Peptide Self-Regulation of Living Systems (Facts and Hypotheses) - Shataeva L. K. 2003

Peptides in Aqueous Solutions
Regulatory Peptides as Carriers of Molecular Information
Frequency Characteristics of Amino Acid Sequences of RI

As data in Tables I–IV of the Appendix show, regulatory Peptides (RPs) from various groups share certain common properties. On the one hand, they all have a relatively small size (the Molecular Weight of these peptides does not exceed 10 kDa) and exhibit physiological activity at ultramicrodoses. In many cases, RP fragments exhibit biological activity by modulating precursor activity: either altering the range of activity or inhibiting it. Apparently, the functional and tissue Specificity of these peptides' action is associated with The Diversity of cellular receptors, although the possibility of receptor-independent Cell penetration and the peptide's direct impact on intracellular processes cannot currently be completely ruled out.

On the other hand, the data in Tables I–IV of the Appendix demonstrate differences in the Amino Acid Composition of peptides belonging to different Tissues and participating in The regulation of tissue-specific Functions. The amino acid composition of each RP group can be used to compare them with one another by the frequency of amino acid residue inclusion, similar to what was done for the "averaged protein" in the work of V. A. Konyshev (1985). The data presented in the aforementioned tables were used for such a comparison, and the obtained results are given in Table 6, which presents only the first 9 ranks, since in the studied systems, amino acid residues belonging to the first 6 ranks account for more than 55%, and residues of the first 9 ranks account for more than 80% of all positions in polypeptide chains. Table 6 also includes data for several regulatory Proteins, which will be discussed in the next section. It is worth noting that the distribution of Amino Acids by frequency rank for natural regulatory Peptides and Proteins differs from that of synthetic proteinoids (see Table 5) by a high rank of leucine, glutamic acid, and Cysteine, but is similar to them in the high rank of Glycine, Alanine, and Lysine.

The frequency characteristic of the amino acid composition of peptides in each group is the obvious reason for the frequent recurrence of the same combinations of amino acid residues in their chains. Less obvious is the reason why amino acid residues included in the peptide chain follow one another with a certain preference (selectivity). Apparently, as statistical polycondensation of amino acids shows (Fox, 1965; Fox & Dose, 1975), this is related to differences in their reactivity. Since during evolution certain selective combinations of amino acid residues proved useful for the vital Functions of the Organism, they were fixed at The Genome level. However, comparing the degeneracy of METABOLISM/28.html">The Genetic Code of each amino acid (the number of codons that ensure its incorporation into the peptide chain during ribosomal synthesis) with the frequency of its inclusion in peptides reveals a certain correlation only for the neuropeptide group. No significant correlations were found for other groups of peptides and high-molecular-weight regulatory proteins.

Class="center">Table 6 Rank order of amino acid residues in RPs and regulatory proteins belonging to different regulatory systems

Note. Amino acid residues with ionogenic side groups are marked with a plus or minus, respectively.

* The index indicates the degree of degeneracy (Lehninger, 1974).

Let us examine the repeats of identical amino acid combinations (regular sequences) within each RP group.

Based on the data in Tables I–III of the Appendix, a statistical analysis was performed on the frequencies of identical repeats of short Amino acid sequences (dimers, trimers, quartets, and quintets) within peptides belonging to different functional groups. Amino acid sequences were read from the N- to the C-terminus.

Tabular sequences of short oligopeptides that are part of already accounted longer Polypeptides of a given group were excluded from the calculation. Table 7 presents the repeating fragments of amino acid sequences for the peptides of each group.

Among higher associations, blocks (quartets and sextets) can be noted where one of the amino acids is replaced by one with similar physicochemical properties: these are YLDS and YLES, as well as TSDFSK and TSDYSK within gastrointestinal peptides.

A similar statistical Analysis of the arrangement of adjacent amino acid residues in the polypeptide chain has been carried out previously (Pankov et al., 1976; Erhan et al., 1980; Pansevich & Barkovsky, 1990). In particular, the same pentapeptide was discovered in The Structure of Histones and ß-galactosidase (Erhan et al., 1980). Within calmodulin, L. I. Pansevich and E. V. Barkovsky (1990) revealed double repeats of trimers and quartets: EAF, AEL, AVD, DKDG, DGDG, DGNG, IREA. Conformational analysis performed by these authors showed that the discovered repeating blocks are predominantly in α-helical or β-sheet Conformations. It was proposed that the obtained data on the similarity of repeating blocks and their conformations be used both to classify organisms belonging to different taxonomic groups (Erhan et al., 1980; Pansevich & Barkovsky, 1990) and to search for correlations between the Amino Acid Sequence in trimers and the nucleotide code matrix (Pankov et al., 1976).

From our perspective, the multiple repetition of individual units within a group of peptides can serve as a sign of this group's functional community and as a basis for the tissue-specific Classification of the polypeptide. According to this criterion, calmodulin does not belong to any of the regulatory peptide groups we studied.

The results presented in Table 7 demonstrate several interesting features in the amino acid sequences of RPs.

First, each group of tissue-specific regulators is characterized by different compositions and sequences of amino acids in repeating blocks, with the exception of the EA and ED blocks, which repeat 3 and 4 times in the compositions of neuro- (NPs) and immunopeptides (IPs).

Second, simple combinatorics shows that out of 20 coded amino acids, 400 dimers differing in composition and residue sequence can be formed. Although not all of them are present in the studied peptides, more than a third of the existing ones repeat twice or more frequently (30, 37, and 47% of dimer repeats in IPs, NPs, and gastrointestinal peptides, respectively). It should be emphasized that each dimer is individual: it has structural a "HEAD" and "tail" combined with a dipole moment vector, spatial arrangement of electrical charges, and molecular mobility.

Table 7 Repeatability of amino acid blocks in regulatory peptides belonging to different physiological systems

Third, both the RPs isolated from various tissues and the repeating blocks within them combine hydrophilic and hydrophobic amino acid residues in their structures—i.e., they are amphiphilic, although the averaged Hydrophobicity of NPs is higher than that of IPs.

We divided peptide regulators into groups in accordance with the existence in the organism of several multifunctional control systems (nervous, immune, digestive), each consisting of many Organs with specialized functions. Therefore, the peptides in each group vary greatly in their range of regulatory functions. For example, NPs are characterized by a "triad" of main actions (Ashmarin & Karazeeva, 1999): 1) contraction or relaxation of smooth Muscles; 2) vasomotor activity; 3) releasing functions.

Peptides regulating the Digestive System are characterized by 1) periodic stimulation of enzymatic processes in various PARTS OF THE GI tract; 2) step-by-step regulation of system peristalsis; 3) sequential and coordinated inhibition of hydrolytic Enzymes in different parts of the GI tract (Klimov, 1983; Galperin & Lazarev, 1986).

Biomedical organ preparations duplicate these tissue-specific functions to a certain extent. In particular, preparations of the cytomedin class (Morozov & Khavinson, 1983) and cytamins (Morozov et al., 2000a), isolated from specific organs and tissues, possess a regulatory specificity that corresponds to the functions of these organs and tissues, although THE SPECTRUM OF functions they regulate is usually narrower than that of the endogenous RP system. Each of these preparations restores impaired self-regulation of a specific organ: the Brain, coronary vessels, Pancreas, Liver, prostate, or Thymus. At the same time, the structures of individual peptides isolated from these preparations using Ion-exchange Chromatography reveal compositional affiliation to one or another RP group. In particular, the preparation Thymalin includes RPs that belong to the immunopeptide group, as they contain the KE and KAK blocks (Morozov et al., 1977).

Apparently, a similar frequency analysis of repeating oligopeptide blocks can be applied to other families of high-molecular-weight polypeptide regulators, such as growth factors, transforming factors, Neurotrophic Factors, and Membrane Receptors, which are characterized not so much by tissue specificity as by functional specificity. Identifying the characteristic oligopeptide blocks of such groups is necessary not only for the targeted counter-synthesis of peptide therapeutic drugs mimicking the functions of natural macromolecules. Common blocks in the structure of regulatory polypeptides—evidence of their belonging to certain families—can serve as a basis for constructing physicochemical models of intermolecular interactions between polypeptides and a living cell; such interactions are, essentially, informational.