SECONDARY METABOLISM: RAISON D'ÊTRE EUGENED. WEINBERG* . . . the organic chemist's view ofnature is unbalanced, even lunatic, but still in some ways more exciting than that ofthe biochemist. While the enzymologist's garden is a dream of uniformity, a green meadow where the cycles of Calvin and Krebs tick round in disciplined order, the organic chemist walks in an untidy jungle of uncouthly named extractives, rainbow displays ofpigments, where in every bush there lurks the mangled shape of some alkaloid, the exotic perfume of some new terpene, or some shocking and explosive polyacetylene—J. D. Bu Lock [i]. I. Introduction Secondary metabolites consist ofa wide diversity ofthousands ofnatural products, each narrowly restricted in taxonomic distribution, formed for a brief period by microbial cells that have recently stopped dividing, and without known function in growth of producer cells [i, 2]. Secondary compounds have been studied intensively during the past thirty years, primarily by natural product organic chemists and by industrial microbiologists . During the first two ofthese three decades, much ofthe applied interest was directed toward the discovery and synthesis ofthat small minority ofsecondary substances (e.g., penicillin) that are toxic to pathogenic microorganisms. In the most recent decade, attention shifted somewhat to the study of the minority of secondary substances (e.g., malformin and anatoxin, respectively) that have pharmacologic effects on plants or animals . The great majority of secondary metabolites have no demonstrable pharmacologic activity; nevertheless, a considerable amount of information is available concerning the chemical identity and pathways ofsynthesis of these materials. Secondary metabolites are produced by algae, fungi, and bacteria in * Department ofMicrobiology and Program in Medical Sciences, Indiana University, Bloomington 47401. 1 am greatly indebted to Dr.J. D. Bu'Lock for his stimulating and instructive discussions ofmany ofthe concepts on which this article is based. This work was supported in part by research grant HD03038 -03 from the National Institute of Child Health and Human Development, U.S. Public Health Service. 565 both natural and laboratory environments. The genetic and environmental conditions required for secondary metabolism havebeen studied mainly in laboratory batch cell cultures. The temporal relationship ofthe kinetics of secondary metabolism to those of bacterial cell multiplication is represented diagrammatically in figure ?. The overall process of secondary metabolism includes (a) derepression of the appropriate portion of the genome to obtain transcription and translation ofspecific synthetases and (b) subsequent activity ofthe latter for a finite time. The synthetases package one or more kinds of surplus primary substances (e.g., acetate, pyruvate, malonate, mevalonate, shikimate , prephenate, amino acids, purines) into biochemically bizarre molecules ranging from abietic acid and ajmaline to zierone and zingiberene . Examples of organic classes in which these molecules are found are listed in table i. Although the metabolic pathways ofthe packaging processes generally are well established, the molecular events that initiate, as well as those that 75 Fig. i.—Diagrammatic representation ofkinetics ofgrowth and secondary metabolism in a bacterial cell culture. Left ordinate, logio viable cells per milliliter; right ordinate, extrinsic secondary metabolite, units per milliliter ofsupemate; abscissa, time of incubation; curve A, viable cells; line B, approximate period oftranscription and translation ofsecondary metabolic synthetases; curve C, amount ofextrinsic secondary metabolite in supemate. 566 Eugene D. Weinberg · Secondary Metabolism Perspectives in Biology and Medicine · Summer 1971 TABLE 1 Some Classes of Organic Compounds in Which Secondary Metabolites Are Found Amine sugars Anthocyanins Anthraquinones Aziridines Benzoquinones Coumarins Diazines Epoxides Ergoline alkaloids Flavonoids Furans Glutaramides Glycopeptides Glycosides Hydroxylamines Indole derivatives Lactones Macrolides Naphthalenes Naphthaquinones Nucleosides Oligopeptides Perylenes Phenazines Phenoxazinones Phthaldehydes Piperazines Polyacetylenes Polyenes Polypeptides Pyrazines Pyridines Pyrones Pyrroles Pyrrolidones Pyrrolines Pyrrolizines Quinolines Quinolinols Quiñones Salicylates Terpenoids Tetracyclines Tetronic acids Triazines Tropolones abruptly terminate, secondary metabolism are but poorly discerned [2]. Equally obscure is an understanding ofthe subject ofthis essay: the function of secondary metabolism. No one can study secondary metabolism for long without asking, or being asked, "What is its purpose? and there is no dearth ofpossible answers . The proposed functions fall logically into three categories: (a) those concerning formation of that minority of secondary substances that can affect growth or differentiation of producer cells, (b) those restricted to synthesis of that minority of secondary materials that are biologically active toward nonproducer cells, and (c) those...