Abstract
The major product of sterol biosynthesis in fungi and some trypanosomes is ergosterol, unlike in mammalian systems which synthesize cholesterol as the major membrane lipid (12, 13). The two sterols differ in a few minor ways: cholesterol has a second double bond (Δ5(6)) in the B ring (Figure 16.1) and has a fully saturated side chain without a methyl group at C24. These small differences are clearly very important as ergosterol has been shown to be essential for the aerobic growth of most fungi. This requirement is demonstrated by the sparking phenomenon discussed by Nes et al. (55), who described the essential structural parts of the sterol molecule needed for growth. Some fungi, however ( Pythium and Phytophthora ), use an alternative terpene-like compound instead of sterols (33).
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References
Akhtar, M., K.A. Munday, A.D. Rahimtula, I.A. Watkinson, and D.C. Wilton. 1969. Mechanism of reduction of double bonds in biological systems: conversion of desmosterol into cholesterol. Chem. Comm. 1969:1287–1288.
Aoyama, Y., Y. Yoshida, and R. Sato. 1984. Yeast cytochrome p-450 catalysing lanosterol 14a-demethylation. J. Biol. Chem. 259:1661–1666.
Atkin, S.D., B. Morgan, K.H. Baggaley, and J. Green 1972. The isolation of 2,3-oxidosqualene from the liver of rats treated with 1-dodecylimidazole, a novel hypocholesterolaemic agent. Biochem. J. 130:153–157.
Bach, T.J., and H.K. Lichtenthaler. 1982. Mechanism of inhibition by mevinolin (MK 803) of microsome-bound radish and of partially purified yeast HMG-CoA reductase (EC.1.1.1.34.) Z. Naturforsch. 38c:212–219.
Balliano, G., F. Viola, M. Ceruti, and L. Cattel. 1988. Inhibition of sterol biosynthesis in Saccharomyces cerevisiae by N,N-diethylazasqualene and derivatives. Biochim. Biophys. Acta. 959:9–19.
Baloch, R.I., E.I. Mercer, T.E. Wiggins, and B.C. Baldwin. 1984. Where do morpholines inhibit sterol biosynthesis? Brit. Crop Protect. Conf. 1984. 3:893–898.
Barrett-Bee, K. 1991. Resistance to azole antifungal agents in several species. J. Med. Vet. Mycol., in press.
Barrett-Bee, K., A.C. Lane, and R.W. Turner. 1986. The mode of antifungal action of tolnaftate. J. Med. Vet. Mycol. 24:155–160.
Barrett-Bee, K., J. Lees, P.E. Pinder, J. Campbell, and L. Newboult. 1988. Biochemical studies with a novel antifungal agent ICI 195,739. Ann. N.Y. Acad. Sci. 544:231244.
Barrett-Bee, K., L. Newboult, and P.E. Pinder. 1991. Biochemical changes associated with the antifungal action of the triazole ICI 153,066 on C. albicans and T. quickeanum. FEMS, Lett. 79:127–132.
Barrett-Bee, K., and P.E. Pinder. 1984. Resistance to ergosterol biosynthesis inhibitors observed in several fungal species. p. 139. In C. Nombela (ed.) Proceedings of FEMS Symposium, The development of antifungal agents. S.E.M., Madrid.
Block, K. 1979. Speculations on the evolution of sterol structure and function. CRC Crit. Rev. Biochem. 91:1–5.
Block, K. 1981. Sterol structure and membrane function. Curr. Top. Cell Regul. 18:289–299.
Bohnen, K. and A. Pfinner. 1979. Fenpropimorph, ein neus systemisches Fungizid zur Bekaempfung von echten Meltau und Rostkrankheiten im Getreidebau, Meded Rijksfac Landbouwwetensch Gent 44:487–497.
Borgers, M. 1985. Antifungal azole derivatives, p. 133–153. In D. Greenwood and F. O’Grady (ed.), Scientific basis of antimicrobial chemotherapy. Cambridge University Press, Cambridge.
Borgers, M., M. De Brabander, H. Vanden Bossche, and J. Van Cutsem. 1979. Promotion of pseudomycelium formation of Candida albicans in culture: A morphological study of the effects of miconazole and ketoconazole. Postgrad. Med. J. 55:687–691.
Boyle, F.T. 1990. Drug discovery: a chemists approach, p. 3–30. In J.F. Ryley (ed.), Chemotherapy of fungal diseases, handbook of experimental pharmacology, vol. 96. Springer Verlag, Berlin.
Butters, J., J. Clark, and D.W. Hollman. 1984. Resistance to inhibitors of sterol biosynthesis in barley powdery mildew. Meded. Rijksfac. Landbouwwetensch Gent. 49:143–151.
Cattel, L., M. Ceruti, G. Balliano, F. Viola, G. Grosa, and F. Schuber. 1989. Drug design based on biosynthetic studies: synthesis, biological activity, and kinetics of new inhibitors of 2,3-oxidosqualene cyclase and squalene epoxidase. Steroids 53:363391.
Cattel, L., M. Ceruti, F. Viola, L. Delprino, G. Balliano, A. Duriatti, and P. Bouvier-Nave. 1986. The squalene-2,3-epoxide cyclase as a model for the development of new drugs. Lipids 21:31–38.
Ceruti, M., F. Viola, G. Balliano, G. Grosa, P. Caputo, and N. Gerst. 1988. Synthesis of a squalenoid oxaziridine and other new classes of squalene derivatives, as inhibitors of sterol biosynthesis. Eur. J. Med. Chem. 23:533–537.
Chang, T.-Y., E.S. Schiavoni, Jr., K.R. McCrae, J.A. Nelson, and T.A. Spencer. 1979. Inhibition of cholesterol biosynthesis in chinese hamster ovary cells by 4,410p-trimethyl-trans-decal-3p-ol. J. Biol. Chem. 254:11258–11263.
Corey, E.J., P.R. Ortiz de Montellano, K. Lin, and P.D.G. Dean. 1967.2,3iminosqualene, a potent inhibitor of the enzymatic cyclization of 2,3-oxidosqualene to sterols. J. Am. Chem. Soc. 89:2797–2798.
Counsell, R.E., P.D. Klimstra, R.E. Ranney, and D.L. Cook. 1962. Hypocholesterolemic agents. 1. 20a-(2-dialkylaminoethyl)aminopregn-5-en-3a-ol derivatives. J. Med. Pharm. Chem. 5:720–729.
Dekker, J. 1984. Development of resistance to antifungal agents, p. 89–112. In A.P.J. Trinci and J.F. Ryley (ed.), Mode of action of antifungal agents. Cambridge University Press, Cambridge.
Delprino, L., G. Balliano, L. Cattel, P. Benveniste, and P. Bouvier. 1983. Inhibition of higher plant, 2,3-oxidosqualene cyclase by 2-aza-2,3-dihydrosqualene and its derivatives. J. Chem. Soc. Chem. Commun. (1983):381
DeWaard, M.A., and J.G. van Nistleroy. 1980. An energy-dependent efflux mechanism for fenarimol in a wild-type strain and fenarimol-resistant mutant of Aspergillus nidulans. Pestic. Biochem. Biophys. 13:255–266.
Duriatti, A., P. Bouvier-Nave, P. Benveniste, F. Schuber, L. Delprino, G. Balliano, and L. Cattel. 1985. In vitro inhibition of animal and higher plant 2,3-oxidosqualene-sterol cyclases by 2-aza-2,3-dihydrosqualene and derivatives, and by other ammonium-containing molecules. Biochem. Pharmacol. 34:2765–2777.
Endo, A., M. Kuroda, and K. Tanzawa. 1976. Competitive inhibition of 3-hydroxy3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 72:323–326.
Ross, H.G., L. Mascaro, M.D. Tsai, and R.W. Woodard. 1979. Stereochemistry of enzymatic transmethylation, p. 135–141. In E. Usdin, R.T. Borchardt, C.R. Creveling (ed.), Transmethylation: developments in neuroscience, vol. 5. Elsevier/North Holland, New York.
Fryberg, M., and A.C. Oehlschlager. 1976. Sterol biosynthesis in antibiotic sensitive and resistant Candida. Arch. Biochem. Biophys. 173:171–177.
Georgopoulos, A., G. Petranyi, H. Mieth, and J. Drews. 1981. In vitro activity of naftifine, a new antifungal agent. Antimicrob. Agents Chemother. 19:386–389.
Goodwin, T.W. 1973. Comparative biochemistry of sterols in eukaryotic microorganisms, p. 1–41. In J.A. Erwin (ed.), Lipids and biomembranes of eukaryotic microorganisms. Academic Press, New York.
Gordee, R.S., and T.F. Butler. 1973. A9145 a new adenine-containing antifungal antibiotic. II. Biological activity. J. Antibiot. 26:466–470.
Greenspan, M.D., J.B. Judkovitz, C.H.L. Lo, J.W. Chen, A.W. Alberts, V.M. Hunt, M.N. Chang, S.S. Yang, K.L. Thompson, Y.P. Chiang, J.C. Chabala, R.L. Monaghan, and R.L. Schwart. 1987. Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659–699. Proc. Natl. Acad. Sci. USA 84:7688–7492.
Hamilton-Miller, J.M.T. 1973. Chemistry and biology of the polyene macrolide antibiotics. Bacteriol. Rev. 37:166–196.
Henry, M.J., and H.D. Sisler. 1979. Effects of miconazole and dodecylimidazole on sterol biosynthesis in Ustilago maydis. Antimicrob. Agents Chemother. 15:603–607.
Hitchcock, C.A., K. Barrett-Bee, and N.J. Russell. 1987. Inhibition of 14a-sterol demethylase activity in Candida albicans-Darlington does not correlate with resistance to azole. J. Med. Vet. Mycol. 25:329–333.
Hitchcock, C.A.,N.J. Russell, and K. Barrett-Bee. 1989. The lipid composition and permeability to the triazole antifungal antibiotic ICI 153,066 of serum grown mycelial cultures of C. albicans. J. Gen. Micro. 135:1949–1955.
Ikeura, R., S. Murakawa, and A. Endo. 1988. Growth inhibition of yeast by compactin (ML-236B) analogues. J. Antibiot. 41:1148–1150.
Kato, T., and Y. Kawase. 1976. Selective inhibition of the demethylation at C-14 in ergosterol biosynthesis by the fungicide Denmert. Agri. Biol. Chem. 40:2379–2388.
Kerkanaar, A. 1987. The mode of action of dimethylmorpholines, p. 523–542. In R.A. Fromtling (ed.), Recent trends in the discovery, development and evaluation of antifungal agents. J.R. Prous Science, Barcelona.
Kerkenaar, A., and D. Barug. 1984. Fluorescence microscope studies of Ustilago maydis and Penicillium italicum after treatment with imazalil and fenpropimorph. Pestic. Sci. 15:199–205.
Kerkenaar, A., M. Uchiyama, and G.G. Versluis. 1981. Specific effects of tridemorph on sterol biosynthesis in Ustilago maydis. Pestic. Biochem. Physiol. 16:97–104.
Kuroda, M., Y. Hazama-Shimada, and A. Endo. 1977. Inhibition of sterol synthesis by citrinin in a cell-free system from rat liver and yeast. Biochim. Biophys. Acta. 486:254–259.
Lee, W.H., B.N., Lutsky, and G.S. Schroepfer. 1969. 5a cholest-8(14)-en-3β-ol, a possible intermediate in the biosynthesis of cholesterol. J. Biol. Chem. 244:5440–5448.
Marriott, M.S. 1980. Inhibition of sterol biosynthesis in Candida albicans by imidazole containing antifungals. J. Gen. Micro. 117:265–275.
Mercer, E.I., P.K. Moms, and B.C. Baldwin. 1985. Differences in the inhibitory effects of N-(1-n-dodecyl)-heterocycles on the 2,3-oxidosqualene lanosterol-cyclase of rat liver and yeast. Comp. Biochem. Physiol. 80B:341–346.
Miller, W.L., and J.L. Gaylor. 1970. Investigation of the component reactions of oxidative sterol demethylation, oxidation of a 4a methyl to a 4a carboxylic-acid during cholesterol biosynthesis. J. Biol. Chem. 245:5369–5381.
Monger, D.J., W.A. Lim, F.J. Kezdy, and J.H. Law. 1982. Compactin inhibits insect HMG-CoA reductase and juvenile hormone biosynthesis. Biochem. Biophys. Res. Commun. 105:1374–1380.
Morita, T., K. Iwata, and Y. Nozawa. 1989. Inhibitory effect of a new antimycotic agent, piritetrate, on ergosterol biosynthesis in pathogenic fungi. J. Med. Vet. Mycol. 27:17–25.
Morita, T., and Y. Nozawa. 1985. Effects of antifungal agents on ergosterol biosynthesis in Candida albicans and Trichophyton mentagrophytes: differential inhibitory sites of naphthiomate and miconazole. J. Invest. Dermatol. 85:434–437.
Nakamura, C.E., and R.H. Abeles. 1985. Mode of interaction of β-hydroxy-βmethylglutaryl coenzyme A reductase with strong binding inhibitors: compactin and related compounds. Biochemistry 24:1364–1376.
Nave, J.-F., H. d’Orchymont, J.-B. Ducep, F. Piriou, and M.J. Jung. 1985. Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate. Biochem. J. 227:247–254.
Nes, W.R., B.C. Sekula, W.D. Nes, and J.H. Adler. 1978. The functional importance of structural features of ergosterol in yeast. J. Biol. Chem. 253:6218–6225.
Nussbaumer, P., N.S. Ryder, and A. Stutz. 1991. Allylamine antimycotics: recent trends in structure-activity relationships and syntheses. Pestic. Sci., in press.
Odds, F. 1988, Candida and candidosis, 2nd ed. Bailliere Tindall, London.
Ohno, T., T. Kesado, J. Awaya, and S. Omura. 1974. Target of inhibition by the anti-lipogenic antibiotic cerulenin of sterol synthesis in yeast. Biochem. Biophys. Res. Comm. 57:1119–1124.
Omura, S., H. Tomoda, H. Kumagai, M.D. Greenspan, J.B. Yodkovitz, J.S. Chen, A.W. Alberts, I. Martin, S. Mochales, R.L. Monaghan, J.C. Chabal, R.E. Schwartz, and A.A. Patchett. 1987. Potent inhibitory effect of antibiotic 1233A on cholesterol 434/Barrett-Bee and Ryder biosynthesis which specifically blocks 3-hydroxy-3-methylglutaryl coenzyme A synthase. J. Antibiot. 11:1356–1357.
Onishi, J.C., G.K. Abruzzo, R.A. Fromtling, G.M. Garrity, J.A. Milligan, B.A. Pelak, W. Rozdilsky, and B. Weissberger. 1988. Mode of action of L-660,631 in Candida albicans. Ann. N.Y. Acad. Sci. 544:229.
Onishi, J.C., G.K. Abruzzo, R.A. Fromtling, G.M. Garrity, J.A. Milligan, B.A. Pelak, W. Rozdilsky, and B. Weissberger. 1988. Mode of action of β-lactone 1233A in Candida albicans. Ann. N.Y. Acad. Sci. 544:230.
Parks, L.W. 1958. S-Adenosylmethionine and ergosterol synthesis. J. Am. Chem. Soc. 80:2023–2024.
Poulter, C.D. 1990. Isopentenyl diphosphate to squalene-enzymology and inhibition, p. 169–188. In P.J. Kuhn, A.P.J. Trinci, M.J. Jung, M.W. Goosey, and L.G. Copping (eds.), Biochemistry of cell walls and membranes of fungi. Springer-Verlag, Berlin.
Reardon, J.E., and R.H. Abeles. 1987. Inhibition of cholesterol biosynthesis by fluorinated mevalonate analogues. Biochemistry 26:4717–4722.
Ryder, N.S. 1985. Specific inhibition of fungal sterol biosynthesis by SF 86–327, a new allylamine antimycotic agent. Antimicrob. Agents Chemother. 27:252–256.
Ryder, N.S. 1987. Squalene epoxidase as the target of antifungal allylamines. Pestic. Sci. 21:281–288.
Ryder, N.S. 1988. Mode of action of allylamines, p. 151–167. In D. Berg and M. Plempel (eds.), Sterol biosynthesis inhibitors: pharmaceutical and agrochemical aspects. Ellis Horwood, Chichester, U.K.
Ryder, N.S. 1990. Inhibition of squalene epoxidase and sterol side-chain methylation of allylamines. Biochem. Soc. Trans. 18:45–46.
Ryder, N.S. 1990. Squalene epoxidase-enzymology and inhibition, p. 189–203. In P.J. Kuhn, A.P.J. Trinci, M.J. Jung, M.W. Goosey, and L.G. Copping (eds.), Biochemistry of cell walls and membranes of fungi. Springer-Verlag, Berlin.
Ryder, N.S., and M.C. Dupont. 1985. Inhibition of squalene epoxidase by allylamine antimycotic compounds: a comparative study of the fungal and mammalian enzymes. Biochem. J. 230:765–770.
Ryder, N.S., M.C. Dupont, and I. Frank. 1986. Inhibition of fungal and mammalian sterol biosynthesis by 2-aza-2,3-dihydrosqualene. FEBS Lett. 204:239–242.
Ryder, N.S., I. Frank, and M.C. Dupont. 1986. Ergosterol biosynthesis inhibition by the thiocarbamate antifungel agents tolnaftate and tolciclate. Antimicrob. Agents Chemother. 29:858–860.
Ryder, N.S., and L.J. Goad. 1980. The effect of the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor ML-236B on phytosterol synthesis in Acer pseudoplatanus tissue culture. Biochim. Biophys. Acta. 619:424–427.
Ryder, N.S., and H. Mieth. 1990. Allylamine antifungal drugs. Curr. Top. Med. Mycol., in press.
Ryder, N.S., G. Seidl, and P.F. Troke. 1984. Effect of the antimycotic drug naftifineon growth of and sterol biosynthesis in Candida albicans. Antimicrob. Agents Chemother. 25:483–487.
Ryley, J.F., R.G. Wilson, and K. Barrett-Bee. 1984. Azole resistance in Candida albicans. Sabouraudia 22:53–63.
Santen, R.J., H. Vanden Bossche, J. Symoens, J. Brugmans, and R. Decoster. 1983. Site of action of low-dose ketoconazole on androgen biosynthesis in men. J. Clin. Endocrinol. Metab. 57:732–736.
Sen, S.E., and G.D. Prestwich. 1989. Trisnorsqualene alcohol, a potent inhibitor of vertebrate squalene epoxidase. J. Am. Chem. Soc. 111:1508–1510.
Sen, S.E. and G.D. Prestwich. 1989. Trisnorsqualene cyclopropylamine: a reversible, tight-binding inhibitor of squalene epoxidase. J. Am. Chem. Soc. 111:8761–8763.
Sen, S.E., C. Wawrzenczyk, and G.D. Prestwich. 1990. Inhibition of vertebrate squalene epoxidase by extended and truncated analogues of trisnorsqualene alcohol. J. Med. Chem. 33:1698–1701.
Servouse, M., and F. Karst. 1986. Regulation of early enzymes of ergosterol biosynthesis in Saccharomyces cerevisiae. Biochem. J. 240:541–547.
Sisler, H.D., R.C. Walsh, and B.N. Ziogas. 1983. Ergosterol biosynthesis a target for fungitoxic action, p. 6218–6225. In J. Miyamo and P.C. Kearney (ed.), Proceedings of the Fifth International Congress of Pesticide Chemistry, vol. 3. Pergamon Press, Elmsford.
Sobus, M.T., C.E. Holmlund, and N.F. Whittaker. 1977. Effects of the hypocholesterolemic agent trifluperidol on the sterol, steryl ester and fatty acid metabolism of S. cerevisiae. J. Bacteriol. 130:1310–1316.
Steel, C.C., R.I. Baloch, E.I. Mercer, and B.C. Baldwin. 1989. The intracellular location and physiological effects of abnormal sterols in fungi grown in the presence of morpholine and functionally related fungicides. Pestic. Biochem. Physiol. 33:101111.
Stutz, A. 1988. Synthesis and structure-activity correlations within allylamine antimycotics. Ann. N.Y. Acad. Sci. 544:46–62.
Stutz, A., A. Georgopoulos, W. Granitzer, G. Petranyi, and D. Berney. 1986. Synthesis and structure-activity relationships of naftifine-related allylamine antimycotics. J. Med. Chem. 29:112–125.
Stutz, A., and G. Petranyi. 1984. Synthesis and antifungal activity of (E)-N-(6,6 dimethy1–2-hepten-4-ynyl)-N-methyl-l-naphthalene-methanimine (SF 86–327) and related allylamine derivatives with enhanced oral activity. J. Med. Chem. 27:1539–1543.
Sud. I.J., and D.S. Feingold. 1985. Effect of ketoconazole in combination with other inhibitors of sterol synthesis on fungal growth. Antimicrob. Agents. Chemother. 28:532–534.
Tomoda, H., H. Kumagai, H. Tanaka, and S. Omura. 1987. F-244 specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A synthase. Biochim. Biophys. Acta. 922:351–356.
Trocha, P.J., and D.B. Sprinson. 1976. Location and regulation of early enzymes of sterol biosynthesis in yeast. Arch. Biochem. Biophys. 174:45–51.
Vanden Bossche, H. 1974. Biochemical effects of miconazole on fungi. 1. Effects on the uptake and/or utilisation of purines, pyrimidines, amino acids and glucose by Candida albicans. Biochem. Pharmacol. 26:887–899.
Vanden Bossche, H., G. Willemsens, P. Marichal, W. Cools, and W. Lauwers. 1985. The molecular basis for the antifungal activation of N-substituted azole derivatives, p. 321–341. In A.P.J. Trinci and J.F. Ryley (ed.), Mode of action of antifungal agents. Cambridge University Press, Cambridge.
Walsh, R.C., and H.D. Sisler. 1982. A mutant of Ustilago maydis deficient in sterol carbon-14 demethylation characteristics and sensitivity to inhibitors of ergosterol biosynthesis. Pestic. Biochem. Physiol. 18:122–131.
Warnock, D.W., G.M. Johnson, and M.D. Richardson. 1983. Modified response to ketoconazole of Candida albicans from a treatment failure. Lancet 1:642–643.
Yeagle, P.L., R.B. Martin, A.K. Lala, H.K. Lin, and K. Bloch. 1977. Differential effects of cholesterol and lanosterol on artificial membranes. Proc. Natl. Acad. Sci. USA 74:4924–4926.
Yoshida, Y. 1988. Cytochrome P450 of fungi: primary target for azole antifungal agents, p. 388–418. In M.R. McGinnis (ed.), Current topics in medical mycology, vol. 2. Springer Verlag, Berlin.
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Barrett-Bee, K., Ryder, N. (1992). Biochemical Aspects of Ergosterol Biosynthesis Inhibition. In: Sutcliffe, J.A., Georgopapadakou, N.H. (eds) Emerging Targets in Antibacterial and Antifungal Chemotherapy. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3274-3_16
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