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Because the experiment described in Table 26-1 revealed a histidine codon with one Aand two Cs, CAC must code for histidine and ACA for threonine.Similarly, an RNA with three bases in a repeating pattern shouldyield three different types of polypeptide. Each polypeptide would bederived from a different reading frame and would contain a single kindof amino acid. An RNA with four bases in a repeating pattern shouldyield a single type of polypeptide with a repeating pattern of fouramino acids (Table 26-3).
Results from all of these experiments withpolymers permitted the assignment of 61 of 64 possible codons. Theother three were identified as termination codons, in part because theydisrupted amino acid coding patterns when included in the sequence ofa synthetic RNA polymer (Fig.
26-6; Table 26-3).Reading frame 1 5'Reading frame 2Reading frame 3\G U Al[A~G UlJA AUA]|A---GJlG U A|[A G U|[A AG U[ A ATable 26-3 Polypeptides produced inresponse to synthetic RNA polymers withrepeating sequences of three and four basesPolynucleotidePolypeptide productsTrinucleotide repeats(UUC)n(Phe) n , (Ser) n , (Leu)n(AAG)n(Lys)n, (Arg)n, (Glu)n(UUG)n(Leu)n, (Cys)n, (Val)n(CCA)n(Pro)B, (His)n, (Thr) n(GUA)n(Val)n, (Ser) n , (chainterminator)*(UAC)ra(Tyr)n, (Thr) n , (Leu)n(AUC)n(Ile)n, (Ser) n , (His)*(GAU)n(Asp)n, (Met)n, (chainterminator)*Tetranucleotide repeats(UAUC)n(IVr-Leu-Ser-Ile) n(UUAC)n(Leu-Leu-Thr-Tyr) n(GUAA)nDi- and tripeptides*(AUAG)nDi- and tripeptides** With these polynucleotides, the patterns of amino acid incorporation into polypeptides are affected by the presence of codons that are termination signals for protein biosynthesis Inthe repeating three-base sequences, one of the three readingframes includes only termination codons and thus only twohomopolypeptides are observed (generated from the remainingtwo reading frames).
In some of the repeating four-base sequences, every fourth codon is a termination codon in everyreading frame, so that only short peptides are produced Thisis illustrated in Figure 26-6 for (GUAA)nFigure 26-6 The effect of a termination codon incorporated within a repeating tetranucleotide. Dipeptides or tripeptides will be synthesized, depending on where the ribosome initially binds. Thethree different reading frames are shown in different colors.
Termination codons (indicated in red)are encountered every fourth codon in all threereading frames.3'898Part IV Information PathwaysWith these approaches the base sequences of all the triplet codewords for each of the amino acids were established by 1966. Since then,these code words have been verified in many different ways. The complete codon "dictionary" for the amino acids is given in Figure 26-7.The cracking of the genetic code is regarded as the greatest scientificdiscovery of the 1960s.Second letter of codonCAUFigure 26-7 The "dictionary" of amino acid codewords as they occur in mRNAs. The codons arewritten in the 5'->3' direction. The third base ofeach codon, shown in bold type, plays a lesser rolein specifying an amino acid than the first two. Thethree termination codons are shaded in red, andthe initiation codon AUG is shaded in green. Notethat all the amino acids except methionine andtryptophan have more than one codon.
In mostcases, codons that specify the same amino acid differ only in the third base.GuuuuucPhePheUCUUCCSerSerUUAUUGLeuLeuUCAUCGSer tIAA StopSer UACt StopCUULeuLeuecuCCCProProCAUCACHis CGUHis CGCArgArgCUACUGLeuLeuCCACCGProProCAACAGGin CGAGin CGGArgArgAUUAUClieHeACUACCThrThrAAUAACAsn AGUAsn AGCSerSerAUAAUGHeMetACAACGThrThrAAAAAGLys AGALys AGGArgArgGUUGUCValValGCUGCCAlaAlaGAUGACAspAspGGUGGCGlyGlyGUAGUGValValGCAGCGAlaAlaGAAGAGGluGluGGAGGGGlyGlyUAUUACTyrTyrUGUUGCCysCysUcueFirstletter ofcodon(5' end)UGA StopUGG TrpGThe Genetic Code Has Several Important CharacteristicsThe key to the organization of the genetic information specifying aprotein can be found in codons and in the array of codons that constitutes a reading frame.
Keep in mind that no punctuation or signal isrequired to indicate the end of one codon and the beginning of the next.The reading frame must therefore be correctly set at the beginning ofthe readout of an mRNA molecule and then moved sequentially fromone triplet to the next. If the initial reading frame is off by one or twobases, or if the ribosome accidentally skips a nucleotide in the mRNA,all the subsequent codons will be out of register and will lead to formation of a "missense" protein with a garbled amino acid sequence.Several of the codons serve special functions. The initiationcodon, AUG, signals the beginning of polypeptide chains.
AUG notonly is the initiation codon in both prokaryotes and eukaryotes but alsocodes for Met residues in internal positions of polypeptides. Of the 64possible nucleotide triplets, three (UAA, UAG, and UGA) do not codefor any known amino acids (Fig. 26-7); they are the termination codons (also called stop codons or nonsense codons), which normally signal the end of polypeptide chain synthesis. The three termination codons acquired the name "nonsense codons" because they were firstfound to result from single-base mutations in E. coli in which certainpolypeptide chains are prematurely terminated. These nonsensemutations, arbitrarily named amber, ochre, and opal, respectively,helped make possible identification of UAA, UAG, and UGA as termination codons.Chapter 26 Protein MetabolismIn a random sequence of nucleotides, one in every 20 codons ineach reading frame, on average, will be a termination codon.
Where areading frame exists without a termination codon for 50 or more codons, the region is called an open reading frame. Long open readingframes usually correspond to genes that encode proteins. An uninterrupted gene coding for a typical protein with a molecular weight of60,000 would require an open reading frame with 500 or more codons.See Box 26-1 (p. 900) for some interesting exceptions to this generalpattern.Perhaps the most striking feature of the genetic code is that it isdegenerate, meaning that a given amino acid may be specified bymore than one codon (Table 26-4). Only methionine and tryptophanhave single codons.
Degenerate does not mean imperfect; the geneticcode is unambiguous because no codon specifies more than one aminoacid. Note that the degeneracy of the code is not uniform. For example,leucine and serine have six codons, glycine and alanine have four, andglutamate, tyrosine, and histidine have two.When an amino acid has multiple codons, the difference betweenthe codons usually lies in the third base (at the 3' end). For example,alanine is coded by the triplets GCU, GCC, GCA, and GCG. The codonsfor nearly all of the amino acids can be symbolized by XYG or XYJ> Thefirst two letters of each codon are therefore the primary determinantsof specificity.
This has some interesting consequences.899Table 26-4 Degeneracy of the genetic codeAminoacidAlaNumber ofcodonsAminoacid4Number ofcodonsLeu6Arg6Lys2Asn2Met1Asp2Phe2Cys2Pro4Gin2Ser6Glu2Thr4Gly4Trp1His2TVr2lie3Val4Wobble Allows Some tRNAs to RecognizeMore than One CodonTransfer RNAs recognize codons by base pairing between the mRNAcodon and a three-base sequence on the tRNA called the anticodon.The two RNAs are paired antiparallel, the first base of the codon (always reading in the 5'—»3' direction) pairing with the third base of theanticodon (Fig.
26-8).One might expect the anticodon triplet of a given tRNA to recognize only one codon triplet through Watson-Crick base pairing, so thatthere would be a different tRNA for each codon of an amino acid. However, the number of different tRNAs for each amino acid is not thesame as the number of its codons. Moreover, some of the tRNAs contain the nucleotide inosinate (designated I), which contains the uncommon base hypoxanthine (see Fig. 12-5b). Molecular models show thatinosinate can form hydrogen bonds with three different nucleotides, U,C, and A, but these pairings are rather weak compared with the stronghydrogen bonds between the Watson-Crick base pairs G ^ C andA=U.
In yeast, for example, one tRNAArg has the anticodon (5')ICG,which can recognize three different arginine codons, (5')CGA, (5')CGU,and (5')CGC. The first two bases of these codons are identical (CG) andform strong Watson-Crick base pairs (blue) with the correspondingbases of the anticodon:3'tRNAAnticodon13 2 I1U A GmRNA 5' •32132Anticodon(3') G-C-IG-C-ICodon(5') C-G-AC-G-U123121321G-C-I (5')C-G-C (3')3123Figure 26-8 The pairing relationship of codon andanticodon. Alignment of the two RNAs is antiparallel. The tRNA is presented in the traditional cloverleaf configuration.900Part IV Information PathwaysBOX 26-1Translational Frameshifting and RNA Editing:mRNAs That Change Horses in MidstreamProteins are synthesized according to a pattern ofcontiguous triplet codons.
Once the reading frameis set, codons are translated in order, without overlap or punctuation, until a termination codon isencountered. Usually, the other two possible reading frames within a gene contain no useful geneticinformation. However, a few genes are structuredso that ribosomes "hiccup" at a certain point in thetranslation of the mRNA, leading to a change inthe reading frame from that point on.
In somecases this appears to be a mechanism used to produce two or more related proteins from a singletranscript or to regulate the synthesis of a protein.The best-documented example occurs in thetranslation of the mRNA for the gag and pol genesof the Rous sarcoma virus (see Fig.
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