Polypeptides 1-step synthesis

Polypeptides (s. a. Tripeptides) —, 1-step synthesis 18, 436 Polyphenyls, synthesis 16, 977 Polyphosphoric acid (s. a. Phosphorus pentoxide/ phosphoric acid) GG"f>0 ... 

The bibliography does not include systematically the articles published later than July 1976, nor the preparation of polypeptides, polynucleotides or polysaccarides, even if the recent step-by-step synthesis on solid supports of oligo-saccharides (212) will surely be of interest for new openings. 

Figure 6. Major steps in initiation of polypeptide chain synthesis. Reproduced, by kind permission of the authors and Grune and Stratton, from "The biosynthesis of hemoglobin" by Benz and Forget (1974), Semin. Hematol. 11 463-523.

The following short descriptions of the steps involved in the synthesis of a tripeptide will demonstrate the complexity of the problem amino acid units. In the later parts of this section we shall describe actual syntheses of well defined oligopeptides by linear elongation reactions and of less well defined polypeptides by fragment condensation. 

The major disadvantage of solid-phase peptide synthesis is the fact that ail the by-products attached to the resin can only be removed at the final stages of synthesis. Another problem is the relatively low local concentration of peptide which can be obtained on the polymer, and this limits the turnover of all other educts. Preparation of large quantities (> 1 g) is therefore difficult. Thirdly, the racemization-safe methods for acid activation, e.g. with azides, are too mild (= slow) for solid-phase synthesis. For these reasons the convenient Menifield procedures are quite generally used for syntheses of small peptides, whereas for larger polypeptides many research groups adhere to classic solution methods and purification after each condensation step (F.M. Finn, 1976). 

The techniques for automated solid phase synthesis were first highly developed for polypeptides and the method is abbreviated as SPPS. Polypeptide synthesis requires the sequential coupling of the individual amino acids. After each unit is added, it must be deprotected for use in the next coupling step. 

The insertion of unsaturated molecules into metal-carbon bonds is a critically important step in many transition-metal catalyzed organic transformations. The difference in insertion propensity of carbon-carbon and carbon-nitrogen multiple bonds can be attributed to the coordination characteristics of the respective molecules. The difficulty in achieving a to it isomerization may be the reason for the paucity of imine insertions. The synthesis of amides by the insertion of imines into palladium(II)-acyl bonds is the first direct observation of the insertion of imines into bonds between transition metals and carbon (see Scheme 7). The alternating copolymerization of imines with carbon monoxide (in which the insertion of the imine into palladium-acyl bonds would be the key step in the chain growth sequence), if successful, should constitute a new procedure for the synthesis of polypeptides (see Scheme 7).348... 

Moreover, if the average yield per step decreases only slightly, let us say down to 85%, the overall yield of the convergent synthesis is still quite acceptable -37%-, but now the overall yield of the linear synthesis would be only 0.004%. It is clear, therefore, that for polypeptides of any complexity and for proteins, linear syntheses in solution are not practicable even if the yields of each step are kept high. However, solid-phase peptide synthesis can be quite efficient. This is because solid-phase synthesis represents an improvement in linear methodology which has, as yet, not found an equivalent in convergent methods [17]. 

Translation involves three stages initiation, elongation and termination. A brief summary of these processes is provided below. However, the first step in polypeptide synthesis, from intracellular amino acids, is the formation of aminoacyl-tRNA. This reaction is particularly important so that the biochemistry is discussed in some detail. In addition, it is also important in the regulation of the rate of translation (see below). 

Figure 20.24 The physiological pathway of polypeptide synthesis. The flux-generating step is that catalysed by the aminoacyl-tRNA synthetases, indicated by the broad arrow. The assumption implicit in this interpretation is that the physiological pathway starts with the intracellular amino acids and ends with the peptide that is formed in the elongation and termination processes. For the majority of enzymes, the concentration of intracellular amino acids is higher than the K, for the synthetase (Chapter 3).

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