Tentative biosynthetic pathways of some microbial diketopiperazines

Applied Microbiology and Biotechnology

Volumn 97, Issue 19, 2013, Pages 8439-8453

  Gu, Binbin ^a   He, Shan ^a   Yan, Xiaojun ^a   Zhang, Lixin ^b  

^a NINGBO UNIVERSITY   (China)

^b INSTITUTE OF MICROBIOLOGY   (China)

Author keywords

Biosynthetic gene clusters; CDPS; Diketopiperazine; NRPS

Indexed keywords

BIOCONVERSION; SCAFFOLDS;

BIOLOGICAL PROPERTIES; BIOSYNTHETIC GENE CLUSTER; BIOSYNTHETIC PATHWAY; CDPS; DIKETOPIPERAZINES; MOLECULAR MECHANISM; NONRIBOSOMAL PEPTIDE SYNTHETASES; NRPS;

BIOSYNTHESIS;

ACETYLASZONALENIN; ALBONOURSIN; CYCLODIPEPTIDE SYNTHASE; CYCLOPEPTIDE; DIKETONE; ERGOPEPTINE; ERYTHROCHELIN; GLANDICOLINE A; GLANDICOLINE B; MELEAGRIN; MYCOCYCLOSIN; NONRIBOSOMAL PEPTIDE SYNTHETASE; PIPERAZINE DERIVATIVE; PULCHERRIMIN; ROQUEFORTINE; SYNTHETASE; THAXTOMIN; UNCLASSIFIED DRUG;

ENZYME; ENZYME ACTIVITY; GENE; MOLECULAR ANALYSIS; PEPTIDE;

ASPERGILLUS FUMIGATUS; ASPERGILLUS ZONATUS; CLAVICEPS PURPUREA; DRUG SYNTHESIS; ENZYME MECHANISM; NEOSARTORYA; NEOSARTORYA FISCHERI; NONHUMAN; PENICILLIUM CHRYSOGENUM; REVIEW; SACCHAROPOLYSPORA; STREPTOMYCES ERYTHRAEUS; STRUCTURE ACTIVITY RELATION;

ANTI-BACTERIAL AGENTS; BIOSYNTHETIC PATHWAYS; DIKETOPIPERAZINES;

EID: 84885385167     PISSN: 01757598     EISSN: 14320614     Source Type: Journal    
DOI: 10.1007/s00253-013-5175-4     Document Type: Review

References (92)

1. Ali H, Ries MI, Nijland JG, Lankhorst PP, Hankemeier T, Bovenberg RA, Vreeken RJ, Driessen AJ (2013) A branched biosynthetic pathway is involved in production of roquefortine and related compounds in Penicillium chrysogenum. PloS One 8:e65328
2. Allen JD, van Loevezijn A, Lakhai JM, van der Valk M, van Tellingen O, Reid G, Schellens JH, Koomen GJ, Schinkel AH (2002) Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol Cancer Ther 1:417-425
3. Aninat C, Hayashi Y, André F, Delaforge M (2001) Molecular requirements for inhibition of cytochrome P450 activities by roquefortine. Chem Res Toxicol 14:1259-1265
4. Aoyagi T, Wada T, Iinuma H, Ogawa K, Kojima F, Nagai M, Kuroda H, Obayashi A, Umezawa H (1985) Influence of angiotensin-converting enzyme inhibitor, foroxymithine, on dynamic equilibrium around the renin-angiotensin system in vivo. J Appl Biochem 7:388-395
5. Balibar CJ, Walsh CT (2006) GliP, a multimodular nonribosomal peptide synthetase in Aspergillus fumigatus, makes the diketopiperazine scaffold of gliotoxin. Biochemistry 45:15029-15038
6. Barry SM, Challis GL (2012) Tailoring reactions catalyzed by heme-dependent enzymes: spectroscopic characterization of the l-tryptophan-nitrating cytochrome P450 TxtE. Methods Enzymol 516:171-194
7. Barry SM, Kers JA, Johnson EG, Song L, Aston PR, Patel B, Krasnoff SB, Crane BR, Gibson DM, Loria R, Challis GL (2012) Cytochrome P450-catalyzed l-tryptophan nitration in thaxtomin phytotoxin biosynthesis. Nat Chem Biol 8:814-816
8. Belin P, Le Du MH, Fielding A, Lequin O, Jacquet M, Charbonnier JB, Lecoq A, Thai R, Courçon M, Masson C, Dugave C, Genet R, Pernodet JL, Gondry M (2009) Identification and structural basis of the reaction catalyzed by CYP121, an essential cytochrome P450 in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 106:7426-7431
9. Belin P, Moutiez M, Lautru S, Seguin J, Pernodet JL, Gondry M (2012) The nonribosomal synthesis of diketopiperazines in tRNA-dependent cyclodipeptide synthase pathways. Nat Prod Rep 29:961-979
10. Bischoff V, Cookson SJ, Wu S, Scheible WR (2009) Thaxtomin A affects CESA-complex density, expression of cell wall genes, cell wall composition, and causes ectopic lignification in Arabidopsis thaliana seedlings. J Exp Bot 60:955-965
11. Bonnefond L, Arai T, Sakaguchi Y, Suzuki T, Ishitani R, Nureki O (2011) Structural basis for nonribosomal peptide synthesis by an aminoacyl-tRNA synthetase paralog. Proc Natl Acad Sci U S A 108:3912-3917
12. Chai CL, Waring P (2000) Redox sensitive epidithiodioxopiperazines in biological mechanisms of toxicity. Redox Rep 5:257-264
13. Chu M, Truumees I, Rothofsky ML, Patel MG, Gentile F, Das PR, Puar MS, Lin SL (1995) Inhibition of c-fos proto-oncogene induction by Sch 52900 and Sch 52901, novel diketopiperazines produced by Gliocladium sp. J Antibiot (Tokyo) 48:1440-1445
14. Correia T, Grammel N, Ortel I, Keller U, Tudzynski P (2003) Molecular cloning and analysis of the ergopeptine assembly system in the ergot fungus Claviceps purpurea. Chem Biol 10:1281-1292
15. Cryle MJ, Bell SG, Schlichting I (2010) Structural and biochemical characterization of the cytochrome P450 CypX (CYP134A1) from Bacillus subtilis: a cyclo-l-leucyl-l-leucyl dipeptide oxidase. Biochemistry 49:7282-7296
16. Degrassi G, Aguilar C, Bosco M, Zahariev S, Pongor S, Venturi V (2002) Plant growth-promoting Pseudomonas putida WCS358 produces and secretes four cyclic dipeptides: cross-talk with quorum sensing bacterial sensors. Curr Microbiol 45:250-254
17. Fischer E (1906) Untersuchungen über aminosäuren, polypeptide und proteine. Ber Dtsch Chem Ges 39:530-610
18. Forseth RR, Fox EM, Chung D, Howlett BJ, Keller NP, Schroeder FC (2011) Identification of cryptic products of the gliotoxin gene cluster using NMR-based comparative metabolomics and a model for gliotoxin biosynthesis. J Am Chem Soc 133:9678-9681
19. Frisvad JC, Rank C, Nielsen KF, Larsen TO (2009) Metabolomics of Aspergillus fumigatus. Med Mycol 47(S1):53-71
20. Fukushima K, Yazawa K, Arai T (1973) Biological activities of albonoursin. J Antibiot (Tokyo) 26:175-176
21. García-Estrada C, Ullán RV, Albillos SM, Fernández-Bodega MÁ, Durek P, von Döhren H, Martín JF (2011) A single cluster of coregulated genes encodes the biosynthesis of the mycotoxins roquefortine C and meleagrin in Penicillium chrysogenum. Chem Biol 18:1499-1512
22. Gardiner DM, Howlett BJ (2005) Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol Lett 248:241-248
23. Gardiner DM, Cozijnsen AJ, Wilson LM, Pedras MSC, Howlett BJ (2004) The sirodesmin biosynthetic gene cluster of the plant pathogenic fungus Leptosphaeria maculans. Mol Microbiol 53:1307-1318
24. Gardiner DM, Waring P, Howlett BJ (2005) The epipolythiodioxopiperazine (ETP) class of fungal toxins: distribution, mode of action, functions and biosynthesis. Microbiology 151:1021-1032
25. Giessen TW, von Tesmar AM, Marahiel MA (2013) A tRNA-dependent two enzyme pathway for the generation of singly and doubly methylated ditryptophan 2,5-diketopiperazines. Biochemistry 52:4274-4283
26. Gondry M, Lautru S, Fusai G, Meunier G, Menez A, Genet R (2001) Cyclic dipeptide oxidase from Streptomyces noursei. Eur J Biochem 268:1712-1721
27. Gondry M, Sauguet L, Belin P, Thai R, Amouroux R, Tellier C, Tuphile K, Jacquet M, Braud S, Courçon M, Masson C, Dubois S, Lautru S, Lecoq A, Hashimoto S, Genet R, Pernodet JL (2009) Cyclodipeptide synthases are a family of tRNA-dependent peptide bond-forming enzymes. Nat Chem Biol 5:414-420
28. Gruenewald S, Mootz HD, Stehmeier P, Stachelhaus T (2004) In vivo production of artificial nonribosomal peptide products in the heterologous host Escherichia coli. Appl Environ Microbiol 70:3282-3291
29. Gu L, Geders TW, Wang B, Gerwick WH, Håkansson K, Smith JL, Sherman DH (2007) GNAT-like strategy for polyketide chain initiation. Science 318:970-974
30. Healy FG, Wach M, Krasnoff SB, Gibson DM, Loria R (2000) The txtAB genes of the plant pathogen Streptomyces acidiscabies encode a peptide synthetase required for phytotoxin thaxtomin A production and pathogenicity. Mol Microbiol 38:794-804
31. Healy FG, Krasnoff SB, Wach M, Gibson DM, Loria R (2002) Involvement of a cytochrome P450 monooxygenase in thaxtomin A biosynthesis by Streptomyces acidiscabies. J Bacteriol 184:2019-2029
32. Holden MT, Ram Chhabra S, De Nys R, Stead P, Bainton NJ, Hill PJ, Manefield M, Kumar N, Labatte M, England D, Rice S, Givskov M, Salmond GP, Stewart GS, Bycroft BW, Kjelleberg S, Williams P (1999) Quorum-sensing cross talk: isolation and chemical characterization of cyclic dipeptides from Pseudomonas aeruginosa and other Gram-negative bacteria. Mol Microbiol 33:1254-1266
33. Huang R, Zhou X, Xu T, Yang X, Liu Y (2010) Diketopiperazines from marine organisms. Chem Biodivers 7:2809-2829
34. Hurne AM, Chai CL, Moerman K, Waring P (2002) Influx of calcium through a redox-sensitive plasma membrane channel in thymocytes causes early necrotic cell death induced by the epipolythiodioxopiperazine toxins. J Biol Chem 277:31631-31638
35. Imoto M, Umezawa K, Komuro K, Sawa T, Takeuchi T, Umezawa H (1987) Antitumor activity of erbstatin, a tyrosine protein kinase inhibitor. Jpn J Cancer Res 78:329-332
36. Johnson EG, Krasnoff SB, Bignell DR, Chung WC, Tao T, Parry RJ, Loria R, Gibson DM (2009) 4-Nitrotryptophan is a substrate for the non-ribosomal peptide synthetase TxtB in the thaxtomin A biosynthetic pathway. Mol Microbiol 73:409-418
37. Kanoh K, Kohno S, Katada J, Hayashi Y, Muramatsu M, Uno I (1999a) Antitumor activity of phenylahistin in vitro and in vivo. Biosci Biotechnol Biochem 63:1130-1133
38. Kanoh K, Kohno S, Katada J, Takahashi J, Uno I (1999b) (-)-Phenylahistin arrests cells in mitosis by inhibiting tubulin polymerization. J Antibiot (Tokyo) 52:134-141
39. Kers JA, Wach MJ, Krasnoff SB, Widom J, Cameron KD, Bukhalid RA, Gibson DM, Crane BR, Loria R (2004) Nitration of a peptide phytotoxin by bacterial nitric oxide synthase. Nature 429:79-82
40. Kers JA, Cameron KD, Joshi MV, Bukhalid RA, Morello JE, Wach MJ, Gibson DM, Loria R (2005) A large, mobile pathogenicity island confers plant pathogenicity on Streptomyces species. Mol Microbiol 55:1025-1033
41. King RR, Calhoun LA (2009) The thaxtomin phytotoxins: sources, synthesis, biosynthesis, biotransformation and biological activity. Phytochemistry 70:833-841
42. Kohn H, Widger W (2005) The molecular basis for the mode of action of bicyclomycin. Curr Drug Targets Infect Disord 5:273-295
43. Kozlovskii AG, Zhelifonova VP, Antipova TV (2013) Fungi of the genus Penicillium as producers of physiologically active compounds (review). Appl Biochem Microbiol 49:5-16
44. Lautru S, Gondry M, Genet R, Pernodet JL (2002) The albonoursin gene cluster of S. noursei: biosynthesis of diketopiperazine metabolites independent of nonribosomal peptide synthetases. Chem Biol 9:1355-1364
45. Lazos O, Tosin M, Slusarczyk AL, Boakes S, Cortés J, Sidebottom PJ, Leadlay PF (2010) Biosynthesis of the putative siderophore erythrochelin requires unprecedented crosstalk between separate nonribosomal peptide gene clusters. Chem Biol 17:160-173
46. Li SM (2010) Prenylated indole derivatives from fungi: structure diversity, biological activities, biosynthesis and chemoenzymatic synthesis. Nat Prod Rep 27:57-78
47. Li SM (2011) Genome mining and biosynthesis of fumitremorgin-type alkaloids in ascomycetes. J Antibiot (Tokyo) 64:45-49
48. Li J, Wang W, Xu SX, Magarvey NA, McCormick JK (2011) Lactobacillus reuteri-produced cyclic dipeptides quench agr-mediated expression of toxic shock syndrome toxin-1 in staphylococci. Proc Natl Acad Sci U S A 108:3360-3365
49. Loria R, Kers J, Joshi M (2006) Evolution of plant pathogenicity in Streptomyces. Annu Rev Phytopathol 44:469-487
50. Macdonald JC, Slater GP (1975) Biosynthesis of gliotoxin and mycelianamide. Can J Biochem 53:475-478
51. Maiya S, Grundmann A, Li SM, Turner G (2006) The fumitremorgin gene cluster of Aspergillus fumigatus: identification of a gene encoding brevianamide F synthetase. Chembiochem 7:1062-1069
52. McLean KJ, Carroll P, Lewis DG, Dunford AJ, Seward HE, Neeli R, Cheesman MR, Marsollier L, Douglas P, Smith WE, Rosenkrands I, Cole ST, Leys D, Parish T, Munro AW (2008) Characterization of active site structure in CYP121. A cytochrome P450 essential for viability of Mycobacterium tuberculosis H37Rv. J Biol Chem 283:33406-33416
53. Munday R (1987) Studies on the mechanism of toxicity of the mycotoxin, sporidesmin. V. Generation of hydroxyl radical by sporidesmin. J Appl Toxicol 7:17-22
54. Mundt K, Wollinsky B, Ruan HL, Zhu T, Li SM (2012) Identification of the verruculogen prenyltransferase FtmPT3 by a combination of chemical, bioinformatic and biochemical approaches. Chembiochem 13:2583-2592
55. Oide S, Moeder W, Krasnoff S, Gibson D, Haas H, Yoshioka K, Turgeon BG (2006) NPS6, encoding a nonribosomal peptide synthetase involved in siderophore-mediated iron metabolism, is a conserved virulence determinant of plant pathogenic ascomycetes. Plant Cell 18:2836-2853
56. Ortiz-Castro R, Díaz-Pérez C, Martínez-Trujillo M, del Río RE, Campos-García J, López-Bucio J (2011) Transkingdom signaling based on bacterial cyclodipeptides with auxin activity in plants. Proc Natl Acad Sci U S A 108:7253-7258
57. Pardo J, Urban C, Galvez EM, Ekert PG, Müller U, Kwon-Chung J, Lobigs M, Müllbacher A, Wallich R, Borner C, Simon MM (2006) The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice. J Cell Biol 174:509-519
58. Park DK, Lee KE, Baek CH, Kim IH, Kwon JH, Lee WK, Lee KH, Kim BS, Choi SH, Kim KS (2006) Cyclo(Phe-Pro) modulates the expression of ompU in Vibrio spp. J Bacteriol 188:2214-2221
59. Patron NJ, Waller RF, Cozijnsen AJ, Straney DC, Gardiner DM, Nierman WC, Howlett BJ (2007) Origin and distribution of epipolythiodioxopiperazine (ETP) gene clusters in filamentous ascomycetes. BMC Evol Biol 7:174
60. Prasad C (1995) Bioactive cyclic dipeptides. Peptides 16:151-164
61. Rabindran SK, Ross DD, Doyle LA, Yang W, Greenberger LM (2000) Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res 60:47-50
62. Sabater-Vilar M, Nijmeijer S, Fink-Gremmels J (2003) Genotoxicity assessment of five tremorgenic mycotoxins (fumitremorgen B, paxilline, penitrem A, verruculogen, and verrucosidin) produced by molds isolated from fermented meats. J Food Prot 66:2123-2129
63. Sauguet L, Moutiez M, Li Y, Belin P, Seguin J, Le Du MH, Thai R, Masson C, Fonvielle M, Pernodet JL, Charbonnier JB, Gondry M (2011) Cyclodipeptide synthases, a family of class-I aminoacyl-tRNA synthetase-like enzymes involved in non-ribosomal peptide synthesis. Nucleic Acids Res 39:4475-4489
64. Scharf DH, Heinekamp T, Remme N, Hortschansky P, Brakhage AA, Hertweck C (2012) Biosynthesis and function of gliotoxin in Aspergillus fumigatus. Appl Microbiol Biotechnol 93:467-472
65. Scheible WR, Fry B, Kochevenko A, Schindelasch D, Zimmerli L, Somerville S, Loria R, Somerville CR (2003) An Arabidopsis mutant resistant to thaxtomin A, a cellulose synthesis inhibitor from Streptomyces species. Plant Cell 15:1781-1794
66. Schrettl M, Carberry S, Kavanagh K, Haas H, Jones GW, O'Brien J, Nolan A, Stephens J, Fenelon O, Doyle S (2010) Self-protection against gliotoxin - a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathog 6:e1000952
67. Schultz AW, Oh DC, Carney JR, Williamson RT, Udwary DW, Jensen PR, Gould SJ, Fenical W, Moore BS (2008) Biosynthesis and structures of cyclomarins and cyclomarazines, prenylated cyclic peptides of marine actinobacterial origin. J Am Chem Soc 130:4507-4516
68. Schwarzer D, Mootz HD, Marahiel MA (2001) Exploring the impact of different thioesterase domains for the design of hybrid peptide synthetases. Chem Biol 8:997-1010
69. Schwarzer D, Mootz HD, Linne U, Marahiel MA (2002) Regeneration of misprimed nonribosomal peptide synthetases by type II thioesterases. Proc Natl Acad Sci U S A 99:14083-14088
70. Schwarzer D, Finking R, Marahiel MA (2003) Nonribosomal peptides: from genes to products. Nat Prod Rep 20:275-287
71. Seguin J, Moutiez M, Li Y, Belin P, Lecoq A, Fonvielle M, Charbonnier JB, Pernodet JL, Gondry M (2011) Nonribosomal peptide synthesis in animals: the cyclodipeptide synthase of Nematostella. Chem Biol 18:1362-1368
72. Shah DT, Glover DD, Larsen B (1995) In situ mycotoxin production by Candida albicans in women with vaginitis. Gynecol Obstet Invest 39:67-69
73. Song F, Liu X, Guo H, Ren B, Chen C, Piggott AM, Yu K, Gao H, Wang Q, Liu M, Liu X, Dai H, Zhang L, Capon RJ (2012) Brevianamides with antitubercular potential from a marine-derived isolate of Aspergillus versicolor. Org Lett 14:4770-4773
74. Stachelhaus T, Mootz HD, Bergendahl V, Marahiel MA (1998) Peptide bond formation in nonribosomal peptide biosynthesis catalytic role of the condensation domain. J Biol Chem 273:22773-22781
75. Stocking EM, Williams RM, Sanz-Cervera JF (2000) Reverse prenyl transferases exhibit poor facial discrimination in the biosynthesis of paraherquamide A, brevianamide A, and austamide. J Am Chem Soc 122:9089-9098
76. Ström K, Sjögren J, Broberg A, Schnürer J (2002) Lactobacillus plantarum MiLAB 393 produces the antifungal cyclic dipeptides cyclo(l-Phe-l-Pro) and cyclo(l-Phe-trans-4-OH-l-Pro) and 3-phenyllactic acid. Appl Environ Microbiol 68:4322-4327
77. Sutton P, Newcombe NR, Waring P, Müllbacher A (1994) In vivo immunosuppressive activity of gliotoxin, a metabolite produced by human pathogenic fungi. Infect Immun 62:1192-1198
78. Sutton P, Waring P, Müllbacher A (1996) Exacerbation of invasive aspergillosis by the immunosuppressive fungal metabolite, gliotoxin. Immunol Cell Biol 74:318-322
79. Tang MR, Sternberg D, Behr RK, Sloma A, Berka RM (2006) Use of transcriptional profiling & bioinformatics to solve production problems: eliminating red pigment production in a Bacillus subtilis strain producing hyaluronic acid. Industrial Biotechnology 2:66-74
80. Vetting MW, Hegde SS, Blanchard JS (2010) The structure and mechanism of the Mycobacterium tuberculosis cyclodityrosine synthetase. Nat Chem Biol 6:797-799
81. Wagener RE, Davis ND, Diener UL (1980) Penitrem A and roquefortine production by Penicillium commune. Appl Environ Microbiol 39:882-887
82. Wallwey C, Li SM (2011) Ergot alkaloids: structure diversity, biosynthetic gene clusters and functional proof of biosynthetic genes. Nat Prod Rep 28:496-510
83. Waring P, Beaver J (1996) Gliotoxin and related epipolythiodioxopiperazines. Gen Pharmacol 27:1311-1316
84. Waring P, Eichner RD, Müllbacher A, Sjaarda A (1988) Gliotoxin induces apoptosis in macrophages unrelated to its antiphagocytic properties. J Biol Chem 263:18493-18499
85. Watanabe K, Oikawa H (2007) Robust platform for de novo production of heterologous polyketides and nonribosomal peptides in Escherichia coli. Org Biomol Chem 5:593-602
86. Wilhite SE, Lumsden RD, Straney DC (2001) Peptide synthetase gene in Trichoderma virens. Appl Environ Microbiol 67:5055-5062
87. Williams DE, Bombuwala K, Lobkovsky E, De Silva ED, Karunatne V, Allen TM, Clardy J, Andersen RJ (1998) Ambewelamides A and B, antineoplastic epidithiapiperazinediones isolated from the lichen Usnea sp. Tetrahedron Lett 39:9579-9582
88. Williams RM, Stocking EM, Sanz-Cervera JF (2000) Biosynthesis of prenylated alkaloids derived from tryptophan. Biosynthesis 209:97-173
89. Woehlecke H, Osada H, Herrmann A, Lage H (2003) Reversal of breast cancer resistance protein-mediated drug resistance by tryprostatin A. Int J Cancer 107:721-728
90. Yin WB, Grundmann A, Cheng J, Li SM (2009) Acetylaszonalenin biosynthesis in Neosartorya fischeri identification of the biosynthetic gene cluster by genomic mining and functional proof of the genes by biochemical investigation. J Biol Chem 284:100-109
91. Zhang L, Yan K, Zhang Y, Huang R, Bian J, Zheng C, Sun H, Chen Z, Sun N, An R, Min F, Zhao W, Zhuo Y, You J, Song Y, Yu Z, Liu Z, Yang K, Gao H, Dai H, Zhang X, Wang J, Fu C, Pei G, Liu J, Zhang S, Goodfellow M, Jiang Y, Kuai J, Zhou G, Chen X (2007) High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections. Proc Natl Acad Sci U S A 104:4606-4611
92. Zhuo Y, Zhang W, Chen D, Gao H, Tao J, Liu M, Gou Z, Zhou X, Ye BC, Zhang Q, Zhang S, Zhang LX (2010) Reverse biological engineering of hrdB to enhance the production of avermectins in an industrial strain of Streptomyces avermitilis. Proc Natl Acad Sci U S A 107:11250-11254