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

Enzymes: Cellular Protein Catalysts
Regulation of Enzymatic Activity
Key Enzymes

Metabolic control is achieved primarily through mechanisms that regulate enzyme localization, Abundance, and catalytic activity [41, 66]¹⁾. In this section, we briefly review these regulatory mechanisms and introduce the terminology and notation that will be used throughout the book. Many of the control mechanisms discussed are summarized in Fig. 6-15.

¹⁾ See also Cohen, P. (1976). Control of enzyme activity, London: Chapman and Hall; Scrutton, M. C., & Schramm, V. L. (1977). Molecular aspects of medicine, 1, No. 4, Modulation of enzymic activity, Oxford: Pergamon Press, pp. 283–366. — Transl. note.

Unraveling the Principles of Metabolic control becomes much simpler if we focus our attention on Enzymes that catalyze rate-limiting steps under given conditions—the key²⁾ enzymes. Key enzymes are frequently those that catalyze: (a) reactions that determine The rate of cellular Respiration; (b) reactions that initiate substrate conversion under conditions where downstream metabolic intermediates do not accumulate; and (c) reactions at which metabolic pathways branch. Typically, the rate-limiting step for the overall process is the first step of a specific biosynthetic pathway (often referred to as the committed step). Such reactions are generally accompanied by a large decrease in Free energy and must be tightly regulated by The Cell. Conversely, enzymes catalyzing intermediate steps may remain unregulated and operate at or near equilibrium.

²⁾ The author uses the term “pacemaker enzymes.” We have deemed it appropriate to replace this term with “key enzymes,” which is equivalent in this context. — Transl. note.

When cellular conditions change, a rate-limiting reaction may cease to be rate-limiting. For example, the concentration of a metabolite may drop to a level where the overall process rate is determined by the rate of its formation in the preceding reaction. Thus, during Glucose METABOLISM in our bodies, rapidly interconverted sugar phosphates are formed—glucose-6-phosphate and fructose-6-phosphate. The key enzyme in glucose metabolism is often Phosphofructokinase [Chap. 11, Sect. E, 4, scheme (13-91), step b], which catalyzes the further metabolism of fructose-6-phosphate. However, under sufficiently high metabolic flux, The formation of glucose-6-phosphate from glucose can become rate-limiting (step a, catalyzed by hexokinase; see the scheme below).

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FIG. 6-15. Selected mechanisms of metabolic control. Throughout this book, the modulation of enzyme activity by allosteric effectors, as well as the modulation of Gene activity (Transcription and Translation), is indicated by dashed lines originating from the respective metabolite. The lines end with a minus sign for inhibition and derepression, and a plus sign for activation and depression. Circles represent direct effects on enzymes, whereas squares denote the repression or induction of enzyme synthesis. (A similar scheme is presented in reference [66a].)

Certain catabolic processes depend on ADP. However, under high metabolic rates, the ADP concentration can drop dramatically due to its near-complete phosphorylation to ATP. Under these conditions, reactions utilizing ADP may become rate-limiting in the corresponding reaction sequences. Depletion of a reactant can also lead to a complete shift in the metabolic pattern. For instance, when Yeast Cells are deprived of oxygen, the reduced coenzyme NADH accumulates and reduces pyruvic acid to lactic acid (Chap. 7, Sect. A, 6), representing a metabolic shift from oxidative metabolism to Fermentation.

In Conclusion, while THE CONCEPT OF key enzymes is extremely valuable, it should be kept in mind that different enzymes may act as key enzymes depending on physiological conditions. It is also important to recognize that reaction rates are frequently governed by the diffusion rate of a particular compound across a membrane. Consequently, membrane transport processes can also serve as rate-limiting steps in metabolism.