Biochemistry - The Chemical Reactions of Living Cells Volume 2 - D. Metzler 1980

Enzymes: Protein Catalysts of Cells
Regulation of Enzymatic Activity
Hormones

An important element of Metabolic control is the binding of Hormones to receptors located on The Cell surface. In some cases, the entire effect of a hormone (such as Glucagon or adrenocorticotropic hormone) can be explained by the activation of the enzyme adenylate cyclase (stage a in the scheme below):

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This enzyme catalyzes The conversion of ATP to cyclic AMP (cyclic adenosine monophosphate, or cAMP). The Chemical aspects of this reaction are discussed in Ch. 7, Sec. D, 8. Cyclic AMP is sometimes referred to as a "second messenger," as it carries the message delivered to the cell by the "first messenger" (the hormone). Cyclic AMP is rapidly hydrolyzed to AMP by phosphodiesterase (stage b in the scheme; see also Ch. 7, Sec. D, 8). However, as long as cAMP persists, it acts as an allosteric effector for protein Kinases (stage c in the scheme), which catalyze modification reactions such as the phosphorylation of Glycogen synthetase (see the previous section, as well as Ch. 11, Sec. E, 3).

¹⁾ To the aforementioned types of Allosteric Regulation of key enzyme activity by cellular metabolites, one should add another important regulatory mechanism—namely, regulation by compounds that indicate the energetic status of the cell (inorganic phosphate, pyrophosphate, adenine or other purine NUCLEOTIDES); this type of regulation is characteristic of degradative pathways as well as amphibolic pathways, which can involve both biosynthetic and degradative processes.—Transl. note.

A typical representative of this group of Enzymes is soluble cAMP-dependent protein kinase, which exhibits broad substrate Specificity. The enzyme isolated from Muscle is an a2ß2 dimer. Its two catalytic subunits remain inactive until cAMP binds to the Regulatory Subunits. The binding of cAMP leads to the dissociation of the complex into active catalytic monomers and a cAMP-containing regulatory subunit composed of two monomers [73a, 73b].

In 1956, E. Sutherland established that cAMP is the compound that mediates the effects of adrenaline and glucagon hormones on Glycogen phosphorylase. For many years, most biochemists viewed cAMP as a mere curiosity and the chemical mechanism of phosphorylase regulation as something exceptional. Recently, however, views on this matter have changed dramatically, as it has been shown that cAMP mediates the action of more than twenty different hormones. Cyclic AMP also appears to mediate the action of Neurotransmitters released at synapses. Even E. coli produces cAMP, which acts as a positive effector in initiating the METABOLISM/31.html">Transcription of certain genes (Ch. 15, Sec. B, 2). In 1971, Sutherland was awarded the Nobel Prize for the successful development of this research field [74, 75].

While in higher organisms cAMP Functions mainly within Cells, in the slime mold Dictyostelium discoideum it transmits information from Cell to Cell (Ch. 1, Sec. G, 1). It is noteworthy that the mechanism for lowering cAMP levels remains the same, relying on the participation of phosphodiesterase [76]. The production of cAMP is oscillatory in nature, which is associated with an autocatalytic control mechanism involving the activation of adenylate cyclase (by 5'-AMP) and a hydrolase (by cAMP) that catalyzes the direct Cleavage of ATP to 5'-AMP [77].

It is known that adenylate cyclase is bound to the inner surface of membranes; nevertheless, its activity changes significantly upon the Interaction of hormones with receptors located on the outer surface of membranes (Ch. 5, Sec. V, 5). The Mechanism of transmembrane chemical signal Transduction remains unclear. Of particular interest is the fact that a protein toxin from Vibrio cholerae causes the diarrhea and salt loss characteristic of Asiatic cholera by stimulating adenylate cyclase in the epithelial Cells of the Small Intestine [78, 79].

The functions performed by cAMP within cells are extremely diverse. The allosteric activation of protein kinases affects a wide range of enzymes related to Energy Metabolism. Not only Histones—Proteins of the Cell Nucleus—but also Membrane Proteins [79a], microtubules, and Ribosomes undergo phosphorylation [79b] (Ch. 15, Sec. I, 2). In cells with different specializations, the exact same mechanism can lead to completely different effects; several specific Examples of this are discussed below.

Many enzymes modified by protein kinases require Calcium Ions. Therefore, the full expression of adenylate cyclase activity also requires the release of Ca²⁺ ions into the Cytoplasm, which is typically triggered by a Nerve Impulse. An increase in Ca²⁺ ion uptake is observed, for example, upon the binding of concanavalin A by T-lymphocytes (Ch. 5, Sec. V, 3) [80]. The control of Ca²⁺ influx into cells appears to play a major role in Intercellular Communication.

The possible conversion of guanosine triphosphate (GTP) into cyclic GMP (cGMP), which can act as a cAMP antagonist in many metabolic control processes, is currently a subject of intense Structure/133.html">Discussion [81–83]. However, cyclic GMP and other Cyclic Nucleotides are present in much smaller amounts than cAMP. It should also be noted that GTP is absolutely essential as an additional allosteric activator that ensures a sufficiently high sensitivity of Liver cell adenylate cyclase to glucagon [84].

Note that although Insulin-specific receptors have been identified (Ch. 5, Sec. V, 5), The Mechanism of this hormone's action on metabolism remains elusive. Its primary effect on Carbohydrate Metabolism appears to be the Regulation of the rate of glucose entry into the cell [85]. It is hypothesized that cyclic GMP plays The Role of a mediator in this process.

The MECHANISM OF ACTION of Steroid Hormones is entirely different. These molecules enter cells and bind to specific receptor proteins located in the Cytosol [86–88]. The hormone-Protein Complexes then migrate to The Nucleus, where they presumably alter Gene activity by regulating transcription or Translation Processes (Fig. 6-15).