Biochemistry - Metabolism, Hormones, Enzymes



The cell is the site of a constant, complex, and orderly set of chemical changes collectively called metabolism. Metabolism is associated with a release of heat. The heat released is the same as that obtained if the same chemical change is brought about outside the living organism. This confirms the fact that the laws of thermodynamics apply to living systems just as they apply to the inanimate world. The pattern of chemical change in a living cell, however, is distinctive and different from anything encountered in nonliving systems. This difference does not mean that any chemical laws are invalidated. It instead reflects the extraordinary complexity of the interrelations of cellular reactions.

Hormones, which may be regarded as regulators of metabolism, are investigated at three levels, to determine (1) their physiological effects, (2) their chemical structure, and (3) the chemical mechanisms whereby they operate. The study of the physiological effects of hormones is properly regarded as the province of the physiologist. Such investigations obviously had to precede the more analytical chemical studies. The chemical structures of thyroxine and adrenaline are known. The chemistry of the sex and adrenal hormones, which are steroids, has also been thoroughly investigated. The hormones of the pancreas—insulin and glucagon—and the hormones of the hypophysis (pituitary gland) are peptides (i.e., compounds composed of chains of amino acids). The structures of most of these hormones has been determined. The chemical structures of the plant hormones, auxin and gibberellic acid, which act as growth-controlling agents in plants, are also known.

The first and second phases of the hormone problem thus have been well, though not completely, explored, but the third phase is still in its infancy. It seems likely that different hormones exert their effects in different ways. Some may act by affecting the permeability of membranes; others appear to control the synthesis of certain enzymes. Evidently some hormones also control the activity of certain genes.

Genes

Genetic studies have shown that the hereditary characteristics of a species are maintained and transmitted by the self-duplicating units known as genes, which are composed of nucleic acids and located in the chromosomes of the nucleus. One of the most fascinating chapters in the history of the biological sciences contains the story of the elucidation, in the mid-20th century, of the chemical structure of the genes, their mode of self-duplication, and the manner in which the DNA of the nucleus causes the synthesis of RNA, which, among its other activities, causes the synthesis of protein. Thus, the capacity of a protein to behave as an enzyme is determined by the chemical constitution of the gene (DNA) that directs the synthesis of the protein. The relationship of genes to enzymes has been demonstrated in several ways. The first successful experiments, devised by the Nobel Prize winners George W. Beadle and Edward L. Tatum, involved the bread mold Neurospora crassa; the two men were able to collect a variety of strains that differed from the parent strain in nutritional requirements. Such strains had undergone a mutation (change) in the genetic makeup of the parent strain. The mutant strains required a particular amino acid not required for growth by the parent strain. It was then shown that such a mutant had lost an enzyme essential for the synthesis of the amino acid in question. The subsequent development of techniques for the isolation of mutants with specific nutritional requirements led to a special procedure for studying intermediary metabolism.

Evolution and origin of life

The exploration of space beginning in the mid-20th century intensified speculation about the possibility of life on other planets. At the same time, man was beginning to understand some of the intimate chemical mechanisms used for the transmission of hereditary characteristics. It was possible, by studying protein structure in different species, to see how the amino acid sequences of functional proteins (e.g., hemoglobin and cytochrome) have been altered during phylogeny (the development of species). It was natural, therefore, that biochemists should look upon the problem of the origin of life as a practical one. The synthesis of a living cell from inanimate material was not regarded as an impossible task for the future.

Applied biochemistry

An early objective in biochemistry was to provide analytical methods for the determination of various blood constituents because it was felt that abnormal levels might indicate the presence of metabolic diseases. The clinical chemistry laboratory now has become a major investigative arm of the physician in the diagnosis and treatment of disease and is an indispensable unit of every hospital. Some of the older analytical methods directed toward diagnosis of common diseases are still the most commonly used—for example, tests for determining the levels of blood glucose, in diabetes; urea, in kidney disease; uric acid, in gout; and bilirubin, in liver and gallbladder disease. With development of the knowledge of enzymes, determination of certain enzymes in blood plasma has assumed diagnostic value, such as alkaline phosphatase, in bone and liver disease; acid phosphatase, in prostatic cancer; amylase, in pancreatitis; and lactate dehydrogenase and transaminase, in cardiac infarct. Electrophoresis of plasma proteins is commonly employed to aid in the diagnosis of various liver diseases and forms of cancer. Both electrophoresis and ultracentrifugation of serum constituents (lipoproteins) are used increasingly in the diagnosis and examination of therapy of atherosclerosis and heart disease. Many specialized and sophisticated methods have been introduced, and machines have been developed for the simultaneous automated analysis of many different blood constituents in order to cope with increasing medical needs.

Analytical biochemical methods have also been applied in the food industry to develop crops superior in nutritive value and capable of retaining nutrients during the processing and preservation of food. Research in this area is directed particularly to preserving vitamins as well as color and taste, all of which may suffer loss if oxidative enzymes remain in the preserved food. Tests for enzymes are used for monitoring various stages in food processing.

Biochemical techniques have been fundamental in the development of new drugs. The testing of potentially useful drugs includes studies on experimental animals and man to observe the desired effects and also to detect possible toxic manifestations; such studies depend heavily on many of the clinical biochemistry techniques already described. Although many of the commonly used drugs have been developed on a rather empirical (trial-and-error) basis, an increasing number of therapeutic agents have been designed specifically as enzyme inhibitors to interfere with the metabolism of a host or invasive agent. Biochemical advances in the knowledge of the action of natural hormones and antibiotics promise to aid further in the development of specific pharmaceuticals.

Methods in biochemistry

Like other sciences, biochemistry aims at quantifying, or measuring, results, sometimes with sophisticated instrumentation. The earliest approach to a study of the events in a living organism was an analysis of the materials entering an organism (foods, oxygen) and those leaving (excretion products, carbon dioxide). This is still the basis of so-called balance experiments conducted on animals, in which, for example, both foods and excreta are thoroughly analyzed. For this purpose many chemical methods involving specific color reactions have been developed, requiring spectrum-analyzing instruments (spectrophotometers) for quantitative measurement. Gasometric techniques are those commonly used for measurements of oxygen and carbon dioxide, yielding respiratory quotients (the ratio of carbon dioxide to oxygen). Somewhat more detail has been gained by determining the quantities of substances entering and leaving a given organ and also by incubating slices of a tissue in a physiological medium outside the body and analyzing the changes that occur in the medium. Because these techniques yield an overall picture of metabolic capacities, it became necessary to disrupt cellular structure (homogenization) and to isolate the individual parts of the cell—nuclei, mitochondria, lysosomes, ribosomes, membranes—and finally the various enzymes and discrete chemical substances of the cell in an attempt to understand the chemistry of life more fully.

Centrifugation and electrophoresis

An important tool in biochemical research is the centrifuge, which through rapid spinning imposes high centrifugal forces on suspended particles, or even molecules in solution, and causes separations of such matter on the basis of differences in weight. Thus, red cells may be separated from plasma of blood, nuclei from mitochondria in cell homogenates, and one protein from another in complex mixtures. Proteins are separated by ultracentrifugation—very high speed spinning; with appropriate photography of the protein layers as they form in the centrifugal field, it is possible to determine the molecular weights of proteins.

Another property of biological molecules that has been exploited for separation and analysis is their electrical charge. Amino acids and proteins possess net positive or negative charges according to the acidity of the solution in which they are dissolved. In an electric field, such molecules adopt different rates of migration toward positively (anode) or negatively (cathode) charged poles and permit separation. Such separations can be effected in solutions or when the proteins saturate a stationary medium such as cellulose (filter paper), starch, or acrylamide gels. By appropriate color reactions of the proteins and scanning of color intensities, a number of proteins in a mixture may be measured. Separate proteins may be isolated and identified by electrophoresis, and the purity of a given protein may be determined. (Electrophoresis of human hemoglobin revealed the abnormal hemoglobin in sickle-cell anemia, the first definitive example of a “molecular disease.”)

Chromatography and isotopes

The different solubilities of substances in aqueous and organic solvents provide another basis for analysis. In its earlier form, a separation was conducted in complex apparatus by partition of substances in various solvents. A simplified form of the same principle evolved as ‘‘paper chromatography,” in which small amounts of substances could be separated on filter paper and identified by appropriate color reactions. In contrast to electrophoresis, this method has been applied to a wide variety of biological compounds and has contributed enormously to research in biochemistry.

The general principle has been extended from filter paper strips to columns of other relatively inert media, permitting larger scale separation and identification of closely related biological substances. Particularly noteworthy has been the separation of amino acids by chromatography in columns of ion-exchange resins, permitting the determination of exact amino acid composition of proteins. Following such determination, other techniques of organic chemistry have been used to elucidate the actual sequence of amino acids in complex proteins. Another technique of column chromatography is based on the relative rates of penetration of molecules into beads of a complex carbohydrate according to size of the molecules. Larger molecules are excluded relative to smaller molecules and emerge first from a column of such beads. This technique not only permits separation of biological substances but also provides estimates of molecular weights.

Perhaps the single most important technique in unraveling the complexities of metabolism has been the use of isotopes (heavy or radioactive elements) in labeling biological compounds and “tracing” their fate in metabolism. Measurement of the isotope-labeled compounds has required considerable technology in mass spectroscopy and radioactive detection devices.

A variety of other physical techniques, such as nuclear magnetic resonance, electron spin spectroscopy, circular dichroism, and X-ray crystallography, have become prominent tools in revealing the relation of chemical structure to biological function.


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