BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 5. STRUCTURE, PROPERTIES, AND FUNCTIONS OF PROTEINS

5.4. Protein Functioning

5.4.2. Substances Affecting Protein Functioning

Although the interaction between a Ligand and the Active Site of a protein is highly specific, it is always possible to find another substance that will also interact with the protein. A ligand that interacts with a protein and impairs its function is called a protein inhibitor. If this substance is structurally similar to the ligand, it is referred to as a structural analogue of the ligand; it also interacts with the protein's active site. An analogue that replaces the natural ligand in the active site of the protein and diminishes its function is termed a competitive protein inhibitor.

Analogues of natural protein ligands are used in medicine as Pharmaceuticals. Such medications are widely applied in regulating the transmission of excitation through synapses.

Signal transmission from nerve to nerve or from a nerve to an effector organ occurs via synapses using chemical molecules known as Neurotransmitters. A neurotransmitter released during the passage of an impulse along nerve endings must interact with high Specificity with receptor Proteins on the postsynaptic membrane. However, by modifying the Chemical Structure of a neurotransmitter, one can obtain substances that also bind to receptors while altering the physiological effect—either decreasing or increasing it. In pharmacology, such substances are designated as antagonists and agonists, respectively.

Inhibitors of receptor proteins in cholinergic synapses. As an example, consider drugs that disrupt the conduction of nerve impulses through cholinergic synapses, where acetylcholine serves as the neurotransmitter. Cholinergic receptor proteins are structurally heterogeneous and capable of binding to ligands other than acetylcholine. They are divided into two major groups:

✵ M-cholinergic receptors (muscarinic receptors), named for their ability to selectively interact with muscarinine (a toadstool toxin);

✵ N-cholinergic receptors (nicotinic receptors), which selectively bind nicotine.

Neuromuscular synapses contain N-cholinergic receptors, the interaction of which with acetylcholine triggers Muscle contraction. To induce muscle relaxation during endoscopic examinations and various surgical Procedures, structural analogues of acetylcholine that act as inhibitors of these receptors are employed. An example of such a substance is dithylin (succinylcholine), which belongs to a group of medicinal substances known as muscle relaxants (inducing muscle relaxation). These properties were first discovered in curare poison, which is why these drugs are also referred to as curare-mimetic agents:

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The best-known specific inhibitor of M-cholinergic receptors is atropine. It is an alkaloid found in certain plants: belladonna, henbane, and thornapple (datura). It binds to M-cholinergic receptors located on the membrane of effector Cells in the region of parasympathetic nerve endings. Atropine prevents their interaction with acetylcholine (acting as a natural ligand antagonist), thereby abolishing the effects of parasympathetic nerve stimulation.

Since acetylcholine binding to M-cholinergic receptors causes the contraction of many smooth Muscles, atropine (as a pharmaceutical drug) relieves muscle spasms (acting as a spasmolytic). Additionally, it reduces acetylcholine-stimulated secretion of glands (bronchial, digestive, and Sweat Glands).

M-cholinergic receptors are present in various Regions of the CNS. An overdose of atropine can cause motor and speech excitation.

Medicinal substances that stimulate Protein Functions. Some structural analogues of receptor protein ligands are not inhibitors; instead, they elicit stronger physiological effects than natural ligands. Their enhanced efficacy is often due to the fact that modified ligands are inactivated and degraded more slowly within the body. For instance, mesaton is structurally similar to the neurotransmitters of the sympathetic Nervous system (norepinephrine and epinephrine). Mesaton increases vascular tone and BP, which is why it is used in cases of hypotension and collapse. It is less susceptible to degradation by inactivating Enzymes, thus exhibiting a longer and more potent effect than its natural analogues:

Poisons as specific ligands of certain proteins. Upon entering The Human Body, certain poisons bind tightly to specific proteins, inhibit them, and thereby cause disruptions in biological functions.

For example, cobra $\alpha$-neurotoxins specifically interact with cholinergic receptors of postsynaptic membranes, blocking their operation and acting similarly to curare. $\alpha$-Neurotoxins are small proteins with a Molecular Weight of up to 7000 D (65-70 amino acid residues). Their tertiary structure is stabilized by four or five specific Disulfide Bonds (depending on the toxin species). The affinity of neurotoxins for cholinergic receptors is very high (K_дис = 10^-11). Evidently, A large number of bonds form between the toxin and the receptor, leading to their practically irreversible combination.

It must be kept in mind that the boundary between drugs and poisons is often very blurry, and The Effect of their action frequently depends on the dose of the administered substance. Thus, medications prescribed in doses exceeding therapeutic levels can act as poisons—that is, cause severe disorders of METABOLISM and bodily functions—whereas poisons in microdoses are frequently used as medicinal preparations. For instance, atropine, which is widely utilized to relieve smooth muscle spasms, causes CNS excitation in large doses, and in even larger doses induces Sleep that progresses into a coma. The well-known hypotensive agent clonidine, in the event of an overdose, causes collapse.