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 most common start codon is AUG (i.e., ATG in the corresponding DNA sequence).

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 overlap.

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

Alternative start codonsEdit

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 transfer RNA (tRNA) is used for initiation.[1]


Alternate start codons (non-AUG) are very rare in eukaryotic genomes. However, naturally occurring non-AUG start codons have been reported for some cellular mRNAs.[2] 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.[3] In addition to the canonical Met-tRNA Met and AUG codon pathway, mammalian cells can initiate translation with leucine using a specific leucyl-tRNA that decodes the codon CUG.[4][5]

Candida albicans uses a CAG start codon.[6]


Prokaryotes use alternate start codons significantly, mainly GUG and UUG. These alternate start codons and the frequency of their use compared to eukaryotes has been studied and shown to refute the common ancestor theory.[7]

E. coli uses 83% AUG (3542/4284), 14% (612) GUG, 3% (103) UUG[8] and one or two others (e.g., an AUU and possibly a CUG).[9][10]

Well-known coding regions that do not have AUG initiation codons are those of lacI (GUG)[11][12] and lacA (UUG)[13] 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.[14][15]


Mitochondrial genomes use alternate start codons more significantly (AUA and AUG in humans).[7] Many such examples, with codons, systematic range, and citations, are given in the NCBI list of translation tables.[16]

Upstream start codonsEdit

These are "alternative" start codons in the sense that they upstream of the regular start codons and thus could be used as alternative start codons. More than half of all human 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 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]

Standard genetic codeEdit

Amino-acid biochemical properties Nonpolar Polar Basic Acidic Termination: stop codon
Standard genetic code
2nd base 3rd
U UUU (Phe/F) Phenylalanine UCU (Ser/S) Serine UAU (Tyr/Y) Tyrosine UGU (Cys/C) Cysteine U
UUA (Leu/L) Leucine UCA UAA Stop (Ochre)[B] UGA Stop (Opal)[B] A
UUG[A] UCG UAG Stop (Amber)[B] UGG (Trp/W) Tryptophan G
C CUU CCU (Pro/P) Proline CAU (His/H) Histidine CGU (Arg/R) Arginine U
CUA CCA CAA (Gln/Q) Glutamine CGA A
A AUU (Ile/I) Isoleucine ACU (Thr/T) Threonine AAU (Asn/N) Asparagine AGU (Ser/S) Serine U
AUA ACA AAA (Lys/K) Lysine AGA (Arg/R) Arginine A
AUG[A] (Met/M) Methionine ACG AAG AGG G
G GUU (Val/V) Valine GCU (Ala/A) Alanine GAU (Asp/D) Aspartic acid GGU (Gly/G) Glycine U
GUA GCA GAA (Glu/E) Glutamic acid GGA A
A The codon AUG both codes for methionine and serves as an initiation site: the first AUG in an mRNA's coding region is where translation into protein begins.[18] The other start codons listed by GenBank are rare in eukaryotes and generally codes for Met/fMet.[19]
B ^ ^ ^ The historical basis for designating the stop codons as amber, ochre and opal is described in an autobiography by Sydney Brenner[20] and in a historical article by Bob Edgar.[21]

Engineered start codonsEdit

Engineered initiator tRNAs (tRNAfMet2 with CUA anticodon) have been used to initiate translation at the amber stop codon UAG.[22] This type of engineered tRNA is called a nonsense suppressor tRNA because it suppresses the translation stop signal that normally occurs at UAG codons. 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 sites.[23]

See alsoEdit


  1. ^ Lobanov, A. V.; Turanov, A. A.; Hatfield, D. L.; Gladyshev, V. N. (2010). "Dual functions of codons in the genetic code". Critical Reviews in Biochemistry and Molecular Biology. 45 (4): 257–65. doi:10.3109/10409231003786094. PMC 3311535. PMID 20446809.
  2. ^ Ivanov IP, Firth AE, Michel AM, Atkins JF, Baranov PV (2011). "Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences". Nucleic Acids Research. 39 (10): 4220–4234. doi:10.1093/nar/gkr007. PMC 3105428. PMID 21266472.
  3. ^ Peabody, D. S. (1989). "Translation initiation at non-AUG triplets in mammalian cells". The Journal of Biological Chemistry. 264 (9): 5031–5. doi:10.1016/S0021-9258(18)83694-8. PMID 2538469.
  4. ^ Starck, S. R.; Jiang, V; Pavon-Eternod, M; Prasad, S; McCarthy, B; Pan, T; Shastri, N (2012). "Leucine-tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I". Science. 336 (6089): 1719–23. Bibcode:2012Sci...336.1719S. doi:10.1126/science.1220270. PMID 22745432. S2CID 206540614.
  5. ^ Dever, T. E. (2012). "Molecular biology. A new start for protein synthesis". Science. 336 (6089): 1645–6. doi:10.1126/science.1224439. PMID 22745408. S2CID 44326947.
  6. ^ Santos, MA; Keith, G; Tuite, MF (February 1993). "Non-standard translational events in Candida albicans mediated by an unusual seryl-tRNA with a 5'-CAG-3' (leucine) anticodon". The EMBO Journal. 12 (2): 607–16. doi:10.1002/j.1460-2075.1993.tb05693.x. PMC 413244. PMID 8440250.
  7. ^ a b Watanabe, Kimitsuna; Suzuki, Tsutomu (2001). "Genetic Code and its Variants". Encyclopedia of Life Sciences. doi:10.1038/npg.els.0000810. ISBN 978-0470015902.
  8. ^ Blattner, F. R.; Plunkett g, G.; Bloch, C. A.; Perna, N. T.; Burland, V.; Riley, M.; Collado-Vides, J.; Glasner, J. D.; Rode, C. K.; Mayhew, G. F.; Gregor, J.; Davis, N. W.; Kirkpatrick, H. A.; Goeden, M. A.; Rose, D. J.; Mau, B.; Shao, Y. (1997). "The Complete Genome Sequence of Escherichia coli K-12". Science. 277 (5331): 1453–1462. doi:10.1126/science.277.5331.1453. PMID 9278503.
  9. ^ Sacerdot, C.; Fayat, G.; Dessen, P.; Springer, M.; Plumbridge, J. A.; Grunberg-Manago, M.; Blanquet, S. (1982). "Sequence of a 1.26-kb DNA fragment containing the structural gene for E.coli initiation factor IF3: Presence of an AUU initiator codon". The EMBO Journal. 1 (3): 311–315. doi:10.1002/j.1460-2075.1982.tb01166.x. PMC 553041. PMID 6325158.
  10. ^ Missiakas, D.; Georgopoulos, C.; Raina, S. (1993). "The Escherichia coli heat shock gene htpY: Mutational analysis, cloning, sequencing, and transcriptional regulation". Journal of Bacteriology. 175 (9): 2613–2624. doi:10.1128/jb.175.9.2613-2624.1993. PMC 204563. PMID 8478327.
  11. ^ E.coli lactose operon with lacI, lacZ, lacY and lacA genes GenBank: J01636.1
  12. ^ Farabaugh, P. J. (1978). "Sequence of the lacI gene". Nature. 274 (5673): 765–769. Bibcode:1978Natur.274..765F. doi:10.1038/274765a0. PMID 355891. S2CID 4208767.
  13. ^ NCBI Sequence Viewer v2.0
  14. ^ Hecht, Ariel; Glasgow, Jeff; Jaschke, Paul R.; Bawazer, Lukmaan A.; Munson, Matthew S.; Cochran, Jennifer R.; Endy, Drew; Salit, Marc (2017). "Measurements of translation initiation from all 64 codons in E. coli". Nucleic Acids Research. 45 (7): 3615–3626. doi:10.1093/nar/gkx070. PMC 5397182. PMID 28334756.
  15. ^ Firnberg, Elad; Labonte, Jason; Gray, Jeffrey; Ostermeir, Marc A. (2014). "A comprehensive, high-resolution map of a gene's fitness landscape". Molecular Biology and Evolution. 31 (6): 1581–1592. doi:10.1093/molbev/msu081. PMC 4032126. PMID 24567513.
  16. ^ Elzanowski, Andrzej; Ostell, Jim. "The Genetic Codes". NCBI. Retrieved 29 March 2019.
  17. ^ a b Andreev, Dmitry E.; Loughran, Gary; Fedorova, Alla D.; Mikhaylova, Maria S.; Shatsky, Ivan N.; Baranov, Pavel V. (2022-05-09). "Non-AUG translation initiation in mammals". Genome Biology. 23 (1): 111. doi:10.1186/s13059-022-02674-2. ISSN 1474-760X. PMC 9082881. PMID 35534899.
  18. ^ Nakamoto T (March 2009). "Evolution and the universality of the mechanism of initiation of protein synthesis". Gene. 432 (1–2): 1–6. doi:10.1016/j.gene.2008.11.001. PMID 19056476.
  19. ^ Blattner, F. R.; Plunkett g, G.; Bloch, C. A.; Perna, N. T.; Burland, V.; Riley, M.; Collado-Vides, J.; Glasner, J. D.; Rode, C. K.; Mayhew, G. F.; Gregor, J.; Davis, N. W.; Kirkpatrick, H. A.; Goeden, M. A.; Rose, D. J.; Mau, B.; Shao, Y. (1997). "The Complete Genome Sequence of Escherichia coli K-12". Science. 277 (5331): 1453–1462. doi:10.1126/science.277.5331.1453. PMID 9278503.
  20. ^ Brenner S. A Life in Science (2001) Published by Biomed Central Limited ISBN 0-9540278-0-9 see pages 101-104
  21. ^ Edgar B (2004). "The genome of bacteriophage T4: an archeological dig". Genetics. 168 (2): 575–82. PMC 1448817. PMID 15514035. see pages 580-581
  22. ^ Varshney, U.; RajBhandary, U. L. (1990-02-01). "Initiation of protein synthesis from a termination codon". Proceedings of the National Academy of Sciences. 87 (4): 1586–1590. Bibcode:1990PNAS...87.1586V. doi:10.1073/pnas.87.4.1586. ISSN 0027-8424. PMC 53520. PMID 2406724.
  23. ^ Vincent, Russel M.; Wright, Bradley W.; Jaschke, Paul R. (2019-03-15). "Measuring Amber Initiator tRNA Orthogonality in a Genomically Recoded Organism" (PDF). ACS Synthetic Biology. 8 (4): 675–685. doi:10.1021/acssynbio.9b00021. ISSN 2161-5063. PMID 30856316. S2CID 75136654.

External linksEdit

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