DISCUSSION Folia Microbiol. 24, 365--367 (1979)
On the Physiological Meaning of Secondary Metabolism I-I.. I. HAAVI]~ DepartmeNt of Research and Development, A/S Apothekernes Laboratorium for Specialpreparater, ~k~yen, Oslo 2, ~Vorway Received September 5, 1978
The distinction between primary and secondary metabolism in microorganisms was introduced by Bu'Loek (1961). The primary metabolism~consists of a pattern of chemical reactions similar in most species. Primary metabolites are essential to cell division. Secondary metabolites, on the other hand, have the following characteristic features (Bu'Lock 1961, 1965, 1975; Ms 1965; Woodruff 1966; Weinberg 1971, 1974; Turner 1971; Drew and Demain 1977): a) Each secondary metabolite is particular to one or a few species. b) They do not seem to be essential to replicatory growth. c) Their production is extremely sensitive to environmental factors. d) Some species may produce several different secondary metabolites whereas other species may produce only a few (this, however, may be a matter of detection). e) Many secondary metabolites are produced as a group of closely related metabolites. The composition of the group produced may depend upon media and growth conditions. f) Secondary metabolism may be controlled by regulatory mechanisms different from those operating in primary metabolism. Since secondary metabolites do not seem to be essential to cell division, it has been suggested t h a t they confer no selective advantage to the producer organisms. Secondary metabolism may just be a chance event in the metabolism or a disposal of energy (Woodruff 1966; Turner 1971; Lechevalier 1975). HHowever, secondary metabolism is a widespread activity among microorganisms, and since secondary metabolites may be formed by very complex enzyme mechanisms (Froyshov et al. 1978) it is likely t h a t they are of significant importance to the producer cells. The hypothesis t h a t secondary metabolites may be waste products from the metabolism or energy-storage compounds is no longer considered as plausible (Weinberg 1971; Demain 1974). Secondary metabolites seem very frequently to be produced in relatively large amounts by cells with limited growth rates or by cells which have stopped dividing (Bu'Lock 1975; Weinberg 1974). Microbial cells faced with unfavourable growth conditions usually start to differentiate, thus it has been suggested that secondary metabolism may have a functional relationship to the differentiation process (Weinberg 197I; Bu'Lock 1975). It is proposed that secondary metabolism has the same general function in all microorganisms, i.e., that secondary metabolism may be a kind of safety valve which transfers accumulating primary metabolites into non-functional secondary metabolites when growth is limited. This may prevent an imbalance of
366
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Vol. 24
metabolism (Bu'Loek 1965) and may be necessary for longevity of both differentiating and non-differentiating microbial cells (Weinberg 1971). The part of this hypothesis which may be subject to discussion is the general nonfunctionality of the individual secondary metabolites. Besides, why should one type of safety valve mechanism result in so many different n0n-functionM products .~ Why not just a few from the key intermediates in primary metabolism .~Another objection is that it seems more natural to just pour the accumulating primary metabolites into the surroundings. An interesting suggestion is that some secondary metabolites may have hormone-like roles during differentiation (Sadoff 1972; Luckner et al. 1977). That secondary metabolites may have hormone-like functions in the cell machinery seems to be a reasonable hypothesis. This may explain why it is so difficult to prove that secondary metabolites have any essential roles during replicatory growth. If they are modifiers of cellular activities, they may or may not be necessary depending upon media and growth conditions. This may also explain why several secondary metabolites have marked effects upon the growth of producer organisms when added to the growth medium (Demain 1974; Haavik and Froyshov 1975; ttaavik 1975). Many microorganisms are very sensitive to secondary metabolites produced by other species. It seems plausible that cells which come into contact with significant amounts of an unknown modifier may be disturbed in their cellular machinery. As a conclusion of this short discussion I would like to stress my opinion about a possible physiological role of secondary metabolism. Since most species seem to produce different secondary metabolites, it is likely that secondary metabolism represents the evolutionary specialization of species. The species have evolved secondary metabolism to better cope with fluctuations and peculiarities in their natural location, or to be able to invade new locations. The secondary metabolites are produced in response to variations of the environmental factors. Both the type and amount of secondary metabolites may be changed depending upon media and growth conditions. Secondary metabolites make the cells more flexible to changing environments by modifying the basic cellular activities such as growth (in size), cell division, differentiation, transport, secretion, energy storage, and movement. Secondary metabolites may also be secreted into the environment in order to make it more suitable to the cells. Thus one can say that secondary metabolism is a mechanism which increases the possibilities of the various species to adapt and to survive in a changing and ruthless world. I am very grateful to Dr. O. Froyshov for valuable discussions in preparing the text, and to Dr. S. Thomassen for his comments on the manuscript. REFERENCES Bu'LocK J. D,: Intermediary metabolism and antibiotic synthesis. Adv. Appl. Microbiol. 3, 293 (1961). Bu'LocK J. D.: The Biosynthesis of Natural Products. McGraw-Hill, London 1965. ]3u'Loc~r J. D.: Secondary metabolism in fungi a n d its relationships to growth a n d development, p. 33 in The Filamentous Eungi (J. E. Smith, D. R. Berry, Eds), Vol. 1. E d w a r d Arnold, London 1975. D E ~ I ~ A. L.: How do antibiotic-producing microorganisms avoid suicide? Ann. 2r Y. Acad. Sci. 235, 601 (1974). DREW S. W., DE~AI~ A. L. : Effect of p r i m a r y metabolites on secondary metabolism. Ann. Rev. Microbiol. 31,343 (1977). F~YSHOV O., ZEMMER T. L., LAZA~rD S. G.: Biosynthesis of microbial pep~ides b y the thiotemplate mechanism. MTP. Int. Rev. Sci. 18, 32 (1978). ~ V / K H. I., FROYS~OV O. : F u n c t i o n of peptide antibiotics in producer organisms. Nature 254, 79 (1975). I-TAAVIKH. I. : The effect of bacitraein a n d Mn(II) ions upon the producer strain Bacillus lieheniformis. Aata Pathol. Mierobiol. Seand., Sect ]3. 83, 513 (1975).
1979
P H Y S I O L O G I C A L M E A N I N G OF S E C O N D A R Y METABOLIS~I
367
LECHEVALIEI~ IrI. A.: Production of the same antibiotics b y members of different genera of microorganisms.
Adv. Appl. Microbiol. 19, 25 (1975). L U C ~ E R M., NOVE~ L., B o ~ H.: Secondary metabolism a n d cell differentiation. Mol. Biol. Biochem. Biophys. 23, 3 (1977). M-~EK I., About mechanisms regulating the biosynthesis of secondary metabolites, p. 11 in Biogenesis of 'Antibiotic Substance8 (Z. Van~k, Z. Ho~t~lek, Eds). Publ. House Czech. Aead. Sci., Prague 1965. SADOFF I'i. L.: The antibiotics of Bacillus species: their possible roles in sporulation. Progr. Ind. Mic~obiol. I I , 1 (1972). TURNER W. B.: Fungal Metabolites. Academic Press, London 1971. W:~INBERO E. D.: Secondary metabolism: raison d'etre. Perspec. Biol. Med. 14, 565 (1971). W~.I~-BERQ E. D.: Secondary metabolism: control b y temperature a n d inorganic phosphate. Develop. Ind. Microbiol. 15, 70 (1974). ~VOODaVFF H. B.: The physiology of antibiotic production: the role of the producing organism. Soc. Gen. Microbiol. Syrup. 16, 22 {1966).
On the Physiological Meaning of Secondary Metabolism I-I.. I. HAAVI]~ DepartmeNt of Research and Development, A/S Apothekernes Laboratorium for Specialpreparater, ~k~yen, Oslo 2, ~Vorway Received September 5, 1978
The distinction between primary and secondary metabolism in microorganisms was introduced by Bu'Loek (1961). The primary metabolism~consists of a pattern of chemical reactions similar in most species. Primary metabolites are essential to cell division. Secondary metabolites, on the other hand, have the following characteristic features (Bu'Lock 1961, 1965, 1975; Ms 1965; Woodruff 1966; Weinberg 1971, 1974; Turner 1971; Drew and Demain 1977): a) Each secondary metabolite is particular to one or a few species. b) They do not seem to be essential to replicatory growth. c) Their production is extremely sensitive to environmental factors. d) Some species may produce several different secondary metabolites whereas other species may produce only a few (this, however, may be a matter of detection). e) Many secondary metabolites are produced as a group of closely related metabolites. The composition of the group produced may depend upon media and growth conditions. f) Secondary metabolism may be controlled by regulatory mechanisms different from those operating in primary metabolism. Since secondary metabolites do not seem to be essential to cell division, it has been suggested t h a t they confer no selective advantage to the producer organisms. Secondary metabolism may just be a chance event in the metabolism or a disposal of energy (Woodruff 1966; Turner 1971; Lechevalier 1975). HHowever, secondary metabolism is a widespread activity among microorganisms, and since secondary metabolites may be formed by very complex enzyme mechanisms (Froyshov et al. 1978) it is likely t h a t they are of significant importance to the producer cells. The hypothesis t h a t secondary metabolites may be waste products from the metabolism or energy-storage compounds is no longer considered as plausible (Weinberg 1971; Demain 1974). Secondary metabolites seem very frequently to be produced in relatively large amounts by cells with limited growth rates or by cells which have stopped dividing (Bu'Lock 1975; Weinberg 1974). Microbial cells faced with unfavourable growth conditions usually start to differentiate, thus it has been suggested that secondary metabolism may have a functional relationship to the differentiation process (Weinberg 197I; Bu'Lock 1975). It is proposed that secondary metabolism has the same general function in all microorganisms, i.e., that secondary metabolism may be a kind of safety valve which transfers accumulating primary metabolites into non-functional secondary metabolites when growth is limited. This may prevent an imbalance of
366
H.I. HAAVIK
Vol. 24
metabolism (Bu'Loek 1965) and may be necessary for longevity of both differentiating and non-differentiating microbial cells (Weinberg 1971). The part of this hypothesis which may be subject to discussion is the general nonfunctionality of the individual secondary metabolites. Besides, why should one type of safety valve mechanism result in so many different n0n-functionM products .~ Why not just a few from the key intermediates in primary metabolism .~Another objection is that it seems more natural to just pour the accumulating primary metabolites into the surroundings. An interesting suggestion is that some secondary metabolites may have hormone-like roles during differentiation (Sadoff 1972; Luckner et al. 1977). That secondary metabolites may have hormone-like functions in the cell machinery seems to be a reasonable hypothesis. This may explain why it is so difficult to prove that secondary metabolites have any essential roles during replicatory growth. If they are modifiers of cellular activities, they may or may not be necessary depending upon media and growth conditions. This may also explain why several secondary metabolites have marked effects upon the growth of producer organisms when added to the growth medium (Demain 1974; Haavik and Froyshov 1975; ttaavik 1975). Many microorganisms are very sensitive to secondary metabolites produced by other species. It seems plausible that cells which come into contact with significant amounts of an unknown modifier may be disturbed in their cellular machinery. As a conclusion of this short discussion I would like to stress my opinion about a possible physiological role of secondary metabolism. Since most species seem to produce different secondary metabolites, it is likely that secondary metabolism represents the evolutionary specialization of species. The species have evolved secondary metabolism to better cope with fluctuations and peculiarities in their natural location, or to be able to invade new locations. The secondary metabolites are produced in response to variations of the environmental factors. Both the type and amount of secondary metabolites may be changed depending upon media and growth conditions. Secondary metabolites make the cells more flexible to changing environments by modifying the basic cellular activities such as growth (in size), cell division, differentiation, transport, secretion, energy storage, and movement. Secondary metabolites may also be secreted into the environment in order to make it more suitable to the cells. Thus one can say that secondary metabolism is a mechanism which increases the possibilities of the various species to adapt and to survive in a changing and ruthless world. I am very grateful to Dr. O. Froyshov for valuable discussions in preparing the text, and to Dr. S. Thomassen for his comments on the manuscript. REFERENCES Bu'LocK J. D,: Intermediary metabolism and antibiotic synthesis. Adv. Appl. Microbiol. 3, 293 (1961). Bu'LocK J. D.: The Biosynthesis of Natural Products. McGraw-Hill, London 1965. ]3u'Loc~r J. D.: Secondary metabolism in fungi a n d its relationships to growth a n d development, p. 33 in The Filamentous Eungi (J. E. Smith, D. R. Berry, Eds), Vol. 1. E d w a r d Arnold, London 1975. D E ~ I ~ A. L.: How do antibiotic-producing microorganisms avoid suicide? Ann. 2r Y. Acad. Sci. 235, 601 (1974). DREW S. W., DE~AI~ A. L. : Effect of p r i m a r y metabolites on secondary metabolism. Ann. Rev. Microbiol. 31,343 (1977). F~YSHOV O., ZEMMER T. L., LAZA~rD S. G.: Biosynthesis of microbial pep~ides b y the thiotemplate mechanism. MTP. Int. Rev. Sci. 18, 32 (1978). ~ V / K H. I., FROYS~OV O. : F u n c t i o n of peptide antibiotics in producer organisms. Nature 254, 79 (1975). I-TAAVIKH. I. : The effect of bacitraein a n d Mn(II) ions upon the producer strain Bacillus lieheniformis. Aata Pathol. Mierobiol. Seand., Sect ]3. 83, 513 (1975).
1979
P H Y S I O L O G I C A L M E A N I N G OF S E C O N D A R Y METABOLIS~I
367
LECHEVALIEI~ IrI. A.: Production of the same antibiotics b y members of different genera of microorganisms.
Adv. Appl. Microbiol. 19, 25 (1975). L U C ~ E R M., NOVE~ L., B o ~ H.: Secondary metabolism a n d cell differentiation. Mol. Biol. Biochem. Biophys. 23, 3 (1977). M-~EK I., About mechanisms regulating the biosynthesis of secondary metabolites, p. 11 in Biogenesis of 'Antibiotic Substance8 (Z. Van~k, Z. Ho~t~lek, Eds). Publ. House Czech. Aead. Sci., Prague 1965. SADOFF I'i. L.: The antibiotics of Bacillus species: their possible roles in sporulation. Progr. Ind. Mic~obiol. I I , 1 (1972). TURNER W. B.: Fungal Metabolites. Academic Press, London 1971. W:~INBERO E. D.: Secondary metabolism: raison d'etre. Perspec. Biol. Med. 14, 565 (1971). W~.I~-BERQ E. D.: Secondary metabolism: control b y temperature a n d inorganic phosphate. Develop. Ind. Microbiol. 15, 70 (1974). ~VOODaVFF H. B.: The physiology of antibiotic production: the role of the producing organism. Soc. Gen. Microbiol. Syrup. 16, 22 {1966).
