Biological Chemistry - Berezov, T. T., & Korovkin, B. F. 1998

Protein Biosynthesis

The whole is greater than the sum of its parts.

Plato

One of the global challenges of modern biology and its cutting-edge fields—molecular biology, bioorganic chemistry, and physical-chemical biology—is to elucidate the molecular foundations and subtle mechanisms of the synthesis of Proteins containing hundreds or sometimes thousands of L-amino acid residues. As established, these residues are arranged not randomly, but in a strictly predetermined sequence, thereby ensuring the structural uniqueness of the synthesized protein molecule, which is endowed with a unique function. In other words, the synthesis mechanism must possess a highly subtle and precise coding system that automatically programs the incorporation of each amino acid residue into a specific site of the polypeptide chain. It has been established that the coding system uniquely determines the Primary Structure, whereas the secondary and tertiary structures of the protein molecule are determined by the physicochemical properties and Chemical Structure of The amino acid radicals within the polypeptide.

Initially, it was hypothesized that Protein Synthesis might be catalyzed by the same Proteolytic Enzymes responsible for its Hydrolysis, driven by the reversibility of the chemical reaction. However, it turned out that synthetic and catabolic reactions proceed not only via different pathways, but even in distinct subcellular fractions. The hypothesis of preliminary synthesis of short Peptides followed by their assembly into a single polypeptide chain was likewise unconfirmed. A more accurate assumption proved to be that protein synthesis requires Energy Sources, the presence of activated free Amino Acids, and several types of cellular Nucleic Acids.

Russian biochemists have made a distinct contribution to elucidating the MOLECULAR MECHANISMS OF protein synthesis. For instance, A.E. Braunstein's laboratory was the first to demonstrate the involvement of ATP in the synthesis of quasi-peptide bonds (using hippuric acid, glutamine, Glutathione, and acetanilide as Examples). Back in the 1950s, V.N. Orekhovich established that The transfer of aminoacyl or peptidyl groups to the NH₂ group of Amino acids can be accomplished not only via an amide or peptide bond, but also via an ester bond. As will be shown below, it is precisely this mechanism that underlies the transpeptidation reaction in the 50S ribosome during the elongation stage of protein synthesis.

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Fig. 14.1. Schematic diagram of METABOLISM/35.html">Protein Biosynthesis (according to A.S. Spirin).

Red circles represent free Amino Acids and their residues within the polypeptide chain.

Considerably later, evidence was obtained that nucleic acids, particularly DNA, play a decisive role in protein synthesis, which occurs primarily in the Cytoplasm. Once it was established that DNA is the carrier and repository of hereditary information, the question arose as to how this Genetic information, inscribed (encoded) in the chemical structure of DNA, is transformed into heritable phenotypic traits and Functional Properties of living organisms. Today, an unequivocal answer can be provided: genetic information programs the Synthesis of specific proteins, which in turn determine the Structural and functional Specificity of Cells, Organs, and the Organism as a whole (Fig. 14.1). In nature, as is well known, There are two types of biopolymer macromolecules: so-called non-informative Biopolymers (represented by repeating monomer units and/or branched structures, such as Polysaccharides, poly-ADP-ribose, peptidoglycans, and Glycoproteins) and informative biopolymers that carry primary genetic information (nucleic acids) and secondary genetic—more precisely, phenotypic—information (proteins). These General Concepts can be expressed by the following sequence of events (the flow of information):

DNA —> RNA —> Protein —> Cell —> Organism

A significant contribution to modern concepts regarding the site, factors, and mechanism of protein synthesis was made by the research of T. Caspersson, M. Hoagland, P. Berg, P. Zamecnik, S. Ochoa, M. Nirenberg, N. Horowitz, F. Haurowitz, S. Weiss, and Russian biochemists A.A. Baev, A.N. Belozersky, A.S. Spirin, and others.

Without dwelling on all HISTORICAL ASPECTS OF The Development of this critical problem, it should be recalled that as early as the 1940s it was established that DNA is localized in the Cell Nucleus, whereas protein synthesis occurs predominantly in cytoplasmic microsomes. The first experimental Evidence for the necessity of nucleic acids in protein synthesis was obtained in T. Caspersson's laboratory. It was also demonstrated that Ribonucleic Acids present in the cytoplasm control the synthesis of cytoplasmic proteins. Thus, even then, a clear picture emerged of a close link between nuclear-localized DNA* and protein synthesis, which takes place in the cytoplasm and is regulated by ribonucleic acids discovered in both the cytoplasm and The Nucleus. Based on these purely morphological data, a Conclusion was drawn—fully confirmed today—that protein biosynthesis, although directly regulated by ribonucleic acids, is indirectly linked to the controlling influence of nuclear DNA, and that RNA is first synthesized in the nucleus and then transported to the cytoplasm, where it acts as a template in protein synthesis. Experimental data obtained much later confirmed the hypothesis that the primary Functions of nucleic acids are the storage of genetic information and the realization of this information through the programmed synthesis of specific proteins.

Within the DNA —> RNA —> Protein sequence, information was initially lacking on how the decoding of hereditary information and the synthesis of specific proteins—which determine the vast diversity of living organisms' traits—actually occur. Currently, the main processes responsible for the transmission of hereditary information have been elucidated: Replication, i.e., the synthesis of DNA using a DNA template; Transcription, i.e., the synthesis of RNA using a DNA template, translating the language and structural type of DNA into an RNA molecule (see above); and Translation, the process in which the genetic information contained in an mRNA molecule directs the Synthesis of the corresponding Amino Acid Sequence in a protein. It should be recalled, however, that many subtle mechanisms of transcription and translation remain not fully understood.