Trace-Metal Control of Specific Biosynthetic Processes

TRACE-METAL CONTROL OF SPECIFIC BIOSYNTHETIC PROCESSES EUGENE D. WEINBERG* . . . there probably does not exist a single enzyme-catalyzed reaction in which either substrate , product, enzyme, or some combination within this triad is not influenced in a very direct and highly specific manner by the precise nature ofthe inorganic ions which surround and "modify" it.—H. R. Mahler (i). I. Introduction During the past quarter-century it has become increasingly apparent that, for efficient metabolism and growth, living matter must be supplied a proper balance ofbiologically available trace metals (2-4). A corollary to this observation has been sometimes recognized: namely, that a specific distortion of normal metabolism often can be achieved by appropriate alteration ofthe balance ofavailable trace metals. Recognition and utilization of this corollary has occurred unevenly in the various basic and applied areas ofbiology; at present, however, a considerable number ofabnormal or diseased metabolic states ofmicrobes, plants, animals, and man are known to be associated with imbalances of trace metals in either the diet or in specific tissues (2-7). Moreover, the selective biological activities ofvitamins, hormones, and drugs are, in numerous instances, believed to be closely associated with and even dependent upon the presence ofspecific trace metals (2, 8-15). The purpose ofthis essay is to direct attention to the pervasiveness of trace-metal control ofspecific biosynthetic processes in fully grown tissues or in mature cell cultures. The studies to be cited are generally restricted to those in which a comparison was made ofthe balance oftrace metals re- * Department ofBacteriology, Indiana University, Bloomington, Indiana. Research for this paper was supported by grant E-4184 from the National Institute of Allergy and Infectious Diseases, U.S.P.H.S. Portions were written during theauthor s appointmentas a Visiting Scientist at Commercial Solvents Corporation, Terre Haute, Indiana. 432 Eugene D. Weinberg · Trace-Metal Control Perspectives in Biology and Medicine · Summer 1962 quired for normal growth and metabolism with the balance required for a specific metabolic distortion. Emphasis will be placed on demonstrations that slight shifts in the kind and quantity ofavailable trace metals required for optimum growth ofa given living system strongly promoted or suppressed the biosynthesis ofa specific metabolite by either the growing or the mature system. In the majority of cases to be described, the shifts had little effect on the rate or extent ofgrowth. The most practical living systems for this type ofstudy are, ofcourse, homogeneous cell cultures. As might be expected because oftheir commercial importance, a good deal of information has been amassed for bacterial and mycotic cell cultures. In contrast, very few such studies have been performed on plant or animal cell cultures, and it is hoped that this paperwillstimulatetheinitiationofsuchprojects.Insomeofthestudiestobe cited, it will be noted that observations were made ofan entire physiological process such as cell differentiation rather than ofthe synthesis ofa specific compound. Such physiological processes are presumably the end result ofthe synthesis ofa "triggering" compound(s); possibly this synthesis is altered by the shift in trace-metal balance described. Alternately, the shift in trace metals may affect a subsequent metabolic step that can cause the process either to abort or to go on to completion. II. Examples of Trace-Metal Control Table ? contains a partial list ofexamples oftrace-metal control ofbiosynthetic processes. As may be noted in columns ? and 2, the synthesis or execution ofa wide variety of metabolites or physiological processes by plant, microbial, and animalcells can be influenced by the presence of one or a few trace metals in concentrations that differ from those required for optimal growth. As might be expected, the kinds ofmetals (columns 3a and 36) that were active in the various systems are usually those that can be activators ofspecific enzymes (1, 3); other metals were either completely inert or else were nonspecific poisons of the entire enzymatic content of the living systems. In nearly all the examples cited in the table, various biologically active trace metals were tested. As may be seen in columns 3