Skip to main content
SpringerLink
Log in

Function of MbtH homologs in nonribosomal peptide biosynthesis and applications in secondary metabolite discovery

  • Review
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

Mycobacterium tuberculosis encodes mycobactin, a peptide siderophore that is biosynthesized by a nonribosomal peptide synthetase (NRPS) mechanism. Within the mycobactin biosynthetic gene cluster is a gene that encodes a 71-amino-acid protein MbtH. Many other NRPS gene clusters harbor mbtH homologs, and recent genetic, biochemical, and structural studies have begun to shed light on the function(s) of these proteins. In some cases, MbtH-like proteins are required for biosynthesis of their cognate peptides, and non-cognate MbtH-like proteins have been shown to be partially complementary. Biochemical studies revealed that certain MbtH-like proteins participate in tight binding to NRPS proteins containing adenylation (A) domains where they stimulate adenylation reactions. Expression of MbtH-like proteins is important for a number of applications, including optimal production of native and genetically engineered secondary metabolites produced by mechanisms that employ NRPS enzymes. They also may serve as beacons to identify gifted actinomycetes and possibly other bacteria that encode multiple functional NRPS pathways for discovery of novel secondary metabolites by genome mining.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Alexander DC, Rock J, He X, Miao V, Brian P, Baltz RH (2010) Development of genetic system for lipopeptide combinatorial biosynthesis in Streptomyces fradiae and heterologous expression of the A54145 biosynthetic gene cluster. Appl Environ Microbiol 76:6877–6887

    Article  PubMed  CAS  Google Scholar 

  2. Alexander DC, Rock J, Gu J-Q, Mascio C, Chu M, Brian P, Baltz RH (2011) Production of novel lipopeptide antibiotics related to A54145 by Streptomyces fradiae mutants blocked in biosynthesis of modified amino acids and assignment of lptI, lptK and lptL gene functions. J Antibiot 64:79–87

    Article  PubMed  CAS  Google Scholar 

  3. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215:403–410

    PubMed  CAS  Google Scholar 

  4. Baltz RH (2008) Renaissance in antibacterial discovery from actinomycetes. Curr Opin Pharmacol 8:557–563

    Article  PubMed  CAS  Google Scholar 

  5. Baltz RH (2010) Streptomyces and Saccharopolyspora hosts for heterologous expression of secondary metabolite gene clusters. J Ind Microbiol Biotechnol 37:759–772

    Article  PubMed  CAS  Google Scholar 

  6. Baltz RH (2010) Genomics and the ancient origins of the daptomycin biosynthetic gene cluster. J Antibiot 63:506–511

    Article  PubMed  CAS  Google Scholar 

  7. Baltz RH (2011) Strain improvement in actinomycetes in the postgenomic era. J Ind Microbiol Biotechnol 38:657–666

    Article  PubMed  CAS  Google Scholar 

  8. Buchko GW, Kim C-Y, Terwilliger TC, Myler PJ (2010) Solution structure of Rv2377c-founding member of the MbtH-like protein family. Tuberculosis 90:245–251

    Article  PubMed  CAS  Google Scholar 

  9. Carter RA, Worsley PS, Sawers G, Challis GL, Dilworth MJ, Carson KC, Lawrence JA, Wexler M, Johnston AWB, Yeoman KH (2002) The vbs genes that direct synthesis of the siderophore vivibactin in Rhizobium leguimosum: their expression in other genera requires ECF σ factor RpoI. Mol Microbiol 44:1153–1166

    Article  PubMed  CAS  Google Scholar 

  10. Challis GL (2008) Mining microbial genomes for new natural products and biosynthetic pathways. Microbiology 154:1555–1569

    Article  PubMed  CAS  Google Scholar 

  11. Chen H, Walsh CT (2001) Coumarin formation in novobiocin biosynthesis: β-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by cytochrome P450 NovI. Chem Biol 8:301–312

    Article  PubMed  CAS  Google Scholar 

  12. Chen H, Hubbard BK, O’Connor SE, Walsh CT (2002) Formation of β-hydroxy histidine in the biosynthesis of nikkomycin antibiotics. Chem Biol 9:103–112

    Article  PubMed  CAS  Google Scholar 

  13. Coëffet-Le Gal M-F, Thurson L, Rich P, Miao V, Baltz RH (2006) Complementation of daptomycin dptA and dptD deletion mutations in-trans and production of hybrid lipopeptide antibiotics. Microbiology 152:2993–3001

    Article  PubMed  Google Scholar 

  14. Corre C, Challis GL (2009) New natural product biosynthetic chemistry discovered by genome mining. Nat Prod Rep 26:977–986

    Article  PubMed  CAS  Google Scholar 

  15. Donadio S, Monciardini P, Sosio M (2007) Polyketide synthases and nonribosomal peptide synthetases: the emerging view from bacterial genomics. Nat Prod Rep 24:1073–1109

    Article  PubMed  CAS  Google Scholar 

  16. Drake EJ, Cao J, Quiz J, Shah MB, Straubinger RM, Gulick AM (2007) The 1.8 Å crystal structure of PA2412, an MbtH-like protein from the pyoverdine cluster of Pseudomonas aeruginosa. J Biol Chem 282:20425–20434

    Article  PubMed  CAS  Google Scholar 

  17. Edwards DJ, Gerwick WH (2004) Lyngbyatoxin biosynthesis: sequence of biosynthetic gene cluster and identification of a novel aromatic prenyltransferase. J Am Chem Soc 126:11432–11433

    Article  PubMed  CAS  Google Scholar 

  18. Eustáquio AS, Gust B, Galm U, Li S-M, Chater KF, Heide L (2005) Heterologous expression of novobiocin and clorobiocin biosynthetic gene clusters. Appl Environ Microbiol 71:2452–2459

    Article  PubMed  Google Scholar 

  19. Felnagle EA, Rondon MR, Berti AD, Crosby HA, Thomas MG (2007) Identification of the biosynthetic gene cluster and an additional gene for resistance to the antituberculosis drug capreomycin. Appl Environ Microbiol 73:4162–4170

    Article  PubMed  CAS  Google Scholar 

  20. Felnagle EA, Barkei JJ, Park H, Podevels AM, McMahon MD, Drott DW, Thomas MG (2010) MbtH-like proteins as integral components of bacterial nonribosomal peptide synthetases. Biochemistry 49:8815–8817

    Article  PubMed  CAS  Google Scholar 

  21. Heemstra JR Jr, Walsh CT, Sattely ES (2009) Enzymatic tailoring of ornithine in the biosynthesis of the Rhizobium cyclic trihydroxamate siderophore vicibactin. J Am Chem Soc 131:15317–15329

    Article  PubMed  CAS  Google Scholar 

  22. Hojati Z, Milne C, Harvey B, Gordon L, Borg M, Flett F, Wilkinson B, Sidebottom PJ, Rudd BA, Hayes MA, Smith CP, Micklefield J (2002) Structure, biosynthetic origin, and engineered biosynthesis of calcium-dependent antibiotics from Streptomyces coelicolor. Chem Biol 9:1175–1187

    Article  PubMed  CAS  Google Scholar 

  23. Huynh MU, Elston MC, Hernandez NM, Ball DB, Kajiyama S, Irie K, Gerwick WH, Edwards DJ (2010) Enzymatic production of (−)-indolactam V by LtxB, a cytochrome P450 monooxygenase. J Nat Prod 73:71–74

    Article  PubMed  CAS  Google Scholar 

  24. Imker HJ, Krahn D, Clerc J, Kaiser M, Walsh CT (2010) N-acylation during glidobactin biosynthesis by the tridomain nonribosomal peptide synthetase module GlbF. Chem Biol 17:1077–1083

    Article  PubMed  CAS  Google Scholar 

  25. Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Ōmura S (2003) Complete genome sequence of and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol 21:526–531

    Article  PubMed  Google Scholar 

  26. Jordan IK, Rogozin IB, Wolf YI, Koonin EV (2002) Microevolutionary genomics of bacteria. Theor Popul Biol 61:435–447

    Article  PubMed  Google Scholar 

  27. Lauer B, Russwurm R, Bormann C (2000) Molecular characterization of two genes from Streptomyces tendae Tü901 required for the formation of the 4-formyl-4-imidazolin-2-one-containing nucleoside moiety of the peptidyl nucleoside antibiotic nikkomycin. Eur J Biochem 267:1698–1706

    Article  PubMed  CAS  Google Scholar 

  28. Lauer B, Russwurm R, Schwarz W, Kálmánczhelyi A, Bruntner C, Rosemeier A, Bormann C (2001) Molecular characterization of co-transcribed genes from Streptomyces tendae Tü901 involved in the biosynthesis of the peptidyl moiety and assembly of the peptidyl nucleoside antibiotic nikkomycin. Mol Gen Genet 264:662–673

    Article  PubMed  CAS  Google Scholar 

  29. Lautru S, Oves-Costales D, Pernodet J-L, Challis GL (2007) MbtH-like protein-mediated cross-talk between non-ribosomal peptide antibiotic and siderophore biosynthetic pathways in Streptomyces coelicolor M145. Microbiology 153:1405–1412

    Article  PubMed  CAS  Google Scholar 

  30. Losey HC, Peczuh MW, Chen Z, Eggert US, Dong SD, Pelczer I, Kahne D, Walsh CT (2001) Tandem action of glycosyltransferases in the maturation of vancomycin and teicoplanin aglycones: novel glycopeptides. Biochemistry 40:4745–4755

    Article  PubMed  CAS  Google Scholar 

  31. Magarvey NA, Haltli B, He M, Greenstein M, Hucul JA (2006) Biosynthetic pathway for mannopeptimycins, lipoglycopeptide antibiotics active against drug-resistant Gram-positive pathogens. Antimicrob Agents Chemother 50:2167–2177

    Article  PubMed  CAS  Google Scholar 

  32. Mast YJ, Wohlleben W, Schinko E (2011) Identification and functional characterization of phenylglycine biosynthetic genes involved in pristinamycin biosynthesis in Streptomyces pristinaespiralis. J Biotechnol (in press)

  33. Medema MH, Trefzer A, Kovalchuk A, van den Berg M, Müller U, Heijne W, Wu L, Alam MT, Ronning CM, Nierman WC, Bovenberg RAL, Breitling R, Takano E (2010) The sequence of a 1.8-Mb bacterial linear plasmid reveals a rich evolutionary reservoir of secondary metabolic pathways. Genome Biol Evol 2:212–224

    Article  PubMed  Google Scholar 

  34. Miao V, Coëffet-LeGal M-F, Brian P, Brost R, Penn J, Whiting A, Martin S, Ford R, Parr I, Bouchard M, Silva CJ, Wrigley SK, Baltz RH (2005) Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry. Microbiology 151:1507–1523

    Article  PubMed  CAS  Google Scholar 

  35. Miao V, Brost R, Chapple J, She K, Coëffet-Le Gal M-F, Baltz RH (2006) The lipopeptide antibiotic A54145 biosynthetic gene cluster from Streptomyces fradiae. J Ind Microbiol Biotechnol 33:129–140

    Article  PubMed  CAS  Google Scholar 

  36. Miao V, Coëffet-Le Gal M-F, Nguyen K, Brian P, Penn J, Whiting A, Steele J, Kau D, Martin S, Ford R, Gibson T, Bouchard M, Wrigley SK, Baltz RH (2006) Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics. Chem Biol 13:269–276

    Article  PubMed  CAS  Google Scholar 

  37. Müller C, Nolden S, Gebhardt P, Heinzelmann E, Lange C, Puk O, Welzel K, Wohlleben W, Schwartz D (2007) Sequencing and analysis of the biosynthetic gene cluster of the lipopeptide antibiotic friulimicin in Actinoplanes friuliensis. Antimicrob Agents Chemother 51:1028–1037

    Article  PubMed  Google Scholar 

  38. Nguyen K, Kau D, Gu J-Q, Brian P, Wrigley SK, Baltz RH, Miao V (2006) A glutamic acid 3-methyltransferase encoded by an accessory gene locus important for daptomycin biosynthesis in Streptomyces roseosporus. Mol Microbiol 61:1294–1307

    Article  PubMed  CAS  Google Scholar 

  39. Nguyen K, Ritz D, Gu J-Q, Alexander D, Chu M, Miao V, Brian P, Baltz RH (2006) Combinatorial biosynthesis of lipopeptide antibiotics related to daptomycin. Proc Natl Acad Sci USA 103:17462–17467

    Article  PubMed  CAS  Google Scholar 

  40. Nguyen K, He X, Alexander DC, Li C, Gu J-Q, Mascio C, Van Praagh A, Morton L, Chu M, Silverman JA, Brian P, Baltz RH (2010) Genetically engineered lipopeptide antibiotics related to A54145 and daptomycin with improved properties. Antimicrob Agents Chemother 54:1404–1413

    Article  PubMed  CAS  Google Scholar 

  41. Novichkov PS, Wolf YI, Dubchak I, Koonin EV (2009) Trends in prokaryotic evolution revealed by comparison of closely related bacterial and archael genomes. J Bacteriol 191:65–73

    Article  PubMed  CAS  Google Scholar 

  42. Ohnishi Y, Ishikawa J, Hara H, Suzuki H, Ikenoya M, Ikeda H, Yamashita A, Hattori M, Horinouchi S (2008) Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. J Bacteriol 190:4050–4060

    Article  PubMed  CAS  Google Scholar 

  43. Oliynyk M, Samborskyy M, Lester JB, Mironenko T, Scott N, Dickens S, Haydock SF, Leadlay PF (2007) Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Nat Biotechnol 25:447–453

    Article  PubMed  CAS  Google Scholar 

  44. Penn K, Jenkins C, Nett M, Udwary DW, Gontang EA, McGlinchey RP, Foster B, Lapidus A, Podell S, Allen EE, Moore BS, Jensen PR (2009) Genetic islands link secondary metabolism to functional adaptation in marine Actinobacteria. ISME J 3:1193–1203

    Article  PubMed  CAS  Google Scholar 

  45. Pojer F, Li S-M, Heide L (2002) Molecular cloning and sequence analysis of the clorobiocin biosynthetic gene cluster: new insights into the biosynthesis of aminocoumarin antibiotics. Microbiology 148:3901–3911

    PubMed  CAS  Google Scholar 

  46. Quadri LEN, Sello J, Keating TA, Weinreb PH, Walsh CT (1998) Identification of Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin. Chem Biol 5:631–645

    Article  PubMed  CAS  Google Scholar 

  47. Reed JA, Walsh CT (2007) The lyngbyatoxin biosynthetic assembly line: chain release by four-electron reduction of a dipeptidyl thioester to the corresponding alcohol. J Am Chem Soc 129:15762–15763

    Article  Google Scholar 

  48. Rhee K-H, Davies J (2006) Transcription analysis of daptomycin biosynthesis genes in Streptomyces roseosporus. J Microbiol Biotechnol 16:1841–1848

    CAS  Google Scholar 

  49. Solenberg PJ, Matsushima P, Stack DR, Wilkie SC, Thompson RC, Baltz RH (1997) Production of hybrid glycopeptide antibiotics in vitro and in Streptomyces toyocaensis. Chem Biol 4:195–202

    Article  PubMed  CAS  Google Scholar 

  50. Sosio M, Stinchi S, Beltrametti F, Lazzarini A, Donadio S (2003) The gene cluster for the biosynthesis of the glycopeptide antibiotic A40926 by Nonomuraea species. Chem Biol 10:541–549

    Article  PubMed  CAS  Google Scholar 

  51. Sosio M, Kloosterman H, Bianchi A, de Vreugd P, Dijkhuizen L, Donodio S (2004) Organization of the teicoplanin gene cluster in Actinoplanes teichomyceticus. Microbiology 150:95–102

    Article  PubMed  CAS  Google Scholar 

  52. Stegmann E, Rausch C, Stockert S, Burkert D, Wohlleben W (2006) The small MbtH-like protein encoded by an internal gene of the balhimycin biosynthetic gene cluster is not required for glycopeptide production. FEMS Microbiol Lett 262:85–92

    Article  PubMed  CAS  Google Scholar 

  53. Thomas MG, Chan YA, Ozanick SG (2003) Deciphering tuberactinomycin biosynthesis: isolation, sequencing, and annotation of the viomycin biosynthetic gene cluster. Antimicrob Agents Chemother 47:2823–2830

    Article  PubMed  CAS  Google Scholar 

  54. Wang G, Nie L, Tan H (2003) Cloning and characterization of sanO, a gene involved in nikkomycin biosynthesis in Streptomyces ansochromogenes. Lett Appl Microbiol 36:452–457

    Article  Google Scholar 

  55. Wang Z-X, Li S-M, Heide L (2000) Identification of the coumermycin A1 biosynthetic gene cluster of Streptomyces rishiriensis DSM 40489. Antimicrob Agents Chemother 44:3040–3048

    Article  PubMed  CAS  Google Scholar 

  56. Wolpert M, Gust B, Kammerer B, Heide L (2007) Effects of deletion of mbtH-like genes on chlorobiocin biosynthesis in Streptomyces coelicolor. Microbiology 153:1413–1423

    Article  PubMed  CAS  Google Scholar 

  57. Yin X, Zabriskie M (2006) The enduracidin biosynthetic gene cluster from Streptomyces fungicidicus. Microbiology 152:2969–2983

    Article  PubMed  Google Scholar 

  58. Yu G, Jia X, Wen J, Lu W, Wang G, Caiyin Q, Chen Y (2011) Strain improvement of Streptomyces roseosporus for daptomycin production by rational screening of He-Ne laser and NTG induced mutants and kinetic modeling. Appl Biochem Biotechnol 163:729–743

    Article  PubMed  CAS  Google Scholar 

  59. Zerbe K, Pylypenko O, Vitali F, Zhang W, Rouset S, Heck M, Vrijbloed JW, Bischoff D, Bister B, Süssmuth RD, Pelzer S, Wohlleben W, Robinson JA, Schlichting I (2002) Crystal structure of OxyB, a cytochrome P450 implicated in the oxidative phenol coupling reaction during vancomycin biosynthesis. J Biol Chem 277:47476–47485

    Article  PubMed  CAS  Google Scholar 

  60. Zerikly M, Challis GL (2009) Strategies for the discovery of new natural products by genome mining. ChemBioChem 10:625–633

    Article  PubMed  CAS  Google Scholar 

  61. Zhang W, Ostach B, Walsh CT (2010) Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics. Proc Natl Acad Sci USA 107:16828–16833

    Article  PubMed  CAS  Google Scholar 

  62. Zhang W, Heemstra JR, Walsh CT, Imker HJ (2010) Activation of the pacidamycin PacL adenylation domain by MbtH-like proteins. Biochemistry 49:9946–9947

    Article  PubMed  CAS  Google Scholar 

  63. Zhao W, Zhong Y, Yuan H, Wang J, Zheng H, Wang Y, Cen X, Xu F, Bai J, Han X, Lu G, Zhu Y, Shao Z, Yan H, Li C, Peng N, Zhang Z, Zhang Y, Lin W, Fan Y, Qin Z, Hu Y, Zhu B, Wang S, Ding X, Zhao G-P (2010) Complete genome sequence of the rifamycin SV-producing Amycolatopsis mediterranei U32 revealed its genetic characteristics in phylogeny and metabolism. Cell Res 20:1096–1108

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CognoGen Biotechnology Consulting, 6438 North Olney Street, Indianapolis, IN, 46220, USA

    Richard H. Baltz

Authors
  1. Richard H. Baltz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard H. Baltz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baltz, R.H. Function of MbtH homologs in nonribosomal peptide biosynthesis and applications in secondary metabolite discovery. J Ind Microbiol Biotechnol 38, 1747–1760 (2011). https://doi.org/10.1007/s10295-011-1022-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10295-011-1022-8

Keywords

Search

Navigation