Metabolic Control Mechanisms

Mechanisms for controlling metabolic pathways are varied in cells. Some include the following:

> Control of enzyme levels - The concentrations of different enzymes vary widely in cellular extracts. Enzyme levels are controlled in large part by controlling the enzyme's rate of synthesis. Enzyme synthesis can often be induced or repressed by the presence or absence of certain metabolites. The rate of enzyme degradation can also be a factor in controlling enzyme levels.

> Control of enzyme activity - The catalytic activity of an enzyme can be controlled in two ways: by reversible interaction with ligands and by covalent modification of the enzyme itself.Low molecular weight ligands can interact with enzymes and exert allosteric effects. Frequently, the first or most important step in a metabolic pathway is under allosteric control in this way, enabling a cell to turn on or turn off an entire pathway easily and efficiently. Covalent modifications include phosphorylations, ADP-ribosylation, and other, more complex alterations. Covalent modification often occurs as a result of action of regulatory cascades. Glycogen metabolism (see here) is regulated in this fashion. Enzymes that phosphorylate other enzymes are called protein kinases.

> Compartmentation - Eukaryotic cells contain many different organelles and enzymes are distributed unevenly throughout them. For example, RNA polymerases are found in the nucleus and the nucleolus, where DNA transcription occurs. Enzymes of the citric acid cycle, on the other hand, are found in the mitochondria (Figure 12.11). Enzymes of fatty acid synthesis are found in the cytoplasm, but enzymes for fatty acid degradation are found in mitochondria.

> Hormonal regulation - Cells must respond to changes in the environment and/or to signals from other cells. The process of transmitting this information from outside of the cell to inside the cell is called signal transduction (Figure 12.13). The extracellular messengers that carry the information include hormones, growth factors, neurotransmitters, and pheromones. Hormones are substances synthesized in specialized cells and carried via the blood to remote target cells. There the hormones interact with specific receptors, resulting in specific metabolic changes in the target cell. An example is the rapid generation of energy that results from secretion of adrenaline (epinephrine). The following two types of metabolic response to hormones are well understood:

> > 1. Steroid hormones involve changes in gene expression.

> > 2. Second messengers that control metabolic reactions are made in response to the binding of an extracellular substance (the first messenger). Common first messengers include glucagon and insulin. Common second messengers include cyclic AMP (or cAMP) and phosphoinositides.

> Distributive control of metabolism - This concept recognizes that control of metabolic pathways is not simply a function of a single allosterically regulated enzyme in the pathway, but rather a function of all of the enzymes of a pathway. While enzymes catalyzing committed steps in pathways often play major roles in regulating the pathway, contributions can be made by all of the enzymes of the pathway.

See also: Systems for Studying Metabolism, Signal Transduction, Covalent Modifications to Regulate Enzyme Activity (from Chapter 11), Hormone Receptors (from Chapter 23), Hormone Hierarchy of Action (from Chapter 23)