-0470015902}}</ref> Many such examples, with codons, systematic range, and citations, are given in the NCBI [[List of genetic codes|list of translation tables]].<ref>{{cite web |last1=Elzanowski |first1=Andrzej |last2=Ostell |first2=Jim |title=The Genetic Codes |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Utils/wprintgc.cgi |website=NCBI |access-date=29 March 2019}}</ref>

=== Archaea ===
Archaea, which are prokaryotes with a translation machinery similar to but simpler than that of eukaryotes, allow initiation at UUG and GUG.<ref name="pmid26779403a" />

== Upstream start codons ==
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 human [[Messenger RNA|mRNAs]] have at least one AUG codon upstream (uAUG) of their annotated translation initiation starts (TIS) (58% in the current versions of the human [[RefSeq]] sequence). Their potential use as TISs could result in translation of so-called upstream [[Open reading frame|Open 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, [[MIER1|MIEF1]], [[MKKS]], and SLC35A4.<ref name=":0">{{Cite journal |last1=Andreev |first1=Dmitry E. |last2=Loughran |first2=Gary |last3=Fedorova |first3=Alla D. |last4=Mikhaylova |first4=Maria S. |last5=Shatsky |first5=Ivan N. |last6=Baranov |first6=Pavel V. |date=2022-05-09 |title=Non-AUG translation initiation in mammals |journal=Genome Biology |volume=23 |issue=1 |pages=111 |doi=10.1186/s13059-022-02674-2 |issn=1474-760X |pmc=9082881 |pmid=35534899 |doi-access=free }}</ref> 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).<ref name=":0" />

== Standard genetic code ==
{{Codon table|T=U}}

== Non-methionine start codons ==

=== Natural ===
Translation started by an [[internal ribosome entry site]] (IRES), which bypasses a number of regular eukaryotic initiation systems, can have a non-methinone start with GCU or CAA codons.<ref>{{cite journal |last1=RajBhandary |first1=Uttam L. |title=More surprises in translation: Initiation without the initiator tRNA |journal=Proceedings of the National Academy of Sciences |date=15 February 2000 |volume=97 |issue=4 |pages=1325–1327 |doi=10.1073/pnas.040579197|doi-access=free |pmid=10677458 |pmc=34295 |bibcode=2000PNAS...97.1325R }}</ref>

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. It proceeds by ribosomal scanning, and a [[Kozak consensus sequence|Kozak context]] enhances initiation efficiency.<ref>{{cite journal |title=Where to Start? Alternate Protein Translation Mechanism Creates Unanticipated Antigens |journal=PLOS Biology |date=26 October 2004 |volume=2 |issue=11 |pages=e397 |doi=10.1371/journal.pbio.0020397|doi-access=free |pmc=524256 }}</ref><ref name="Starck2012">{{Cite journal
 |pmid = 22745432 |year = 2012 |last1 = Starck |first1 = S. R. |title = Leucine-tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I |journal = Science |volume = 336 |issue = 6089 |pages = 1719–23 |last2 = Jiang |first2 = V |last3 = Pavon-Eternod |first3 = M |last4 = Prasad |first4 = S |last5 = McCarthy |first5 = B |last6 = Pan |first6 = T |last7 = Shastri |first7 = N |doi = 10.1126/science.1220270 |bibcode = 2012Sci...336.1719S|s2cid = 206540614 }}</ref><ref name="Dever2012">{{Cite journal |pmid = 22745408 |year = 2012 |last1 = Dever |first1 = T. E. |title = Molecular biology. A new start for protein synthesis |journal = Science |volume = 336 |issue = 6089 |pages = 1645–6 |doi = 10.1126/science.1224439 |s2cid = 44326947 |url = https://zenodo.org/record/1230920 }}</ref>

=== Engineered start codons ===
Engineered initiator tRNA (tRNA{{sup sub|fMet|CUA}}, changed from a MetY tRNA{{sup sub|fMet|CAU}}) have been used to initiate translation at the [[Amber codon|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.<ref>{{Cite journal |last1=Varshney |first1=U. |last2=RajBhandary |first2=U. L. |date=1990-02-01 |title=Initiation of protein synthesis from a termination codon |journal=Proceedings of the National Academy of Sciences |volume=87 |issue=4 |pages=1586–1590 |doi=10.1073/pnas.87.4.1586 |pmid=2406724 |pmc=53520 |issn=0027-8424 |bibcode=1990PNAS...87.1586V |doi-access=free }}</ref> (Recall from above that the bacterial translation initiation system does not specifically check for methionine, only the formyl modification).<ref name=p28204695/> 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 upstream [[Shine-Dalgarno sequence|Shine-Dalgarno sites]].<ref>{{Cite journal |last1=Vincent |first1=Russel M. |last2=Wright |first2=Bradley W. |last3=Jaschke |first3=Paul R. |date=2019-03-15 |title=Measuring Amber Initiator tRNA Orthogonality in a Genomically Recoded Organism |journal=ACS Synthetic Biology |volume=8 |issue=4 |pages=675–685 |language=en |doi=10.1021/acssynbio.9b00021 |pmid=30856316 |s2cid=75136654 |issn=2161-5063 |url=https://www.biorxiv.org/content/biorxiv/early/2019/01/18/524249.full.pdf }}</ref>

{{missing information|section|new progress mentioned in introduction of [[doi:10.3389/fchem.2021.772648]] (Ngo et al., 2013 might be worth a special mention)|date=December 2023}}

== See also ==
* [[Central dogma of molecular biology]]
* [[Codon]]
* [[Messenger RNA]]
* [[Missense mRNA]]
* [[Stop codon]]
* [[Transfer RNA]]
* [[translation (biology)|Translation]]

== References ==
{{reflist|30em}}

== External links ==
* The Genetic Codes. Compiled by Andrzej (Anjay) Elzanowski and Jim Ostell, National Center for Biotechnology Information (NCBI), Bethesda, Maryland, US [https://www.ncbi.nlm.nih.gov/Taxonomy/Utils/wprintgc.cgi]

{{GeneticTranslation}}

[[Category:DNA]]
[[Category:Molecular genetics]]