enzymes

enzymes are most familiarly associated with digestion, as substances in the alimentary tract that are necessary for the breakdown of food into simpler stuffs that can be absorbed into the body proper. These are indeed important, but they are in a small minority among the vast population of the body's enzymes. They also differ from the majority in acting outside rather than inside the cells that make them.

All living cells are teeming with enzymes. The name comes from the Greek meaning ‘in leaven’ or yeast. They are proteins, synthesized in cells, which act as catalysts, causing all the body's chemical processes to advance with the necessary rapidity and completeness. Enzymes are ubiquitous in body cells and fluids, and they are specific — each enzyme is responsible for catalyzing one particular chemical process. Their existence and their function came to be recognized during the nineteenth century; understanding advanced with burgeoning twentieth-century biochemistry; and molecular biologists continue to elucidate their ultimate structure and mode of action, and the genes that make them.

The names and nature of enzymes

The naming of enzymes in most cases reveals their function; ‘-ase’ is added to the name either of the substance (the substrate) on which they act (like peptidase for those acting on peptides), or of the type of reaction induced (such as hydrolase, for those causing hydrolysis, the splitting of a substance with addition of water, or transferase, for those moving some chemical group from one molecule to another). Some of the first enzymes to be discovered have unique names, such as pepsin in the stomach, and trypsin from the pancreas, which are both proteinases.

So what sort of proteins are they, and how do they function? With molecular masses of 10 000 to 1 000 000, enzymes are themselves large molecules, but some also exist in larger complexes that facilitate a sequence of changes. An enzyme molecule is a ‘globular’ protein that has an area on its surface to which can be bound only the specific substrate that the enzyme is designed to accept. This binding leads to changes in both molecules that result in the formation of the required product, and restoration of the enzyme molecule to its original state, ready to take on another substrate molecule. With progressively higher concentrations of substrate the rate of product yield increases, but the increment in rate diminishes as it approaches a maximum at a certain substrate concentration; beyond this point only an increase in the concentration of the enzyme itself can accelerate the process. This behaviour is consistent with progressive occupation of binding sites on all available enzymes, until they are all functioning at a maximal turnover rate.

Range and sites of enzyme function

Enzymes operate at every stage of life. Even the head of the sperm releases an enzyme that dissolves its path through the outer covering of the ovum to reach and penetrate it. Cell division in the embryo and throughout life involves replication of the DNA that carries the genetic information. A series of specific enzymes is needed for this, to unwind the double helix, to replicate it by the synthesis of new strands, and to put it and the new pairs back together again — whilst other enzymes meanwhile supply energy by the breakdown of adenosine triphosphate (ATP). Yet others are involved in the formation of messenger RNA and in all subsequent synthesis of proteins in a cell that results from the genetic coding.

Enzymes implement every event in the internal life of every cell in the body, and in its interaction with its environment. Each enzyme, or chain of enzymes acting in rapid sequence, has a specific function. There are those that are necessary for respiration and energy production; for transport mechanisms across the cell membrane and between internal components; for modifications of cellular metabolism in response to hormones; and for any specialized activity, including secretion by glandular cells, contraction by muscle cells, synthesis, release, and reuptake of neurotransmitters by nerve cells. The continual potential damage to tissues by the generation of free radicals is crucially limited by the body's antioxidant enzymes.

All cells have enzymes in their membrane, in the cytoplasm, and in the organelles within them. Those at the heart of cellular metabolism are the complex sequence of respiratory enzymes in the mitochondria that make possible the utilization of oxygen for the conversion of nutrient substrates to carbon dioxide and water, synthesis of ATP, and its breakdown for release of energy.

Cell membranes are furnished with ‘sodium pumps’ — protein molecules spanning the cell membrane that pump sodium ions out and potassium ions in. Facing inwards is an enzyme site that binds and breaks down ATP to supply the energy for pumping. Other enzyme molecules in the cell membrane may have, in addition to a site for substrate-binding, another that acts as receptor for a ‘messenger’ that activates the catalytic process: for example, the insulin receptor spans the cell membrane of muscle or fat cells; its outer site binds insulin, and its inner site handles the first of a series of enzyme-catalyzed reactions inside the cell that result in the several effects of insulin.

At synapses between nerves, and at neuromuscular junctions, enzymes are present that break down redundant neurotransmitters, preventing persistence of their effects. An example is acetylcholinesterase, found in the synaptic clefts on motor end plates in skeletal muscle, which hydrolyses excess acetylcholine, the neurotransmitter released by the motor nerve terminals.

Within skeletal muscle fibres, the enzymes vary according to their type of metabolism: whether it is predominantly aerobic (utilizing oxygen: ‘slow’ or ‘red’ muscle) or anaerobic (‘fast’ or ‘pale’ muscle). The sequence of events leading from activation of a muscle fibre by neurotransmitter, to contraction by means of interaction between myosin and actin filaments, depends on enzymes at every stage.

Enzymes in the blood

In the circulating blood there are enzymes both inside the blood cells, and outside in the plasma. Blood cells, in common with all cells, have the necessary enzymes for membrane transport and energy production. White blood cells have respiratory enzymes for aerobic metabolism, and others suited to their particular functions. Red blood cells are without mitochondria and respire anaerobically, so have enzymes appropriate to anaerobic glycolysis. Important for their function in whole-body respiratory gas exchange, they contain carbonic anhydrase, which promotes the uptake from the tissues of carbon dioxide and its carriage in the blood as bicarbonate, by catalyzing its combination with water to form carbonic acid, and its release in the lungs by this reaction in reverse.

Some enzymes exist as pro-enzymes or zymogens; they require some molecular change to be triggered into their active forms. These include proteins in the plasma that are involved in blood clotting: prothrombin is synthesized in the liver, and becomes thrombin when clotting is activated, and plasminogen can come into action as plasmin, a clot-dissolving enzyme. In the stomach, pepsinogen is secreted, and activated into pepsin by the acid that is secreted at the same site.

Enzymes that are normally secreted only into the gut or inside cells may, in pathological conditions, appear in significant quantities in the plasma, so that their measurement may be clinically useful. Examples are digestive enzymes that leak into the blood in acute pancreatitis, and creatine kinase, an enzyme from muscle tissue, that can appear in skeletal muscle disorders or, along with other intracellular enzymes, after a coronary thrombosis resulting in breakdown of some of the cardiac muscle.

Conditions for enzyme activity

All enzymes need the right environment for effective function, notably an optimal acidity, which differs in accordance with the site at which a particular enzyme acts (for example, more acidic inside cells than outside, and, for digestive enzymes, acidic in the stomach and alkaline in the duodenum). Like any chemical reactions, the rate of those that are catalyzed by enzymes varies with temperature. Local heat generation, for example in exercising muscle, enhances all such reactions within it. Likewise, whole-body metabolic rate increases in fever and decreases in hypothermia, because of the effect on all enzyme-catalyzed reactions. Extremes of pH or temperature irreversibly abolish enzyme activity, and so also do some substances that bind to the active sites of particular enzymes. These include an organophosphate ‘nerve gas’ that blocks acetylcholinesterase (causing persistent accumulation of acetylcholine at neuromuscular junctions, and thus uncontrollable muscle contraction). Poisoning by cyanide is due to blocking an essential enzyme in mitochondria and so fatally preventing all tissue respiration.

Medical applications

It is possible to inhibit the action of an enzyme without destroying it, and this has important therapeutic implications. There are substances that compete with the natural substrate for binding to an enzyme by having a similar structure, and others that act on other components of the enzyme molecule, preventing its ability to catalyze. Acetylcholinesterase inhibition is again an example — though in this context useful and reversible — in the treatment of the condition of myasthenia gravis, when the receptors on muscles cells for acetylcholine are deficient; the similar molecular structure of neostigmine allows it to bind to the enzyme, preventing binding and breakdown of acetylcholine; this can then accumulate sufficiently to enhance neuromuscular transmission. Drugs are used similarly to reverse the neuromuscular blockade deliberately induced during general anaesthesia. A different and important medical application of enzyme inhibition is in the use of antibiotics that block enzymes in microorganisms that are essential for their life or growth.

There are also many necessary co-enzymes, or co-factors for enzymes — organic non-protein molecules, smaller than the enzymes themselves, which either enhance or are necessary for the enzyme's activity. These again are widespread throughout the body, and are of many different molecular structures. Some require for their synthesis small amounts of essential substances from the diet. This is the basis of the need for the vitamins of the B group — they provide components for co-enzymes which could not otherwise be made in the body. Ions of several metals are also essential as co-factors, as well as for incorporation in some enzyme molecules themselves.

Sheila Jennett

See also alimentary system; cell; cell membrane; metabolism; respiration; transport.