Genetics of polyketide metabolism in Aspergillus nidulans

Metabolites

Volumn 2, Issue 1, 2012, Pages 100-133

  Klejnstrup, Marie L ^a   Frandsen, Rasmus J N ^a   Holm, Dorte K ^a   Nielsen, Morten T ^a   Mortensen, Uffe H ^a   Larsen, Thomas O ^a   Nielsen, Jakob B ^a  

^a TECHNICAL UNIVERSITY OF DENMARK   (Denmark)

Author keywords

Aspergillus nidulans; Biosynthesis; Gene clusters; Polyketide synthases; Polyketides; Secondary metabolites

Indexed keywords

ACYL CARRIER PROTEIN; ACYLTRANSFERASE; AFLATOXIN; ASPERFURANONE; ASPERTHECIN; ASPYRIDONE; EMERICELLAMIDE; EMODIN; METHYLTRANSFERASE; MONODICTYPHENONE; POLYKETIDE; POLYKETIDE SYNTHASE; S ADENOSYLMETHIONINE; STERIGMATOCYSTIN; UNCLASSIFIED DRUG; VERSICOLORIN A;

ASPERGILLUS NIDULANS; BIOSYNTHESIS; CRYSTALLOGRAPHY; FUNGUS; GENE CLUSTER; GENE EXPRESSION; GENE SEQUENCE; GENETICS; HETEROLOGOUS EXPRESSION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; NONHUMAN; NORTHERN BLOTTING; NUCLEAR MAGNETIC RESONANCE; PROTEIN METABOLISM; REVIEW;

EID: 84871240349     PISSN: None     EISSN: 22181989     Source Type: Journal    
DOI: 10.3390/metabo2010100     Document Type: Review

References (124)

1. Pontecorvo, G.; Roper, J.A.; Hemmons, L.M.; MacDonald, K.D.; Bufton, A.W.J. The genetics of Aspergillus nidulans. Adv. Genet. Incorp. Mol. Genet. Med. 1953, 5, 141-238.
2. Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 2007, 70, 461-477.
3. Crawford, J.M.; Townsend, C.A. New insights into the formation of fungal aromatic polyketides. Nat. Rev. Microbiol. 2010, 8, 879-889.
4. Hertweck, C. The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. 2009, 48, 4688-4716.
5. Cox, R.J. Polyketides, proteins and genes in fungi: Programmed nano-machines begin to reveal their secrets. Org. Biomol. Chem. 2007, 5, 2010-2026.
6. Bingle, L.E.H.; Simpson, T.J.; Lazarus, C.M. Ketosynthase domain probes identify two subclasses of fungal polyketide synthase genes. Fun. Gen. Biol. 1999, 26, 209-223.
7. Crawford, J.M.; Vagstad, A.L.; Ehrlich, K.C.; Townsend, C.A. Starter unit specificity directs genome mining of polyketide synthase pathways in fungi. Bioorg. Chem. 2008, 36, 16-22.
8. Crawford, J.M.; Thomas, P.M.; Scheerer, J.R.; Vagstad, A.L.; Kelleher, N.L.; Townsend, C.A. Deconstruction of iterative multidomain polyketide synthase function. Science 2008, 320, 243-246.
9. Yadav, G.; Gokhale, R.S.; Mohanty, D. Towards prediction of metabolic products of polyketide synthases: An in silico analysis. PLoS Comp. Biol. 2009, 5, e1000351:1-e1000351:14.
10. Du, L.; Lou, L. PKS and NRPS release mechanisms. Nat. Prod. Rep. 2010, 27, 255-278.
11. Nielsen, M.L.; Nielsen, J.B.; Rank, C.; Klejnstrup, M.L.; Holm, D.K.; Brogaard, K.H.; Hansen, B.G.; Frisvad, J.C.; Larsen, T.O.; Mortensen, U.H. A genome-wide polyketide synthase deletion library uncovers novel genetic links to polyketides and meroterpenoids in Aspergillus nidulans. FEMS Microbiol. Lett. 2011, 321, 157-166.
12. Chung, Y.S.; Kim, J.M.; Han, D.M.; Chae, K.S.; Jahng, K.Y. Ultrastructure of the cell wall of a null pigmentation mutant, npgA1, in Aspergillus nidulans. J. Microbiol. 2003, 41, 224-231.
13. Jahn, B.; Boukhallouk, F.; Lotz, J.; Langfelder, K.; Wanner, G.; Brakhage, A.A. Interaction of human phagocytes with pigmentless Aspergillus conidia. Infect. Immun. 2000, 68, 3736-3739.
14. Wright, P.J.; Pateman, J.A. Ultraviolet-light sensitive mutants of Aspergillus nidulans. Mutation Res. 1970, 9, 579-587.
15. Yuill, E. Two new Aspergillus mutants. J. Bot. 1939, 77, 174-175.
16. Clutterbuck. A.J. Absence of laccase from yellow-spored mutants of Aspergillus nidulans. J. Gen. Microbial. 1972, 70, 423-435.
17. Agnihotri, V.P. Role of trace elements in the growth and morphology of five ascosporic Aspergillus species. Can. J. Bot. 1967, 45, 73-79.
18. O'Hara, E.B.; Timberlake, W.E. Molecular characterization of the Aspergillus nidulans yA locus. Genetics 1989, 121, 249-254.
19. Mayorga, M.E.; Timberlake, W.E. Isolation and molecular characterization of the Aspergillus nidulans wA gene. Genetics 1990, 126, 73-79.
20. Marshall, M.A.; Timberlake, W.E. Aspergillus nidulans wetA activates spore-specific gene expression. Mol. Cell. Biol. 1991, 11, 55-62.
21. Adams, T.H.; Wieser, J.K.; Yu, J.H. Asexual sporulation in Aspergillus nidulans. Microbiol. Mol. Biol. Rev. 1998, 62, 35-54.
22. Mayorga, M.E.; Timberlake, W.E. The developmentally regulated Aspergillus nidulans wA gene encodes a polypeptide homologous to polyketide and fatty acid synthases. Mol. Gen. Genet. 1992, 235, 205-212.
23. Watanabe, A.; Ono, Y.; Fujii, I.; Sankawa, U.; Mayorga, M.E.; Timberlake, W.E.; Ebizuka, Y. Product identification of polyketide synthase coded by Aspergillus nidulans wA gene. Tetrahedron Lett. 1998, 39, 7733-7736.
24. Fujii, I.; Watanabe, A.; Sankawa, U.; Ebizuka, Y. Identification of Claisen cyclase domain in fungal polyketide synthase WA, a naphthopyrone synthase of Aspergillus nidulans. Chem. Biol. 2001, 8, 189-197.
25. Watanabe, A.; Fujii, I.; Sankawa, U.; Mayorga, M.E.; Timberlake, W.E.; Ebizuka, Y. Re-identification of Aspergillus nidulans wA gene to code for a polyketide synthase of naphthopyrone. Tetrahedron Lett. 1999, 40, 91-94.
26. Watanabe, A.; Ebizuka, Y. A novel hexaketide naphthalene synthesized by a chimeric polyketide synthase composed of fungal pentaketide and heptaketide synthase. Tetrahedron Lett. 2002, 43, 843-846.
27. Nekam, L.; Polgar, P. The inhibitory effect of a mold upon Staphylococcus. Urol. Cutan. Rev. 1948, 52, 372-373.
28. Hatsuda, Y.; Kuyama, S. Studies on the metabolic products of Aspergillus versicolor. Part 1. Cultivation of Aspergillus versicolor, isolation and purification of metabolic products. J. Agric. Chem. Soc. Jpn. 1954, 28, 989-991.
29. Hatsuda, Y.; Kuyama, S.; Terashima, N. Studies on the metabolic products of Aspergillus versicolor. Part 2. Physical and chemical properties and the chemical structure of sterigmatocystin. J. Agric. Chem. Soc. Jpn. 1954, 28, 992-998.
30. Bullock, E.; Underwood, J.G.V.; Roberts, J.C. Studies in mycological chemistry. 11. Structure of isosterigmatocystin and an amended structure for sterigmatocystin. J. Chem. Soc. 1962, 10, 4179-4183.
31. Holker, J.S.E.; Mulheirn, L.J. Biosynthesis of sterigmatocystin. Chem. Comm. 1968, 24, 1574-1579.
32. Brechbühler, S.; Buchi, G.; Milne, G. Absolute configuration of aflatoxins. J. Org. Chem. 1967, 2641-2642.
33. Fukuyama, K.; Hamada, K.; Tsukihara, T.; Katsube, Y.; Hamasaki, T.; Hatsuda, Y. Crystalstructures of sterigmatocystin and O-methylsterigmatocystin, metabolites of genus Aspergillus. Bull. Chem. Soc. Jpn. 1976, 49I, 1153-1154.
34. Fukuyama, K.; Tsukihara, T.; Katsube, Y.; Tanaka, N.; Hamasaki, T.; Hatsuda, Y. Crystal and molecular structure of p-bromobenzoate of sterigmatocystin. Bull. Chem. Soc. Jpn. 1975, 48, 1980-1983.
35. Blount, W.P. Turkey "X" disease. Turkey 1961, 61, 55-58.
36. Terao, K. Sterigmatocystin-A masked potent carcinogenic mycotoxin. J. Toxicol. Toxin Rev. 1983, 2, 77-110.
37. Bennett, J.W.; Klinch, M. Mycotoxins. Clin. Microbiol. Rev. 2003, 16, 497-516.
38. Bhatnager, D.; Yu, J.; Ehrlich, K.C. Toxins of filamentous fungi. Chem. Immunol. 2002, 81, 167-206.
39. Yu, J.; Chang, P.K.; Ehrlich, K.C.; Cary, J.W.; Bhatnagar, D.; Cleveland, T.E.; Payne, G.A.; Linz, J.E.; Woloshuk, C.P.; Bennett, J.W. Clustered pathway genes in aflatoxin biosynthesis. Appl. Environ. Microbiol. 2004, 70, 1253-1262.
40. Yabe, K.; Nakajima, H. Enzyme reactions and genes in aflatoxin biosynthesis. Appl. Microbiol. Biotechnol. 2004, 64, 745-755.
41. Brown, D.W.; Yu, J.H.; Kelkar, H.S.; Fernandes, M.; Nesbitt, T.C.; Keller, N.P.; Adams, T.H.; Leonard, T.J. Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in Aspergillus nidulans. Proc. Natl. Acad. Sci. USA 1996, 93, 1418-1422.
42. Yu, J.H.; Leonard, T.J. Sterigmatocystin biosynthesis in Aspergillus nidulans requires a novel type I polyketide synthase. J. Bacteriol. 1995, 177, 4792-4800.
43. McDonald, T.; Hammond, T.; Noordermeer, D.; Zhang, Y.Q.; Keller, N. The sterigmatocystin cluster revisited: lessons from a genetic model. In Food Science and Technology/Aflatoxin and Food Safety; Abbas, H.K., Ed.; CRC Press: Boca Raton, FL, USA, 2005; pp. 117-136.
44. Ehrlich, K.C.; Li, P.; Scharfenstein, L.; Chang, P.K. HypC, the anthrone oxidase involved in aflatoxin biosynthesis. Appl. Environ. Microbiol. 2010, 76, 3374-3377.
45. Henry, K.M.; Townsend, C.A. Ordering the reductive and cytochrome P450 oxidative steps in demethylsterigmatocystin formation yields general insights into the biosynthesis of aflatoxin and related fungal metabolites. J. Am. Chem. Soc. 2005, 127, 3724-3733.
46. Ehrlich, K.C.; Montalbano, B.; Boué, S.M.; Bhatnagar, D. An aflatoxin biosynthesis cluster gene encodes a novel oxidase required for conversion of versicolorin A to sterigmatocystin. Appl. Environ. Microbiol. 2005, 71, 8963-8965.
47. Cary, J.W.; Ehrlich, K.C.; Bland, J.M.; Montalbano, B.G. The aflatoxin biosynthesis cluster gene, aflX, encodes an oxidoreductase involved in conversion of versicolorin A to demethylsterigmatocystin. Appl. Environ. Microbiol. 2006, 72, 1096-1101.
48. Yu, J.H.; Butchko, R.A.E.; Fernandes, M.; Keller, N.P.; Leonard, T.J.; Adams, T.H. Conservation of structure and function of the aflatoxin regulatory gene aflR from Aspergillus nidulans and A. flavus. Curr. Genet. 1996, 29, 549-555.
49. Meyers, D.M.; Obrian, G.; Du, W.L.; Bhatnagar, D.; Payne, G.A. Characterization of aflJ, a gene required for conversion of pathway intermediates to aflatoxin. Appl. Environ. Microbiol. 1998, 64, 3713-3717.
50. Bok, J.W.; Keller, N.P. LeaA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell 2004, 3, 527-535.
51. Bayram, Ö.; Krappmann, S.; Ni, M.; Bok, J.W.; Helmstaedt, K.; Valerius, O.; Braus-Stromeyer, S.; Kwon, N.J.; Keller, N.P. VelB/VeA/LaeA complex coordinates light sighal with fungal development and secondart metabolism. Science 2008, 320, 1504-1506.
52. Shwab, E. K; Bok, J.W.; Tribus, M.; Galehr, J.; Graessle, S.; Keller, N.P. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot. Cell 2007, 6, 1656-1664.
53. Fisch, K.M.; Gillaspy, A.F.; Gipson, M.; Henrikson, J.C.; Hoover, A.R.; Jackson, L.; Najar, F.Z.; Wägele, H.; Cichewicz, R.H. Chemical induction of silent biosynthetic pathway transcription in Aspergillus niger. J. Ind. Microbiol. Biotechnol. 2009, 36, 1199-1213.
54. Watanabe, C.M.H.; Townsend, C.A. Initial characterization of a type I fatty acid synthase and polyketide synthase multienzyme complex NorS in the biosynthesis of aflatoxin B1. Chem. Biol. 2002, 9, 981-988.
55. Yabe, K.; Nakamura, Y.; Nakajima, H.; Ando, Y.; Hamasaki, T. Enzymatic conversion of norsolorinic acid to averufin in aflatoxin biosynthesis. Appl. Environ. Microbiol. 1991, 57, 1340-1345.
56. Trail, F.; Chang, P.K.; Cary, J.; Linz, J.E. Structural and functional analysis of the nor-1 gene involved in the biosynthesis of aflatoxins by Aspergillus parasiticus. Appl. Environ. Microbiol. 1994, 60, 4078-4085.
57. Keller, N.P.; Watanabe, C.M.H.; Kelkar, H.S.; Adams, T.H.; Townsend, C.A. Requirement of monooxygenase-mediated steps for sterigmatocystin biosynthesis by Aspergillus nidulans. Appl. Environ. Microbiol. 2000, 66, 359-362.
58. Yabe, L.; Matsuyama, Y.; Ando, Y.; Nakajima, H.; Hamasaki, T. Stereochemistry during aflatoxin biosynthesis: Conversion of norsolorinic acid to averufin. Appl. Environ. Microbiol. 1993, 59, 2486-2492.
59. Chang, P.K.; Yu, J.; Ehrlich, K.C.; Boue, S.M.; Montalbano, B.G.; Bhatnagar, D.; Cleveland, T.E. adhA in Aspergillus parasiticus is involved in conversion of 5'-hydroxyaverantin to averufin. Appl. Environ. Microbiol. 2000, 66, 4715-4719.
60. Sakuno, E.; Yabe, K.; Nakajima, H. Involvement of two cytosolic enzymes and a novel intermediate 5'-oxoaverantin in the pathway from 5'-hydroxyaverantin to averufin in aflatoxin biosynthesis. Appl. Environ. Microbiol. 2003, 69, 6418-6426.
61. Chang, P.K.; Yabe, K.; Yu, J. The Aspergillus parasiticus estA-encoded esterase converts versiconal hemiacetal acetate to versiconal and versiconol acetate to versiconol in aflatoxin biosynthesis. Appl. Environ. Microbiol. 2004, 70, 3593-3599.
62. Silva, J.C.; Minto, R.E.; Barry, C.E., III; Holland, K.A.; Townsend, C.A. Isolation and characterization of the versicolorin B synthase gene from Aspergillus parasiticus. J. Biol. Chem. 1996, 271, 13600-13608.
63. Kelkar, H.S.; Skloss, T.W.; Haw, J.F.; Keller, N.P.; Adams, T.H. Aspergillus nidulans stcL encodes a putative cytochrome P-450 monooxygenase required for bisfuran desaturation during aflatoxin/sterigmatocystin biosynthesis. J. Biol. Chem. 1997, 272, 1589-1594.
64. Keller, N.P.; Kantz, N.J.; Adams, T.H. Aspergillus nidulans verA is required for production of the mycotoxin sterigmatocystin. Appl. Environ Microbiol. 1994, 60, 1444-1450.
65. Keller, N.P.; Segner, S.; Bhatnagar, D.; Adams, T.H. stcS, a putative P-450 monooxygenase, is required for the conversion of versicolorin A to sterigmatocystin in Aspergillus nidulans. Appl. Environ. Microbiol. 1995, 61, 3628-3632.
66. Kelkar, H.S.; Keller, N.P.; Adams, T.H. Aspergillus nidulans stcP encodes an O-methyltransferase that is required for sterigmatocystin biosynthesis. Appl. Environ. Microbiol. 1996, 62, 4296-4298.
67. Slot, J.C.; Rokas, A. Horizontal transfer of a large and highly toxic secondary metabolic gene cluster between fungi. Curr. Biol. 2011, 21, 134-139.
68. Bergmann, S.; Schümann, J.; Scherlach, K.; Lange, C.; Brakhage, A.A.; Hertweck, C. Genomicsdriven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat. Chem. Biol. 2007, 3, 213-217.
69. Chiang, Y.M.; Szewczyk, E.; Nayak, T.; Davidson, A.D.; Sanchez, J. F; Lo, H.C.; Ho, W.Y.; Simityan, H.; Kuo, E.; Praseuth, A.; et al. Molecular genetic mining of the Aspergillus secondary metabolome: Discovery of the emericellamide biosynthetic pathway. Chem. Biol. 2008, 15, 527-532.
70. Sims, J.W.; Fillmore, J.P.; Warner, D.D.; Schmidt, E.W. Equisetin biosynthesis in Fusarium heterosporum. Chem. Commun. 2005, 186-188.
71. Song, Z.; Cox, R.J.; Lazarus, C.M.; Simpson, T.J. Fusarin C biosynthesis in Fusarium moniliforme and Fusarium venenatum. ChemBioChem 2004, 5, 1196-1203.
72. Liu, X.; Walsh, C.T. Cyclopiazonic acid biosynthesis in Aspergillus sp.: Characterization of a reductase-like R* domain in cyclopiazonate synthetase that forms and releases cyclo-acetoacetyl-L-tryptophan. Biochemistry 2009, 48, 8746-8757.
73. Xu, W.; Cai, X.; Jung, M.E.; Tang, Y. Analysis of intact and dissected fungal polyketide synthase-nonribosomal peptide synthetase in vitro and in Saccharomyces cerevisiae. J. Am. Chem. Soc. 2010, 132, 13604-13607.
74. Halo, L.M.; Marshall, J.W.; Yakasai, A.A., Song, Z.; Butts, C.P.; Crump, M.P.; Heneghan, M.; Bailey, A.M.; Simpson, T.J.; Lazarus, C.M.; Cox, R.J. Authentic heterologous expression of the tenellin iterative polyketide synthase nonribosomal peptide synthetase requires coexpression with an enoyl reductase. ChemBioChem 2008, 9, 585-594.
75. Eley, K.L.; Halo, L.M.; Song, Z.; Powles, H.; Cox, R.J.; Bailey, A.M.; Lazarus, C.M.; Simpson, T.J. Biosynthesis of the 2-pyridone tenellin in the insect pathogenic fungus Beauveria bassiana. ChemBioChem 2007, 8, 289-297.
76. Fujita, Y.; Oguri, H.; Oikawa, H. Biosynthetic studies on the antibiotics PF1140: a novel pathway for a 2-pyridone framework. Tetrahedron Lett. 2005, 46, 5885-5888.
77. McInnes, A.G.; Smith, D.G.; Wat, C.K. Tenellin and Bassianin, Metabolites of Beauveria Species. Structure elucidation with 15N-and doubly 13C-enriched compounds using 13C nuclear magnetic resonance spectroscopy. J. Chem. Soc. Chem. Commun. 1974, 8, 281-282.
78. Halo, L.M.; Heneghan, M.N.; Yakasai, A.A.; Song, Z.; Williams, K.; Bailey, A.M.; Cox, R.J.; Lazarus, C.M.; Simpson, T.J. Late stage oxidations during the biosynthesis of the 2-pyridone tenellin in the entomopathogenic fungus Beauveria bassiana. J. Am. Chem. Soc. 2008, 130, 17988-17996.
79. Oh, D.C.; Kauffman, C. A; Jensen, P.R.; Fenical, W. Induced production of emericellamides A and B from the marine-derived fungus Emericella sp. in competing co-culture. J. Nat. Prod. 2007, 70, 515-520.
80. Howard, B.H.; Raistrick, H. Studies in the biochemistry of micro-organism. 94. The colouring matters of species in the Aspergillus nidulans group. Part I. Asperthecin, a crystailline colouring matter of Aspergillus quadrilineatus Thom & Raper. Biochem. J. 1955, 59, 475-484.
81. Birkinshaw, J.H.; Gourlay, R. Studies in the biochemistry of micro-organisms. 109. The structure of asperthecin. Biochem. J. 1961, 81, 618-622.
82. Neelakantan, S.; Pocker, A.; Raistrick, H. Studies in the biochemistry of micro-organisms. 101. The colouring matters of species in the Aspergillus nidulans group. Part 2. Further observations on the structure of asperthecin. Biochem. J. 1957, 66, 234-237.
83. Szewczyk, E.; Chiang, Y.M.; Oakley, C.E.; Davidson, A.D.; Wang, C.C. C; Oakley, B.R. Identification and characterization of the asperthecin gene cluster of Aspergillus nidulans. Appl. Environ. Microbiol. 2008, 74, 7607-7612.
84. Wong, K.H.; Todd, R.B.; Oakley, B.R.; Oakley, C.E.; Hynes, M.J.; Davis, M.A. Sumoylation in Aspergillus nidulans: sumO inactivation, overexpression and live-cell imaging. Fungal Genet. Biol. 2008, 45, 728-737.
85. Awakawa, T.; Yokota, K.; Funa, N.; Doi, F.; Mori, N.; Watanabe, H.; Horinouchi, S. Physically discrete β-lactamase-type thioesterase catalyzes product release in atrochrysone synthesis by iterative type I polyketide synthase. Chem. Biol. 2009, 16, 613-623.
86. Chiang, Y.M.; Oakley, B.R.; Keller, N.P.; Wang, C.C.C. Unraveling polyketide synthesis in members of the genus Aspergillus. Appl. Microbiol. Biotechnol. 2010, 86, 1719-1736.
87. Li, Y.; Chooi, Y.H.; Sheng, Y.; Valentine, J.S.; Tang, Y. Comparative characterization of fungal anthracenone and naphthacenedione biosynthetic pathways reveals an α-hydroxylation-dependent claisen-like cyclization catalyzed by a dimanganese thioesterase. J. Am. Chem. Soc. 2011, 133, 15773-15785.
88. Li, Y.; Xu, W.; Tang, Y. Classification, prediction, and verification of the regioselectivity of fungal polyketide synthase product template domains. J. Biol. Chem. 2010, 285, 22764-22773.
89. Chiang, Y.M.; Szewczyk, E.; Davidson, A.D.; Keller, N.; Oakley, B.R.; Wang, C.C.C. A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. J. Am. Chem. Soc. 2009, 131, 2965-2970.
90. Wang, C.C. C; Chiang, Y.M.; Praseuth, M.B.; Kuo, P.L.; Liang, H.L.; Hsu, Y.L. Asperfuranone from Aspergillus nidulans inhibits proliferation of human non-small cell lung cancer A549 cells via blocking cell cycle progression and inducing apoptosis. Basic Clin. Pharmacol. Toxicol. 2010, 107, 583-589.
91. Matsuzaki, K.; Tahara, H.; Inokoshi, J.; Tanaka, H.; Masuma, R.; Omura, S. New brominated and halogen-less derivatives and structure-activity relationship of azaphilones inhibiting gp120-CD4 binding. J. Antibiot. 1998, 51, 1004-1011.
92. Bailey, A.M.; Cox, R.J.; Harley, K.; Lazarus, C.M.; Simpson, T.J.; Skellam, E. Characterisation of 3-methylorcinaldehyde synthase (MOS) in Acremonium strictum: First observation of a reductive release mechanism during polyketide biosynthesis. Chem. Commun. 2007, 39, 4053-4055.
93. Bergmann, S.; Funk, A.N.; Scherlach, K.; Schroeckh, V.; Shelest, E.; Horn, U.; Hertweck, C.; Brakhage, A.A. Activation of a silent fungal polyketide biosynthesis pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster. Appl. Environ. Microbiol. 2010, 76, 8143-8149.
94. Liu, T.; Chiang, Y.M.; Somoza, A.D.; Oakley, B.R.; Wang, C.C.C. Engineering of an "unnatural" natural product by swapping polyketide synthase domains in Aspergillus nidulans. J. Am. Chem. Soc. 2011, 133, 13314-13316.
95. Lu, P.; Zhang, A.; Dennis, L.M.; Dhal-Roshak, A.M.; Xia, Y.Q.; Arison, B.; An, Z.; Tkacz, J.S. A gene (pks2) encoding a putative 6-methylsalicylic acid synthase from Glarea lozoyensis. Mol. Gen. Genomics 2005, 273, 207-216.
96. Bok, J.W.; Chiang, Y.M.; Szewczyk, E.; Reyes-Dominguez, Y.; Davidson, A.D.; Sanchez, J.F.; Lo, H.C.; Watanabe, K.; Strauss, J.; Oakley, B.R.; et al. Chromatin-level regulation of biosynthetic gene clusters. Nat. Chem. Biol. 2009, 5, 462-464.
97. Chiang, Y.M.; Szewczyk, E.; Davidson, A.D.; Entwistle, R.; Keller, N.P.; Wang, C.C.C.; Oakley, B.R. Characterization of the Aspergillus nidulans monodictyphenone gene cluster. Appl. Environ. Microbiol. 2010, 76, 2067-2074.
98. Sanchez, J.F.; Entwistle, R.; Hung, J.H.; Yaegashi, J.; Jain, S.; Chiang, Y.M.; Wang, C.C.C.; Oakley, B.R. Genome-based deletion analysis reveals the prenyl xanthone biosynthesis pathway in Aspergillus nidulans. J. Am. Chem. Soc. 2011, 133, 4010-4017.
99. Jowett, H.A.D.; Potter, C.E. CXXVII-The constitution of chrysophante acid and of emodin. J. Chem. Soc. Trans. 1903, 83, 1327-1334.
100. Beal, G.D.; Okey, R. The qualitative identification of the drugs containing emodin. J. Am. Chem. Soc. 1917, 39, 716-725.
101. Gatenbeck, S. Incorporation of labelled acetate in emodin in Penicillum islandicum. Acta Chem. Scand. 1958, 12, 1211-1214.
102. Basu, S.; Ghosh, A.; Hazra, B. Evaluation of the antibacterial activity of Ventilago madraspatana Gaertn., Rubia cordifolia Linn. and Lantana camara Linn.: Isolation of emodin and physcion as active antibacterial agents. Phytother. Res. 2005, 19, 888-894.
103. Chen, J.; Zhang, L.; Zhang, Y.; Zhang, H.; Du, J.; Ding; J.; Guo, Y.; Jiang, H.; Shen, X. Emodin targets the β-hydroxyacyl carrier protein dehydratase from Helicobactor pylori: Enzymatic inhibition assay with crystal structural and thermodymamic characterization. BMC Microbiol. 2009, 9, 91:1-91:12.
104. Huang, Q.; Lu, G.; Shen, H.M.; Chung, M.C.M.; Ong, C.N. Anti-cancer properties of anthraquinones from rhubarb. Med. Res. Rev. 2007, 27, 609-630.
105. Srinivas, G.; Babykutty, S.; Sathiadevan, P.P.; Srinivas, P. Molecular mechanism of emodin action: Transition from laxative ingredient to an antitumor agent. Med. Res. Rev. 2007, 27, 591-608.
106. Zargar, B.A.; Masoodi, M.H.; Ahmed, B.; Ganie, S.A. Phytoconstituents and therapeutic uses of Rheum emodi wall. Ex Meissn. Food Chem. 2011, 128, 585-589.
107. Chen, Z.G., Fujii, I.; Ebizuka, Y.; Sankawa, U. Purification and characterization of emodinanthrone oxygenase from Aspergillus terreus. Phytochemistry 1995, 38, 299-305.
108. Huang, K.X.; Fujii, I.; Ebizuka, Y.; Gomi, K.; Sankawa, U. Molecular cloning and heterologous expression of the gene encoding dihydroheodin oxidase, a multicopper blue enzyme from Aspergillus terreus. J. Biol. Chem. 1995, 270, 21495-21502.
109. Couch, R.D.; Gaucher, G.M. Rational elimination of Aspergillus terreus sulochrin production. J. Biotech. 2004, 108, 171-178.
110. Henry, K.M.; Townsend, C.A. Synthesis and fate of o-carboxybenzophenones in the biosynthesis of aflatoxin. J. Am. Chem. Soc. 2005, 127, 3300-3309.
111. Sato, S.; Morishita, T.; Hosoya, T.; Ishikawa, Y. Novel pentacyclec compounds, F-9775A and F-9775B, their manufacture with Paecilomyces carneus, and their use for treatment of osteoporosis. Japan Pat. JP11001480A 19990106, 1999.
112. Schroeckh, V.; Scherlach, K.; Nützmann, H.W.; Shelest, E.; Schmidt-Heck, W.; Schuemann, J.; Martin, K.; Hertweck, C.; Brakhage, A.A. Intimate bacterial-fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc. Natl. Acad. Soc. USA 2009, 106, 14558-14563.
113. Gaucher, G.M.; Sherpherd, M.G. Isolation of orsellinic acid synthase. Biochem. Biophys. Res. Commun. 1968, 32, 664-671.
114. Leo, H.; Yamamoto, Y.; Kim, J.A.; Jung, J.S.; Koh, Y.J.; Hur, J.S. Lecanoric acid, a secondary lichen substance with antioxidant properties from Umbilicaria antarctica in maritime Antarctica (King George Island). Polar Biol. 2009, 32, 1033-1040.
115. Sanchez, J.F.; Chiang, Y.M.; Szewczyk, E.; Davidson, A.D.; Ahuja, M.; Oakley, C.E.; Bok, J.W.; Keller, N.P.; Oakley, B.R.; Wang, C.C.C. Molecular genetic analysis of the orsellinic acid/F9775 gene cluster of Aspergillus nidulans. Mol. BioSyst. 2010, 6, 587-593.
116. Nahlik, K.; Dumkow, M.; Bayram, Ö.; Helmstaedt, K.; Busch, S.; Valerius, O.; Gerke, J.; Hoppert, M.; Schwier, E.; Opitz, L.; et al. The COP9 signalosome mediates transcriptional and metabolic response to hormones, oxidative stress production and cell wall rearrangement during fungal development. Mol. Microbiol. 2010, 78, 964-979.
117. Nützmann, H.W.; Reyes-Doninguez, Y.; Scherlach, K.; Schroeckh, V.; Horn, F.; Gacek, A.; Schümann, J.; Hertweck, C.; Strauss, J.; Brakhage, A.A. Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation. Proc. Natl. Acad. Soc. USA 2011, 108, 14282-14287.
118. Scherlach, K.; Sarkar, A.; Schroeckh, V.; Dahse, H.M.; Roth, M.; Brakhage, A.A.; Horn, W.; Hertweck, C. Two induced fungal polyketide pathways converge into antoproliferative spiroanthrones. ChemBioChem 2011, 12, 1836-1839.
119. Simpson, T.J.; Stenzel, D.J.; Bartlett, A.J.; O'Brien, E.; Holker, J.S.E. Studies on fungal metabolites. Part 3. 13C-NMR spectral and structural studies on Austin and new related meroterpenoids from Aspergillus ustus, Aspergillus variecolor, Penicillum diversum. J. Chem. Soc. Perkin Trans. I 1982, 11, 2687-2692.
120. Geris, R.; Simpson, T.J. Meroterpenoids produced by fungi. Nat. Prod. Rep. 2009, 26, 1063-1094.
121. Márquez-Fernández, O.; Trigos, Á.; Ramos-Balderas, J.L.; Viniegra-González, G.; Deising, H.B.; Aguirre, J. Phosphopantetheinyl transferase CfwA/NpgA is required for Aspergillus nidulans secondary metabolism and asexual development. Eukaryot. Cell 2007, 6, 710-720.
122. Bode, H.B.; Bethe, B.; Höfs, R.; Zeeck, A. Big effects from small changes: possible ways to explore nature's chemical diversity. ChemBioChem 2002, 3, 619-627.
123. Simpson, T.J.; Stenzel, D.J. Biosynthesis of austin, a polyketide-terpenoid metabolite of Aspergillus ustus. JCS Chem. Commun. 1981, 20, 1042-1043.
124. Scott, F.E.; Simpson, T.J.; Trimble, L.A.; Vederas, J.C. Biosynthesis of the meroterpenoid austin by Aspergillus ustus: Synthesis and incorporation of 13C, 18O-labelled ethyl 3,5-dimethylorsellinate. J.C.S. Chem. Comm. 1986, 3, 214-215.