The Chemistry and Biology of Proteins - F. Haurowitz 1953

Protein Synthesis
The Mechanism of Protein Synthesis

In the preceding sections of this chapter, the sparse available data regarding Protein Synthesis via polymerization and enzymatic Condensation were outlined. The question of the site of protein synthesis within Cells, and The Relationship of this process to other metabolic pathways, was also touched upon to some extent. The results of research conducted to date can be summarized in the following points.

1. Protein synthesis appears to take place within or near the nucleolus, as well as in small cytoplasmic granules of cells and in virus particles.

2. All particles in which protein synthesis occurs contain large amounts of ribonucleic acid.

This data is, of course, entirely insufficient to construct a more or less substantiated theory of The mechanism of protein synthesis. The most we are currently able to do is to put forward a few hypotheses on this issue and examine the extent to which these assumptions align with current data on the PHYSICOCHEMICAL PROPERTIES OF Proteins. The fundamental question of the entire problem of Protein synthesis is how proteins possessing high Specificity are formed within the Organism. In previous chapters of this book, it was repeatedly emphasized that each animal species has its own specific proteins, and that the proteins of many Organs also possess a definite specificity that distinguishes them from the proteins of other Organs of the same animal. Protein specificity is determined by their Amino Acid Composition, The sequence of Amino Acids in the peptide chain, and the specific conformation of folded peptide chains.

How can all these facts be explained? Many researchers suggest that The Cell contains a certain invariant Structure, something like a template or matrix, by means of which protein synthesis occurs. Although no one has ever observed this template and there is no direct evidence of its existence, we are nevertheless forced to accept this explanation, as we currently have no other way to account for the consistent Formation of the same specific proteins in every cell.

In connection with the fundamental question of THE ORIGIN OF protein specificity, the following questions arise: 1) Is the shape of the protein formed in the cell identical to the shape of the template, or does it represent a negative imprint of that template? 2) Does the template consist of proteins, Nucleic Acids, Nucleoproteins, or is it constructed from Other Compounds?

Various authors give conflicting Answers to these questions. Some believe that protein synthesis is essentially a reproduction—i.e., that the synthesized proteins form a positive imprint of the template; others, conversely, suggest that the synthesized proteins represent its negative imprint. Nor is there a consensus regarding The Role of nucleic acids in protein synthesis.

Hypotheses can be classified as follows [62].

1. Nucleic acids form the template upon which synthesized proteins are shaped.

2. Nucleic acids react with proteins to form insoluble compounds, As a result of which the synthesized proteins are continuously removed from solution. Consequently, the equilibrium between protein precursors and synthesized proteins is constantly shifted to the right, creating conditions for further protein synthesis.

3. Nucleic acids supply energy for protein synthesis; this can be derived from The oxidation of pentose or purine bases that are part of the nucleic acids.

4. Nucleic acids serve as material for The formation of Coenzymes, since ribose, adenine, and phosphoric acid can be utilized to form flavin and pyridine NUCLEOTIDES.

When considering the views outlined above, we must first discuss whether protein molecules represent positive or negative imprints of the hypothetical cellular template. We know that protein molecules consist of long peptide chains and that these chains are folded in such a way as to form a three-dimensional globular molecule. The diameter of this globular particle can range from 20 to 100 Å. At present, we know of no forces by means of which the aforementioned template could act over such a great distance. The action of forces governing reactions between ions and polar groups (see Chapter X) drops off sharply as the distance between these groups increases, and their effect is felt only at distances not exceeding 4–5 Å. Only if the reacting groups were located in a vacuum could these forces act at distances greater than 4–5 Å. However, in biological systems, we are dealing not with a vacuum, but with systems in which Water molecules—which are polar particles with a high dielectric constant—are always present between the reacting groups.

The action of forces responsible for electrostatic attraction and repulsion will therefore be significantly diminished by the counteraction of water molecules and will not exceed 1/80 of the effect these forces exert in a vacuum. In other words, the action of electrostatic forces In aqueous solutions extends to distances of no more than 4–5 Å. From these considerations, it is clear that the hypothesis of direct Reproduction of a globular molecule 20–100 Å in diameter via Intermolecular Forces is incompatible with available data on the range and efficiency of these forces.

Consistent with these data [135–137] is a single hypothesis put forward many years ago, which states that the reproduction of protein molecules can occur only if the corresponding reactions take place in stretched monomolecular films [133, 134]. According to this hypothesis, the formation of the peptide chains of a protein molecule occurs within a monomolecular film spread across The surface of the template; the folding and transformation of the two-dimensional peptide layer into a three-dimensional protein globule is a secondary process occurring elsewhere and distinct from The process of true peptide chain synthesis.

A number of physicochemical considerations lead the author of this book to accept that the aforementioned two-dimensional Peptide Structure represents a positive imprint of the template.

At first glance, this proposition contradicts the notion that the shape of an antibody molecule geometrically complements the shape of an antigen molecule, and the shape of an enzyme molecule complements that of its substrate. In Chapter XIV, when examining the correspondence between the shapes of antigen and antibody molecules, we noted that the antigen in this case serves as the template, and the antibody molecules as its negative imprints. This view, supported by all currently available data on antibody formation and the Antigen-Antibody Reaction, does not, however, contradict the hypothesis of protein peptide chain formation in a monomolecular layer. It is easy to conceive that the antigen plays the role of a template in the aforementioned secondary reaction—specifically, in the process of converting the stretched two-dimensional peptide film into a three-dimensional globular antibody molecule. Accordingly, the shape of the antibody molecule geometrically complements the shape of the globular antigen molecule, rather than the shape of its stretched molecular film. Antibody synthesis represents a special case of protein synthesis, and there is no reason to think that it differs in any essential way from the normal Synthesis of Other proteins, such as serum globulins—that is, that two distinct Mechanisms of Protein synthesis exist. One can therefore consider that protein synthesis proceeding in normal cells also leads to the formation of molecules whose shapes geometrically Complement the determining groups of adjacent template molecules. Thus, we generalize METABOLISM/2.html">THE CONCEPT OF geometrically complementary shapes, extending it not only to antibody synthesis, but to the synthesis of all other proteins. Normal cellular proteins formed under physiological conditions have been proposed to be termed autoantibodies [138] to signify that their molecular shape geometrically complements the shape of templates located at the site of their formation. Only when normal templates are coated or enveloped by a foreign antigen protein is the natural process of transforming stretched peptide chains into normal globular molecules disrupted, and instead, synthesis of Antibodies with molecules geometrically complementary in shape to the antigen molecules takes place [135].

The concept of a template upon which a negative imprint is formed has been utilized by many authors to explain the Mechanism of formation of various proteins [139, 140]. In particular, the formation of Cancer tissue proteins was viewed as a consequence of templates in such tissue having an abnormal structure [142], caused either by coplanar rings of carcinogenic substances [141] or by their electronic structure [143].

The author fully shares Pauling's opinion [144] that all specific biological processes are driven by the same intermolecular forces, the action of which is, in turn, determined by atomic contact and the process of imprint formation. Developing this concept, the author postulates that The First stage of protein synthesis is the formation of a positive imprint from the primary template, with both the template and the imprint existing as monomolecular films. The Second Stage is the formation of a negative globular imprint whose shape geometrically complements the shape of a second, likewise globular template.

If we accept this concept for intracellular Protein synthesis in vivo, we must also answer a number of questions concerning The Nature of the template and the mechanism of its action. How is the stretched protein film actually formed on this two-dimensional template? Does the template consist of protein, nucleic acid, or some other compound?

As is well-known, nucleic acids are invariably present in those regions of cells where protein synthesis occurs; this led many authors to conclude that nucleic acids constitute the putative templates for PROTEIN SYNTHESIS AND that they determine the specificity of all newly formed proteins in animal and plant organisms.

Nucleic acids are polar compounds possessing many negatively charged phosphoric acid groups, polar hydrophilic sugar hydroxyl groups, and positively charged groupings that are part of purine and pyrimidine bases. There is no doubt that all these groupings can exert a strong influence on neighboring molecules. Earlier (see Chapter XI), compelling evidence was already cited showing that when nucleic acids bind to proteins, the molecular conformation of both the protein and the nucleic acids changes [145].

It is hypothesized that positively charged groups of protein diamino acids react with negatively charged phosphoric acid groups of nucleic acids, thereby generating a negative imprint of the nucleic acid, which Functions in this case as a template [140, 146]. However, in the author's opinion, the high acidity of nucleic acids can hardly serve as proof that they play the role of a specific template, since their acidity is so high that they react nonspecifically with many proteins. Furthermore, one must take into account that nucleic acids consist of only seven or eight distinct building blocks: adenine, guanine, cytosine, uracil, thymine, phosphoric acid, and ribose or deoxyribose. It is therefore difficult to imagine that a nucleic acid as a template could determine such subtle differences between proteins as those observed, for example, between human and bovine serum albumins, which differ only slightly in their amino acid composition [147]. Moreover, we still do not know whether nucleic acids possess species specificity. If they lack this property, they cannot form specific templates at all. However, even granting species specificity to nucleic acids, it is very difficult to conceive how they could determine the specific positions of various amino acids in the resulting peptide chain, given that the phosphoric acid of nucleic acids should react primarily with the basic amino acids of the protein.

It remains unknown whether there is any specific sequence in the arrangement of purine bases within the nucleic acid molecule. We only know that they consist of mononucleotides, each containing a single phosphoric acid group. The distances between these groups in a stretched polynucleotide molecule are equal. The negatively charged phosphoric acid groups repel one another, as a result of which the entire molecule tends to remain in an extended conformation.

At present, there is no way to answer the question of how this more or less regularly structured nucleic acid molecule can dictate the formation of an infinite number of specific proteins. In this regard, it is entirely pointless to further discuss the hypothesis attributing to nucleic acids the role of a primary template upon which monomolecular protein films are formed. We shall therefore proceed to consider those views according to which this primary template is formed by a layer of protein.

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Fig. 51. Duplication of a protein template [135]. The peptide chains of the template and the copy are formed by Lysine, Alanine, Tyrosine, aspartic acid, and leucine.

Ш — template; К — copy.

According to this hypothesis, the newly formed extended protein film should represent a copy of another extended protein film [135, 136]. We must imagine in this case that each of the l-amino acids located in the template layer attracts an l-amino acid of the same type from the surrounding environment, and that the amino acids constituting the emerging copy bind to one another through the action of nonspecific Proteolytic Enzymes such as Trypsin or Papain. In this case, the formation of the copy can proceed as schematically illustrated in Fig. 51, where the peptide chains of the template and its copy are formed by lysine, alanine, tyrosine, aspartic acid, and leucine.

The aforementioned view, according to which the defining moment of the entire protein synthesis process is the specific adsorption of the same amino acids from the environment by the template amino acids, is in rather good agreement with a number of well-established chemical and physicochemical concepts.

This adsorption process can be compared to crystallization, which, as is well known, is also characterized by high specificity. If we saturate a solution containing many different amino acids with respect to one of them so that part of The amino acid remains in the precipitate, and then slowly evaporate the solution, only the molecules of this amino acid will be adsorbed onto the crystalline particles of the undissolved precipitate, causing these particles to grow in size. It has never been observed that any other amino acid is incorporated into the lattice of a growing crystal. If we evaporate the solution to such an extent that Other Amino Acids begin to precipitate, they will, in most cases, form separate crystals. From this example, it is clear that the adsorption of molecules present in solution by the lattices of the same molecules present in the precipitate is a highly specific process.

This analogy between crystallization specificity and biological specificity has attracted the attention of many biologists and chemists [133, 135, 144, 148]. The idea that a solid particle of a substance can serve as a Nucleus upon which other particles of this substance are deposited has received a certain amount of confirmation from a number of discoveries in other fields of biochemistry. One such discovery is the ESTABLISHMENT OF THE role played by the Glycogen framework in the enzymatic synthesis of new glycogen molecules.

The work of Cori and Cori [149] established that the Nature of the polysaccharide formed during the enzymatic synthesis of Polysaccharides from glucose-1-phosphate depends on the traces of which polysaccharide are present in the solution. If a polysaccharide with branched chains is added as a primer, branched-chain polysaccharides are formed. If, however, a polysaccharide with unbranched chains is added, only such polysaccharides will be formed as a result of enzymatic synthesis. The added polysaccharide can thus be regarded as a substance that initiates the reaction and determines its direction, i.e., as a primer.

This new concept is undoubtedly of great importance for The Development of The problem of macromolecule formation in the organism. According to this view, we must consider that the Terminal Groups of the branched or unbranched primer molecule play the role of a specific organizer that influences the action of the nonspecific enzyme.

Thus, the need to assume the presence of a multitude of specific catalysts in the organism disappears. Such an assumption has always seemed unlikely. The specificity of synthetic processes can now be attributed not to the specificity of catalysts, but to the specificity of organizers, or primers.

These organizers can be visualized as compounds lacking enzymatic activity and analogous to the elementary structural units of crystals, whose sole purpose is to determine the shape of the substances deposited on them. Facts similar to those found by Cori and Cori in their study of Polysaccharide synthesis have also been discovered in the investigation of protein synthesis.

As already indicated in Ch. XI, hemocyanin—a copper-containing respiratory pigment of invertebrates—can be split into particles whose molecular weight is only 1/2 or even 1/8 of the Molecular Weight of hemocyanin. This splitting of hemocyanin occurs when it is in an alkaline solution at pH 8.5. If the pH of the solution is shifted toward the acidic side and brought to 6.85, the reverse process occurs, namely, the association of the degradation products, and the original hemocyanin molecule is formed. However, it turned out that fragments of hemocyanin from one species can associate only with fragments of the same hemocyanin, and not with fragments of hemocyanin obtained from another species. For example, hemocyanin fragments of Helix pomatia do not associate with hemocyanin fragments obtained from the organism Littorina littorea [150].

All these observations on crystal growth specificity, the role of the primer, and the association of fragments indicate that under certain conditions, molecules of the same type selectively attract molecules of the same type. The forces responsible for the mutual attraction of these molecules are in many cases purely ionic forces.

The simplest example of this type of attraction is the growth of a sodium chloride crystal, which is mainly due to the mutual attraction of positively charged sodium ions and negatively charged chloride ions. This explanation, however, is not applicable to the growth of non-electrolyte crystals, such as naphthalene crystals. Although naphthalene contains neither ionic nor polar hydroxyl or keto groups, still only naphthalene molecules attach themselves to naphthalene crystals in a solution containing, besides naphthalene, other closely related Hydrocarbons. The specificity of naphthalene crystal growth can only be explained by the fact that the shape of the naphthalene molecules in solution corresponds to the shape of the molecules forming the lattice of naphthalene crystals, as a result of which they can penetrate the gaps between the lattice parts more easily than other molecules. This process is thus a purely topochemical phenomenon associated with surface phenomena on the solid phase. Various substances can be adsorbed On the surface of this phase, but molecules of the same type will always have the advantage in this respect.

The fact that the affinity between molecules of the same type is higher than the affinity between molecules of different types is well known to physical chemists.

The magnitude of the binding energy can be determined by measuring the heat of solution or the heat of fusion. The melting point of pure substances is always higher than the melting point of substances containing impurities; in other words, more Energy is required to separate molecules of the same type than to separate molecules of different types.

The attraction of molecules will, of course, be even higher if it is caused by the interaction of oppositely charged ionic groups of these molecules. For this reason, ionic-type crystals are hard and have a high melting point, whereas non-polar-type crystals are soft and melt at low temperatures.

The Study of crystallization helps to understand the process of protein formation, which occurs through the deposition of amino acids from solution onto the amino acids of the stretched template film. One might object, however, that the template protein film contains only amino acid residues linked to each other in peptide chains and differing in shape from the free amino acids present in solution. This objection is not without foundation. However, it should be taken into account that free Amino Acids and amino acid residues in the peptide chain are identical in the shape of their main parts, as can be seen, for example, from the following formulas:

Leucine dissolved in the cell fluid undoubtedly comes closer in shape to the leucine residue in the peptide chain than any other amino acid (see Fig. 51).

According to the concepts outlined above, the amino acids deposited on the template surface subsequently form a peptide chain. This process is enzymatic, but there is no evidence that specific enzymes take part in it, and consequently, there is no need to postulate the presence of such specific enzymes. Proteolytic enzymes isolated from organs are not specific, since they catalyze the Hydrolysis of A wide variety of animal and plant proteins. These same enzymes can also catalyze the process of Peptide Synthesis from amino acids, as was convincingly demonstrated by Bergmann and his coworkers [18, 20]. In previous sections of this chapter, it was already pointed out that protein synthesis cannot be regarded simply as the reverse of their degradation, and that intermediate synthesis reactions may proceed differently than the corresponding hydrolytic reactions. The most important point is that we have absolutely no Evidence for the Specificity of the enzymes involved in both Protein Hydrolysis and synthesis. The specificity of the resulting protein can be quite satisfactorily explained by the specific adsorption of amino acids on the template surface.

Before proceeding to the consideration of issues concerning the second phase of protein synthesis—the phase in which the folding of peptide chains occurs—it is necessary to try to answer the following two questions: 1) What is the role of nucleic acids? 2) How does the template protein film differ from the protein copy formed on it? Why does only the latter form a globular molecule, while the template film remains stretched and insoluble?

Apparently, the answer to both these questions is as follows.

The role of nucleic acids probably boils down to keeping the template protein film in a stretched state. Protein films can remain in such a state only under The Influence of forces acting between interfaces. These forces cause the unfolding of peptide chains and keep them unfolded in a stretched monomolecular film. It can be assumed, and this is very likely, that various Types of Nucleic acids play the role of carriers of template protein films and that the replacement of one nucleic acid by another can to some extent affect the formation of the copy. This influence cannot, however, be particularly strong unless the template protein film itself is damaged in the process.

Turning to the question of why the resulting copy of the protein film folds to form soluble globules, whereas the template protein film remains insoluble, the following must be taken into account. Each peptide layer has a thickness of 8–10 Å, and therefore a globular particle can consist of only a few peptide layers. We still do not know whether these peptide layers actually form folds or whether several two-dimensional layers combine with each other in such a way as to form a globular particle. This question has been investigated to date only with respect to Hemoglobin (see Ch. XI). The putative STRUCTURE OF THE hemoglobin molecule is depicted in Fig. 52 [151]. The molecule consists of four peptide layers, each of which is formed by a zigzag-folded peptide chain arranged in five folds.

Fig. 52. Hemoglobin molecule [151].

A — cross-section showing folded peptide chains; B — vertical section showing chain packing.

As already noted on several occasions, the results of immunological studies lead to the Conclusion that the three-dimensional antibody molecules have a shape that is geometrically complementary to that of the introduced antigen.

The antigen apparently participates in the folding process of the antibody peptide chains, as a result of which the resulting antibody molecule represents a negative imprint of the determinant groups of the antigen. During the synthesis of ordinary proteins—that is, in the absence of a foreign antigen—this role is performed by polar molecules present within the cell, and therefore the resulting Proteins can be regarded as autoantibodies [138]. The shape of their molecules is geometrically complementary to certain determinant structures of a normal cell. Lipids, CARBOHYDRATES, proteins, and nucleic acids can all act as determinant structures. Landsteiner's work demonstrated quite convincingly that practically all polar compounds influence antibody formation to some degree, and this role can also be played by synthetic products such as azo and nitro compounds. Thus, there is no reason to exclude any polar compounds from the group of substances that influence protein synthesis.

When dealing with higher animals or plants, we cannot say anything definitive about the Chemical Nature of the three-dimensional templates that participate In the second phase of protein synthesis—that is, The conversion of a two-dimensional protein film into a three-dimensional protein molecule.

Simple Viruses are virtually devoid of fats and carbohydrates. Nevertheless, although viruses contain only proteins and nucleic acids, Protein synthesis proceeds within them very intensively. From this, one can conclude that in viruses, and possibly in more complex organisms as well, the role of secondary templates is performed chiefly by proteins, nucleic acids, or nucleoproteins.

When investigating protein synthesis in viruses, we are dealing with a further simplification of conditions, since viruses contain only a single type of protein. It must therefore be assumed that this protein performs both the role of a two-dimensional template in The first phase of synthesis and the role of a three-dimensional template in the second phase, unless one of these functions is assumed by host proteins. It is conceivable that one part of the viral protein, combined with nucleic acid to form a two-dimensional template, participates in the first phase of synthesis, whereas another part of the same protein, present in a three-dimensional globular form, determines the specificity of the process in the second phase—namely, the Conversion of the two-dimensional film into a three-dimensional globule.

Is the template a catalyst? Can the introduced antigen be regarded as a catalyst? Many biochemists answer these questions in the affirmative. However, in the author's view, a distinction must be made between substances that alter the course of a reaction without affecting its rate and true catalysts. The difference between these Two Types of substances becomes apparent when considering the research data of Bredig, which have already been discussed in detail by Sevag [152].

Bredig showed that when the reaction between benzaldehyde and hydrogen cyanide is catalyzed by dihexylamine bound to Cellulose, an optically active mandelonitrile is formed. The formation of the optically active isomer is evidently due to the asymmetric structure of cellulose and does not depend on the amine, whose alkaline groups exhibit catalytic activity even in the absence of cellulose. Cellulose cannot obviously be regarded as a catalyst in this reaction. The term "pillar substances" has been proposed to designate substances that alter the course of a reaction in such a way that predominantly one of the possible optical isomers is formed [154]. Cellulose fibers form a sort of pillar against which benzaldehyde and hydrogen cyanide molecules constantly collide. During these collisions, they are oriented by the asymmetric cellulose fibers in a manner that facilitates the formation of one of the mandelonitrile stereoisomers. Cellulose in this reaction can also be called an organizer or inducer of asymmetric synthesis, to emphasize the distinction between it and a true catalyst, the amine. Of all the terms, "organizer" is the most suitable to describe the function of cellulose, as it indicates that its principal function is to "organize" the reaction so that it proceeds in a strictly defined direction. By analogy with this phenomenon, the hypothetical templates in the aforementioned theory of protein synthesis are likewise not catalysts; their role consists merely in adsorbing amino acids in a specific manner, thereby creating the conditions for the enzymatic formation of peptide chains of only one defined structure. These templates consequently prevent the formation of peptide chains with randomly arranged amino acids.

Summarizing everything we know about the mechanism of protein synthesis, this process can be divided into the following phases:

1. Specific adsorption of amino acids from the cellular contents by identical amino acid residues that form part of the stretched protein film.

2. Action of a non-specific enzyme on the adsorbed amino acids, resulting in the formation of a copy of the template protein film.

3. Folding of the two-dimensional protein film and formation of a three-dimensional globular molecule. The shape of this three-dimensional molecule is determined by the shape and electrostatic field of the polar groups that are constituents of the cellular contents and are located in the immediate vicinity of the synthesis site. In the case of antibody synthesis, the shape of the globular molecule is determined by the shape of the antigen's determinant groups.

One of the main tenets of the aforementioned hypothesis is the concept that enzyme action is non-specific and that the Specificity of protein synthesis is determined solely by the electrostatic field and surface shape of the template. This assertion is based on the fact that no enzyme exhibiting species specificity has yet been found. For example, the action of chicken Pepsin on swine pepsinogen yields swine pepsin rather than chicken pepsin [156]. PLANT AND ANIMAL proteins are cleaved equally easily by proteolytic enzymes of both plant and animal origin.

Despite these findings, some authors still recognize the existence of enzymes that catalyze the Synthesis of specific proteins. For instance, Burnet [155], based on a number of considerations outlined in Chapter XIV (see p. 351), believes that Antibodies Are Formed not only in the presence of sensitizing Antigens, but also when the antigen is destroyed or eliminated from the sensitized organism. According to Burnet, antibody production is characteristic not only of directly stimulated cells, but also of the cells derived from them.

In support of his views, Burnet refers to experiments demonstrating the formation of adaptive enzymes by Molds and Bacteria "trained" to foreign substrates.

The notion of the existence of enzymes responsible for the formation of specific proteins, as already noted, is not supported by any experimental data; however, we currently lack experimental data that would allow us to definitively reject it either. The principal theoretical objection to this assertion is that it can hardly be reconciled with modern physicochemical concepts of the nature of catalysis. It is impossible to conceive of a catalyst that would direct the synthesis of specific peptide chains by linking amino acids in a strictly predetermined order. The action of all known catalysts and enzymes is limited at any given moment to influencing one specific molecular grouping. After performing its function once, an enzyme can repeatedly exert the exact same action. However, it is impossible to imagine an enzyme that would catalyze, for example, the attachment of tyrosine to the terminal amino group of a peptide chain, and then promote the attachment of alanine, glutamic acid, Cysteine, and other amino acids. All available data on enzyme action indicate that an enzyme selectively catalyzes a single reaction and that the nature of its action remains unchanged.

Earlier, in discussing the mechanism of protein synthesis, we spoke, on the one hand, of the role of proteins as templates for this synthesis, and on the other hand, of the role of enzymes. We must not forget, however, that enzymes are also proteins, and that many proteins previously thought to lack enzymatic functions have actually proved to be enzymes once suitable substrates were found for them. Northrop [150], who proved that enzymes are formed from zymogens, suggests that proteins may likewise be formed from proteinogens in an analogous manner. According to Northrop, the first step in protein synthesis is the formation of a standard protein—proteinogen—from amino acids, and the subsequent step is the autocatalytic formation of individual proteins from proteinogen [156].

At present, however, there is no way to critically discuss this viewpoint, since there are no data regarding the mechanism of the conversion of zymogen into enzyme and of proteinogen into protein.

The main purpose of all the aforementioned arguments concerning the mechanism of protein synthesis was to demonstrate that a physicochemical explanation of this process can be reconciled with modern concepts in physical chemistry and biology.

This reconciliation is achieved in this case by eliminating everything that contradicts established physicochemical concepts or experimental data. Of course, it would be much better to formulate a theory of protein synthesis based solely on experimentally derived facts. At present, however, this is still impossible, which necessitates resorting to various hypotheses and assumptions.

Research work is unthinkable without guiding ideas. The formulation of new hypotheses is therefore permissible where experimental data are lacking for the construction of sufficiently substantiated theories.