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

Enzymes: Protein Catalysts of the Cell
Regulation of Enzymatic Activity
Regulation of Enzyme Activity

There are relatively rapid regulatory mechanisms that act directly on Enzymes. For instance, a practically inactive enzyme can be converted into its active form through covalent modification [72]²¹. Conversely, covalent modification sometimes results in Enzyme inactivation. For example, the activities of two enzymes involved in Glycogen METABOLISM—Glycogen phosphorylase and glycogen synthase—are regulated by phosphorylation (The transfer of a terminal phosphate group from ATP to a specific Serine residue; see Ch. 11, Sec. E, 3)³). In this process, The enzyme catalyzing glycogen breakdown (phosphorylase b) is converted into a more active form (phosphorylase a), whereas the enzyme catalyzing glycogen synthesis is converted into an inactive form. As a result, the direction of cellular metabolism shifts from polysaccharide (glycogen) storage to its degradation, thus providing The Cell with energy. Dephosphorylation of both enzymes is catalyzed by a phosphatase, which restores them to their initial state (Fig. 6-15). Both the modification-catalyzing enzyme (a kinase; Ch. 7, Sec. D, 6) and the phosphatase are regulated allosterically. These rather complex mechanisms are capable of supplying the cell with a modified enzyme within a very short span of time.

The activity of Glutamine Synthetase (Ch. 14, Sec. B, 2) is altered via adenylylation of the side group of a strictly specific Tyrosine residue, a reaction that utilizes ATP [73]. The reverse reaction is catalyzed by a deadenylylating enzyme.

The most widespread Mechanism of enzyme regulation in Cells appears to be allosteric activation or inhibition, as briefly outlined above (Sec. B, 6). Metabolic pathways are controlled by A wide variety of allosteric mechanisms, the two most common of which are as follows. The first can be termed precursor activation. A metabolite acting as an allosteric effector "switches on" the enzyme that catalyzes The conversion of either this same metabolite or a product occurring slightly further down the metabolic chain. For example, in Fig. 6-15, metabolite C (the precursor) activates the enzyme that catalyzes the virtually irreversible conversion of compound D. In other cases, activation is less direct. The "switched-on" enzyme may participate in The formation of a second substrate, the interaction of which with the activating metabolite yields the required metabolic product.

¹⁾ Note that reversible enzyme association [Kurganov, B. I. (1978). Allosteric Enzymes. Moscow: Nauka, pp. 117–174; Frieden, C. (1971). Ann. Rev. Biochem., 40, 653–695] or reversible adsorption of enzymes onto subcellular structures [Wilson, J. E. (1978). Trends Biochem. Sci., 3, 124–125; Masters, C. J. (1978). Trends Biochem. Sci., 3, 206–208; Kurganov, B. I., & Loboda, N. I. (1977). Bioorg. Khim., 3, 1407–1419], controlled by cellular metabolites, may also have regulatory significance. — Translator's Note.

²⁾ See also Proceedings in Life Sciences: Metabolic Interconversion of Enzymes, IV International Symposium held in Arad, Israel, April–May 1975, Shaltiel, H. (Ed.), Springer-Verlag, Berlin, 1976, p. 234. — Translator's note.

³⁾ For recent data on The regulation of phosphorylase and glycogen synthase activity via phosphorylation-dephosphorylation, the reader is referred to the following reviews: Cohen, P. (1978). In: Regulatory Mechanisms of Carbohydrate Metabolism, Proc. 11th FEBS Meeting, Vol. 42, Symp. A1, Esmann, V. (Ed.), Oxford, Pergamon Press, pp. 31–40; Nimmo, H. G., & Cohen, P. (1977). Adv. Cyclic Nucleotide Res., 8, 145–266. — Translator's note.

A more common type of regulation than precursor activation is negative feedback inhibition, wherein the accumulation of the end product of a metabolic pathway leads to the "switching off" of the enzymes required for its synthesis. Most frequently, the activity of the first enzyme occupying a key position in the biosynthetic chain is suppressed. At the same time, the product often inhibits the activity of more than one enzyme in the chain (Fig. 6-15). When a cell produces two or more Isoenzymes, a specific product frequently inhibits only one of them. For instance, in Fig. 6-15, product P inhibits the activity of only one of the two isoenzymes catalyzing the conversion of A to B; the activity of the other is controlled via chemical modification.

A concrete example of this kind is presented in Fig. 14-6: the conversion of aspartate into β-aspartyl phosphate—the precursor of the end products (Threonine, isoleucine, Methionine, and Lysine)—is catalyzed by three isoenzymes. As shown in the figure, each product inhibits only one of the isoenzymes¹⁾.