Patterns of metabolic regulation

The rate at which different pathways operate is controlled by changes in the activity of key enzymes. In general, the first reaction unique to a given pathway or branch of a pathway will be the one most subject to regulation, although the activities of other enzymes are also regulated. The enzymes that exert the greatest control over flux (flow of metabolites) through a pathway are often those that catalyse essentially unidirectional reactions, i.e. those for which the substrates and products are far from thermodynamic equilibrium.

Within any one cell the activities of regulatory enzymes may be controlled by two mechanisms that act instantaneously:

  • the availability of substrates;
  • inhibition or activation by accumulation of precursors, end-products or intermediates of a pathway.

On a whole-body basis, metabolic regulation is achieved by the actions of hormones. A hormone is released from the organ (endocrine gland) in which it is synthesized in response to a stimulus such as the blood concentration of metabolic fuels, circulates in the bloodstream and acts only on target cells that have receptors for that hormone. In addition, locally acting hormones (sometimes called paracrine agents) are secreted into the interstitial fluid (rather than the bloodstream) by cells that are close to target cells. Other compounds secreted by cells act on the secretory cells themselves — these are known as autocrine agents.

There are two types of response to hormones:

  • Fast responses due to changes in the activity of existing enzymes as a result of covalent modification of the enzyme protein. Fast-acting hormones activate cell-surface receptors, leading to the release of a second messenger inside the cell. The second messenger then acts directly or indirectly to activate an enzyme that catalyses the covalent modification of the target enzymes.
  • Slow responses due to changes in the rate of synthesis of enzymes. Slow-acting hormones activate intracellular receptors that bind to regulatory regions of DNA and increase or decrease the rate of transcription of one or more genes.

Regardless of the mechanism by which a hormone acts to regulate a pathway, there are three key features of hormonal regulation:

  • tissue selectivity, determined by whether or not the tissue contains receptors for the hormone;
  • amplification of the hormone signal;
  • a mechanism to terminate or reverse the hormone action as its secretion decreases.

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