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

Peptides in Aqueous Solutions
Tissue-Specific Regulatory Peptides

The evolutionary transition from unicellular organisms to multicellular systems and organisms was accompanied by The Development of highly sophisticated Intercellular Communication mechanisms to coordinate The behavior of all Cells for the benefit of the Organism as a whole. This gave rise to a system of endogenous signaling molecules—predominantly Amino Acid and peptide derivatives—that enables a Cell, via its Plasma Membrane and Membrane Receptors, to distinguish its native cellular environment from foreign ones. This system of intercellular molecular signals allows each cell to determine its position and coordinate the timing of division and apoptosis with its neighbors. For example, while a Yeast cell exists as an individual organism, it influences the proliferation of neighboring yeast cells. When such local "social" control over Cell Division fails in a multicellular organism, malignant growth of a specific tissue begins, which is fatal to the entire organism.

In mammals, Three types of information transfer and functional coordination are distinguished among Organs and Tissues: neural, endocrine, and paracrine.

The neuronal system controls and coordinates the Functions of all organs and the behavior of the organism as a whole. Neurons belong to the family of electrically excitable cells, which also includes Muscle and endocrine cells. Upon depolarization of The Cell membrane, neurons generate an Action Potential, or Nerve Impulse, which propagates along the axon from one neuron to another at speeds of up to 100 m/s. While the length of axons varies across different neurons, the longest can reach up to 1 m (Alberts et al., 1994). Cell membrane depolarization can be triggered by various physicochemical factors, including peptide-type Neurotransmitters.

The endocrine signaling system consists of specialized cells that release signaling molecules (Hormones) directly into the bloodstream, including regulatory Peptides (RPs). Circulating throughout the body via the bloodstream, hormones reach target organs and cells, where they are captured by specific receptors. On average, the affinity binding constants of hormones to their receptors exceed 10⁸ L/mol, allowing hormones to exert biological effects at concentrations below 10^-8 M.

Signals in the paracrine regulatory system are transmitted via endogenous molecules (local mediators) whose effects are restricted to the immediate cellular microenvironment. Local mediators include regulatory substances of various classes: alarmones, Eicosanoids, and peptides (Alberts et al., 1994).

Thus, every cell in a multicellular organism is controlled both by the coordinating information systems of the whole organism and by its immediate cellular surroundings. It not only perceives signals intended for it, but can also secrete its own signaling molecules targeted at its environment. This constitutes the autocrine signaling system. Its signaling molecules do not travel long distances; instead, they are perceived by neighboring cells or sequestered by the Extracellular matrix (Alberts et al., 1994). The autocrine system is crucial during the final stages of organismal development, when cells in formed organs transition to the differentiation stage. When a group of identical neighboring cells begins to differentiate, autocrine signaling molecules are secreted simultaneously, locking in the transition of the cells and the entire organ to a new functional stage (Paltsev, Ivanov, 1995).

The Diversity of autocrine signaling systems across various organs is driven by tissue-specific families of relatively short regulatory peptides. In most cases, they are synthesized within The Cell as relatively large precursor peptides, with the precursor typically containing multiple segments that, upon Cleavage, acquire The ability to regulate specific biological functions. This endogenous regulation represents one of the most ancient self-regulatory mechanisms in living systems, although it remains insufficiently understood to this day.

Likewise, the relationship between The Structure of an RP and the specific cellular function it regulates remains an unresolved problem. Only one thing is clear: this relationship is highly specific and precludes random variations in the Peptide Structure.

According to I. I. Schmalhausen, the integration of Amino Acids into a peptide chain during early evolutionary stages was a purely chemical, stochastic process (Schmalhausen, 1961). In the 1950s and 1960s, prior to the development of targeted chemical Peptide Synthesis Methods, synthetic Polypeptides were produced by polycondensation of amino acids in the presence of phosphoric acid or polyphosphate. It was demonstrated that statistical polypeptides (proteinoids) obtained in this manner exhibit significant amino acid selectivity when choosing a neighboring amino acid to form a peptide bond. Proteinoids derived from an equimolar mixture of amino acids differed from the starting mixture by an Abundance of glutamic acid, Lysine, and Alanine (Fox, 1965). When the initial mixture contained an excess of glutamic acid or lysine, the Amino Acid Composition of the products also varied in the content of hydrophobic amino acids (Table 5). These results indicate varying reactivities of amino acids in statistical copolycondensation reactions. Later, it was shown that in the presence of condensing agents, free Amino Acids and adenylic acid readily form aminoacyl adenylates, and a mixture of aminoacyl adenylates, in turn, spontaneously forms high-molecular-weight proteinoids at pH 9.0 (Lehninger, 1974).

Class="center">Table 5. Amino acid composition of high-molecular-weight proteinoids obtained at 60 °C after 150 h of incubation of amino acid mixtures containing an excess of lysine or glutamic acid, % (after: Fox, Dose, 1975)

* The content of Other Amino Acids did not exceed 2%.

This approach formed the basis for the empirical synthesis of biologically active statistical polypeptides. In this manner, polypeptides with an undetermined Amino Acid Sequence (COP-1 preparation) were synthesized from a mixture of L-Ala, L-Glu, L-Lys, and L-Tyr in a ratio of 6.0 : 1.9 : 4.7 : 1.0; these polypeptides have proven highly effective in treating various Brain pathologies (Teitelbaum et al., 1971; Bornstein et al., 1987). However, this approach does not allow for the Determination of the relationship between an RP's structure and its specific MECHANISM OF ACTION.

In biological peptide synthesis, The amino acid sequence is genetically determined. An evolutionary approach to RP functions allows them to be divided into three main groups based on their ontogenetic origin from different germ layers and the subsequent distribution of vital organismal functions among various organs and tissues. During early embryonic development, three differentiated cell layers are distinguished: the endoderm (the inner layer), the mesoderm (the intermediate layer), and the ectoderm (the outer layer of the embryo). This primary differentiation stage dictates the subsequent development of individual organs and tissues. The ectoderm gives rise to organs associated with contact, sensory, and integumentary functions: the epithelium, the brain, the Spinal Cord, and Sensory Organs (Vision, Hearing, smell). The endoderm serves as the foundation for the Development of the digestive tract, respiratory organs, and internal viscera (Heart, Endocrine glands, and reproductive organs). The intermediate layer, the mesoderm, drives The formation of organs with supportive and trophic functions: the Skeleton, Muscles, Circulatory system, and Connective Tissue. The structures and tissue Specificity of known regulatory peptides correlate to a certain extent with their ancestral origins, and in some cases, their structures exhibit cross-tissue specificity. The grouping of regulatory peptides according to their origin can be used to correlate their Amino acid sequences with specific biological activities in the body.

A prior statistical Analysis of the amino acid sequences of endogenous regulatory oligopeptides contained in the EROP-Moscow database in 1989 revealed an elevated content of amino acids with positively charged and cyclic side chains (Zamyatnin, 1990). To a large extent, this observation stemmed from the fact that the analysis primarily focused on Neuropeptides and neurohormones. Over the past decade, the volume of data regarding the amino acid sequences of peptides that regulate immune and gastrointestinal functions has expanded significantly. This section discusses only peptides of moderate length as the most stable (conserved) structures that have preserved their regulatory functions throughout Phylogenetic and Ontogenetic development. Their categorization into groups is largely conventional—they are classified according to their primary localization, functions, and ontogeny. It should also be noted that these peptides are generally species-nonspecific, meaning they occur and function in most higher organisms. In particular, ubiquitin shares the same structure and performs its diverse regulatory functions in yeast, plants, and humans alike.

This section does not cover regulatory metallopeptides (such as calmodulin, which contains 4 calcium atoms in its structure), which lack defined tissue specificity and essentially act as Coenzymes for numerous enzyme systems (Oxford Dictionary..., 1997), nor does it cover the heterogeneous group of interleukins—species-specific Proteins with molecular weights of 12–21 kDa that act as signaling molecules between different leukocyte populations.