Protein synthesis errors

There are at least two answers to question (i). First, abnormal proteins can arise in cells due to spontaneous denaturation, errors in protein synthesis, errors in post-translational processing, failure of the correct folding of the protein or damage by free radicals. They are then degraded and replaced by newly synthesised proteins. Secondly, turnover helps to maintain concentrations of free amino acids both within cells and in the blood. This is important to satisfy the requirements for synthesis of essential proteins and peptides (e.g. hormones) and some small nitrogen-containing compounds that play key roles in metabolism (see Table 8.4). 

Error Correction by RNA Polymerases DNA polymerases are capable of editing and error correction, whereas the capacity for error correction in RNA polymerases appears to be quite limited. Given that a single base error in either replication or transcription can lead to an error in protein synthesis, suggest a possible biological explanation for this striking difference. 

The overall error rate of protein synthesis ( 1 mistake per 104 amino acids incorporated) is not nearly as... 

List some types of error that are likely to be made during protein synthesis. What mechanisms have cells developed to deal with these ... 

Not all aminoacyl-tRNA synthetases have editing sites. The cysteinyl- and tyrosyl-tRNA synthetases bind the correct substrates so much more tightly than their competitors that they do not need to edit.13,14 Similarly, since the accuracy of transcription of DNA by RNA polymerase is better than the overall observed error rate in protein synthesis at about 1 part in 104, RNA polymerases do not need to edit.15 The same should be true for codon-anticodon interactions on the ribosome. However, it is possible that accuracy has been sacrificed to achieve higher rates in this case, which is analogous to a change from Michaelis-Menten to Briggs-Haldane kinetics, and so an editing step is required.16... 

The second difference enables errors in DNA replication to be corrected with relative ease. During protein synthesis, the growing end of the polypeptide chain is activated and transferred to the next amino acid in the sequence (Figure 13.5). There is no means of removing an incorrectly added residue and reactivating the polypeptide. Error correction has to be made before polymerization. But in the synthesis of DNA, the monomeric nucleotide is activated and added to the unactivated growing chain. This has enabled the evolution of a mechanism for the editing of errors after polymerization has occurred. 

The genetic code invariance persuaded evolutionists to throw the first shy proponents of polyphyletic models into the dungeons.17, 18 The contention that chance would not have provided even for two origins with an identical triplet codon for protein synthesis was then and still is absolutely correct and certainly relevant, but the conclusion reached because of it by nearly everyone was not. Multiple origins were declared impossible whereas chance should have been disqualified as an inappropriate term in this equation (which it is), and this was the error that has dominated thinking for more than 150 years and is still defended with vehemence. 

The dynamic process is akin to the error checking mechanisms employed in protein synthesis each reaction is reversible until the correct product has formed. In any evolutionary chemical system it is important to ensure copying fidelity and the success of dynamic combinatorial libraries indicates that concepts associate with supramolecular chemistry can be valuable in advancing chemical evolution. 

A system that contains heavy protoribosomes can avoid error catastrophes because high-molecular-weight structures absorb thermal noise, and are immune to a wide range of perturbations. This conclusion is based on a general engineering principle that Burks (1970) expressed in this way There exists a direct correlation between the size of an automaton - as measured roughly by number of components - and the accuracy of its function. In the case of protein synthesis, this means that, in order to be precise, ribosomes must be immune to thermal noise and must therefore be heavy. 

The fidelity of DNA replication is enhanced by a proofreading function, whereby errors in the complementary sequence are excised and repaired (Chap. 16). Why is a similar mechanism not found in protein synthesis ... 

The consequences of errors in protein synthesis are not as serious. A single defective protein molecule will, in general, not cause deleterious effects such a protein may not function properly or may be unstable, and may represent an energy wastage to the cell however, such errors do not become perpetuated in future generations. 

The error catastrophe hypothesis suggests that through random errors in translation or transcription, erroneous copies of proteins associated with chromosomes lead to genetic abnormalities (02). This, in turn, may result in persistently abnormal protein synthesis, and an eventual error catastrophe destroys the cell. As a result, the ability of a cell to produce its normal complement of functional proteins depends not only on the correct genetic specification of the various amino acid sequences, but also on the competence and fidelity of the protein-synthesizing apparatus (i.e., the information must be translated correctly). 

How accurate must protein synthesis be Let us consider error rates. The probability p of forming a protein with no errors depends on n, the number of amino acid residues, and e, the frequency of insertion of a wrong amino acid ... 

As Table 29.1 shows, an error frequency of 10 2 would be intolerable, even for quite small proteins. An e value of 10 3 would usually lead to the error-free synthesis of a 300-residue protein ( 33 kd) but not of a 1000-residue protein ( 110 kd). Thus, the error frequency must not exceed approximately 10 4 to produce the larger proteins effectively. Lower error frequencies are conceivable however, except for the largest proteins, they will not dramatically increase the percentage of proteins with accurate sequences. In addition, such lower error rates are likely to be possible only by a reduction in the rate of protein synthesis because additional time for proofreading will be required. In fact, the observed values of s are... 

The error rates of DNA, RNA, and protein synthesis are of the order of lO io, 10-5, and 10 4, respectively, per nucleotide (or amino acid) incorporated. The fidelity of all three processes depends on the precision of base pairing to the DNA or mRNA template. No errors are corrected in RNA synthesis. In contrast, the fidelity of DNA synthesis... 

Wilhelm JM, Jessop JJ, Pettitt SE, Aminoglycoside antibiotics and eukaryotic protein synthesis stimulation of errors in the translation of natural messengers in extracts of cultured human cells, Biochem, 1978,17(7) 1149-53. 

Although the accuracy of translation (approximately one error per 104 amino acids incorporated) is lower than those of DNA replication and transcription, it is remarkably higher than one would expect of such a complex process. The principal reasons for the accuracy with which amino acids are incorporated into polypeptides include codon-anticodon base pairing and the mechanism by which amino acids are attached to their cognate tRNAs. The attachment of amino acids to tRNAs, considered the first step in protein synthesis, is catalyzed by a group of enzymes called the aminoacyl-tRNA synthetases. The precision with which these enzymes esterify each specific amino acid to the correct tRNA is now believed to be so important for accurate translation that their functioning has been referred to collectively as the second genetic code. 

---