Steroidal triterpenes: Design of substrate-based inhibitors of ergosterol and sitosterol synthesis

Molecules

Volumn 14, Issue 11, 2009, Pages 4690-4706

  Liu, Jialin ^a   Nes, William David ^a  

^a TEXAS TECH UNIVERSITY   (United States)

Author keywords

Ergosterol; Ergosterol biosynthesis inhibitors; Mechanismbased inactivator; Sitosterol; Sterol C24 methyltransferase (24 SMT); Transition state analogs; Triterpenes

Indexed keywords

ERGOSTEROL; METHYLTRANSFERASE; SITOSTEROL; SITOSTEROL DERIVATIVE; TRITERPENE;

BIOSYNTHESIS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; ENZYME ACTIVATION; METABOLISM; REVIEW; SYNTHESIS;

ENZYME ACTIVATION; ERGOSTEROL; METHYLTRANSFERASES; MOLECULAR STRUCTURE; SITOSTEROLS; TRITERPENES;

EID: 73349119089     PISSN: None     EISSN: 14203049     Source Type: Journal    
DOI: 10.3390/molecules14114690     Document Type: Review

References (60)

1. Jayasimha, J.; Bowman, C. B.; Pedroza, J. M.; Nes, W. D. Engineering pathway enzymes to understand the function and evolution of sterol structure and activity. Rec. Adv. Phytochem. 2006, 40, 212-251.
2. Roberts, C. W.; Mcleod, R.; Rice, D. W.; Ginger, M.; Chance, M. L.; Goad, L. J. Fatty acid and sterol metabolism: Potential antimicrobial targets in Apicomplexan and Trypansomatid parasitic protozoa. Mole. Biochem. Parasit. 2003, 126, 129-142.
3. Benveniste, P. Biosynthesis and accumulation of sterols. Annu. Rev. Plant Biol. 2004, 55, 429-457.
4. Goad, L. J.; Akihisa, T. Analysis of Sterols; Blackie Academic & Professional: London, UK, 1997; pp. 1-300.
5. Varkony, T. H.; Smith, D. H.; Djerassi, C. Computer-assisted structure manipulation: Studies in the biosynthesis of natural products. Tetrahedron 1978, 34, 841-852.
6. Nes, W. D. Enzyme mechanisms for sterol C-methylations. Phytochemistry 2003, 64, 75-95.
7. 24 (25)-Sterol methyltransferase: Interacellular localization and azazsterol sensitivity in Leishmania major promastigotes overexpressing the enzyme. Int. J. Parasit. 2008, 39, 307-314.
8. Zinser, E.; Paltauf, F.; Daum, G. Sterol composition of yeast organelle membranes and subcellular distribution of enzymes involved in sterol metabolism. J. Bacteriol. 1993, 175, 2853-2858.
9. Lederer, E. C-Methylation in biological systems. Israel J. Med. Sci. 1965, 1, 1129-1147.
10. Nes, W. D.; Zhou, W.; Ganapathy, K.; Liu, J.; Vatsyayan, R.; Chamala, S.; Hernandez, K.; Miranda, M. Sterol 24-C-methyltranferase: An enzymatic target for the disruption of ergosterol biosynthesis and homeostasis in Cryptococcus neoformans. Arch. Biochem. Biophys. 2009, 481, 210-218.
11. Kanagasabai, R.; Zhou, W.; Liu, J.; Nguyen, T. T. M.; Veeramachaneni, P.; Nes, W. D. Disruption of ergosterol biosynthesis, growth and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C25 in the sterol side chain. Lipids 2004, 39, 737-746.
12. 24 (28)-sterol methyltransferase as possible agents against Pareacoccidiodes brasiliensis. Antimicrob. Agents Chem. 2003, 47, 2966-2970.
13. 24 (25)-sterol methyltransferase inhibitors and their combinations with ketoconazole. Mol. Biochem. Parasit. 1995, 73, 199-20117
14. 24 (25)-sterol methyltransferase block sterol synthesis and cell proliferation in Pneumocystis carinii. Antimicrob. Agents Chemother. 1997, 41, 1428-1432.
15. Lorente, S. O.; Rodriques, J. C. F.; Jimenez-Jimenez, C.; Joyce-Menekse, M.; Rodriques, C.; Croft, S. L.; Yardley, V.; de Luca-Fradley, K.; Ruiz-Perez, L. M.; Urbina, J.; De Souza, W.; Pacanowska, D. G.; Gilbert, I. H. Novel azasterols as potential agents for treatment of Leishmaniasis and Trypanosomiasis. Antimicrob. Agents Chemother. 2004, 48, 2937-2950.
16. Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Enzyme mechanisms for polycyclic triterpene formation. Angew. Chem. Int. Ed. 2000, 39, 2812-2833.
17. Hoshino, T.; Sato, T. Squalene-hopene cyclase: Catalytic mechanism and substrate recognition. Chem. Commun. 2002, 291-301.
18. Nes, W. R.; McKean, M. L. Biochemistry of Steroids and Other Isopentenoids; University Park Press: Baltimore, MD, USA. 1977.
19. De Souza, W.; Rodriques, J. C. Sterol biosynthesis pathway as target for anti-trypanosomatid drugs. Interdiscip. Perspect. Infect. Diseases 2009, 1-19.
20. Urbina, J. A. Ergosterol biosynthesis and drug development for Chagas disease. Mem. Inst. Oswaldo Cruz. 2009, 104, 311-318.
21. Song, Z.; Nes, W. D. Sterol biosynthesis inhibitors: Potential for transition state analogs and mechanism-based inactivators targeted at sterol methyltransferase. Lipids 2007, 42, 15-33.
22. Visba, G.; Sna-blas, G.; Murgich, J.; Franco, H. Paracoccidiodes brasiliensis, Paracoccidiomycosis and antifungal antibiotics. Cur. Drug Targets-Infect. Disorders 2005, 5, 1-16.
23. Burbiel, J.; Bracher, F. Azasteroids as antifungals. Steroids 2003, 68, 587-594.
24. Kaneshiro, E. S. Sterol biosynthesis in Pneumocystis: Unique steps that define unique targets. Drug Resist. Updates 2002, 5, 259-268.
25. 24 (25)-sterol methyl transferase from Saccharomyces cerevisiae. Biochim. Biophys. Acta 1996, 1299, 313-324
26. Neelakandan, A. K.; Song, Z.; Wang, J.; Richards, M. H.; Wu, X.; Babu, V.; Nguyen, H. T.; Nes, W. D. Cloning, functional expression, and phylogenetic analysis of plant sterol 24-methyltransferase involved with sitosterol biosynthesis. Phytochemistry 2009, in press.
27. 24 (28)-sterol methyl transferase enzyme from Saccharomyces cerevisiae. Arch. Biochem. Biophys. 1998, 353, 297-311.
28. Nes, W. D.; Jayasimha, P.; Zhou, W.; Ragu, K.; Jin, C.; Jaradat, T. T.; Shaw, R. W.; Bujnicki, J. M. Sterol methyltransferase: Functional analysis of highly conserved residues by site-directed mutagenesis. Biochemistry 2004, 43, 569-576.
29. Jayasimha, P.; Nes, W. D. Photoaffnity labeling and mutational analysis of 24-C-sterol methyl transferase defines the AdoMet binding site. Lipids 2008, 43, 681-693.
30. 2-transfer activity. Biochim. Biophys. Acta 2008, 1781, 344-351.
31. Nes, W. D.; Song, Z.; Dennis, A. L.; Zhou, W.; Nam, J.; Miller, M. Biosynthesis of phytosterols: Kinetic mechanism for the enzymatic C-methylation of sterols. J. Biol. Chem. 2003, 278, 34505-34516.
32. Zhou, W.; Lepesheva, G. I.; Waterman, M. R.; Nes, W. D. Mechanistic analysis of a multiple product sterol methyltransferase from Trypanosoma brucei implicated in ergosterol biosynthesis. J. Biol. Chem. 2006, 281, 6290-6296.
33. Wang, J.; Nes, W. D. Cyclobranol: A substrate for C25 methyl sterol side chains and potent mechanistic-based inactivator of plant sterol methyltransferase. Bioorg. Med. Chem. Lett. 2008, 18, 3878-3881.
34. Ganapathy, K.; Liu, J.; Nes, W. D. Site-directed Mutagenesis and Mechanistic Analysis of the Trypanosoma brucei Sterol 24C-methyltransfedrase. Presented at the 238th Meeting of the American Chemical Society, Washington, D. C., USA, August 19th 2009.
35. Nes, W. D.; Sinha, A.; Jayasimha, P.; Zhou, W.; Song, Z.; Dennis, A. L. Probing the sterol binding site of soybean sterol methyltransferase by site-directed mutagenesis: Functional analysis of conserved aromatic amino acids in Region 1. Arch. Biochem. Biophys. 2006, 448, 23-30.
36. Nes, W. D.; Marshall, J. A.; Jia, Z.; Jaradat, T. T.; Song, Z.; Jayasimha, P. Active site mapping and substrate channeling in the sterol methyl transferase pathway. J. Biol. Chem. 2002, 277, 42459-42556.
37. 24 (25)-sterol methyl transferase from Saccharomyces cerevisiae. Arch. Biochem. Biophys. 1997, 342, 68-81.
38. Mangla, A. T.; Nes, W. D. Sterol C-methyl transferase from Prototheca wickerhamii: Mechanism, sterol specificity and inhibition. Bioorg. Med. Chem. 2000, 8, 925-936.
39. Narula, A. S.; Rahier, A.; Benveniste, P.; Schuber, F. 24-Methyl-25-azacycloartenol, an analogue of a carbonium high energy intermediate, is a potent inhibitor of (S)-adenosyl-L-methionine: Sterol C-24-methyltransferase in higher plants. J. Amer. Chem. Soc. 1981, 103, 2408-2409.
40. Rahier, A.; Genot, J. C.; Schuber, F.; Benveniste, P.; Narula, A. S. Inhibition of S-adenosyl-L-methionine sterol C-24 methyltransfersase by analogues of a carbocationic ion high energy intermediate. J. Biol. Chem. 1984, 259, 15215-15223.
41. 24-sterol methyltransferase in Saccharomyces cerevisiae. Biochemistry 1984, 23, 3582-3589.
42. 24-sterol methyltransferase. Bioorg. Med. Chem. 1997, 5, 821-832.
43. 24 (25)-sterol methyl transferase. II. Inhibition by analogs of the transition state coordinate. J. Biol. Chem. 1992, 267, 25856-25863.
44. 24-sterol methyltransferase. J. Med. Chem. 1992, 35, 100-106.
45. 24-sterol methyltransferase from Candida albicans and Candida tropicalis. Biochemistry 1989, 28, 9633-9640.
46. Rahman, M. D.; Pascal, R. A., Jr. Inhibitors of ergosterol biosynthesis and growth of the Trypanosomatid Protozoan Crithidia fasciculata. J. Biol. Chem. 1990, 265, 4989-4996.
47. Zhou, W.; Song, S.; Liu, J.; Miller, M. B.; Nes, W. D. 24-Thiacycloartenol, a potent mechanismbased inactivator of plant sterol methyltransferase. Tetrahedron Lett. 2004, 45, 875-878.
48. Chung, S. K.; Ryoo, C. H.; Yang, H. W.; Shim, J. Y.; Kang, M. G.; Lee, K. W.; Kang, H. I. Synthesis and bioactivities of steroid derivatives as antifungal agents. Tetrahedron 1998, 54, 15899-15914.
49. Lorente, S. O.; Jimenez-Jimenez, C.; Gros, L.; Yardley, V.; de Luca-Fradley, K.; Croft, S. L.; Urbina, J. A.; Ruiz-Perez, L. M.; Pacanowska, D. G.; Gilbert, I. H. Preparation of transition state analogs of sterol 24-methyltransferase as potential antiparasitics. Bioorg. Med. Chem. 2005, 13, 5435-5453.
50. Gros, L.; Lorente, S. O.; Jimenez-Jimenez, C.; Yardley, V.; Rattray, L.; Wharton, H.; Little, S.; Croft, S. I.; Ruiz-Perez, L. M.; Gonzalez-Pacanowska, D.; Gilbert, I. H. Evaluation of azasterols as anti-parasitics. J. Med. Chem. 2006, 49, 6094-6103.
51. Zhou, W.; Cross, G. M. A.; Nes, W. D. Cholesterol import fails to prevent catalyst-based inhibition of ergosterol synthesis and cell proliferation of Trypanosoma brucei. J. Lipid Res. 2007, 48, 665-673.
52. Chung, S. K.; Lee, K. W.; Kang, H. I.; Yamashita, C.; Kudo, M.; Yoshida, Y. Design and synthesis of potential inhibitors of the ergosterol biosynthesis as antifungal agents. Bioorg. Med. Chem. 2000, 8, 2475-2486.
53. Zhou, W.; Song, Z.; Kanagasabai, R.; Liu, J.; Jayasimha, P.; Sinha, A.; Veeramachanemi, P.; Miller, M. B.; Nes, W. D. Mechanism-based enzyme inactivators of phytosterol biosynthesis. Molecules, 2004, 9, 185-203.
54. Zhou, W.; Song, Z.; Nes, W. D. Comparison of transition state analogs and mechanism-based inhibitors of sterol methyl transferase activity on growth and sterol biosynthesis in human cultured cells. Unpublished data.
55. Nes, W. D.; Marshall, J. A.; Zhou, W.; He, L.; Dennis, A. L. Mechanism-based active site modification of sterol methyltransferase by tritium-labeled 26-homocholesta-8, 14, 24-trien-yn-3βol. Tetrahedron Lett. 1998, 39, 8575-8678.
56. Song, Z.; Nes, W. D. Inactivation of soybean sterol 24-C- methyltransferase by elongated sterol side chains at C26. Bioorg. Med. Chem. Lett. 2007, 17, 5902-5906.
57. Nes, W. D.; Jayasimha, P.; Song, Z. Yeast sterol C24-methyltransferase: Role of highly conserved tyrosine in catalytic competence studied by site-directed mutagenesis and thermodynamic analysis. Arch. Biochem. Biophys. 2008, 477, 313-323.
58. th meeting of the Am. Chem. Soc. Washington, D. C., USA, August 16th, 2009.
59. Venkatramesh, M.; Guo, D.; Harman, J. G.; Nes, W. D. Sterol Specificity of the Saccharomyces cerevisiae ERG6 Gene Product Expressed in Escherichia coli. Lipids 1996, 31, 373-377.
60. Wang, J.; Liu, J.; Song, Z.; Nes, W. D. Sterol C24-methyltransferase: Mechanistic studies of the C-methylation reaction with 24-fluorocycloartenol. Bioorg. Med. Chem. Lett. 2008, 18, 232-235. © 2009