Biosynthetic systems for nonribosomal peptide antibiotic assembly

Current Opinion in Chemical Biology

Volumn 1, Issue 4, 1997, Pages 543-551

  Mootz, Henning D ^a   Marahiel, Mohamed A ^a  

^a PHILIPPS UNIVERSITY MARBURG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFECTIVE AGENT; GRAMICIDIN; PEPTIDE SYNTHASE;

AMINO ACID SEQUENCE; BIOSYNTHESIS; CHEMICAL MODEL; CHEMISTRY; ENZYME SPECIFICITY; GENETICS; METABOLISM; MULTIGENE FAMILY; PROTEIN CONFORMATION; PROTEIN SECONDARY STRUCTURE; REVIEW;

AMINO ACID SEQUENCE; ANTI-BACTERIAL AGENTS; GRAMICIDIN; MODELS, CHEMICAL; MULTIGENE FAMILY; PEPTIDE SYNTHASES; PROTEIN CONFORMATION; PROTEIN STRUCTURE, SECONDARY; SUBSTRATE SPECIFICITY;

EID: 0031322936     PISSN: 13675931     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1367-5931(97)80051-8     Document Type: Article

References (54)

1. Stachelhaus T, Schneider A, Marahiel MA: Engineered biosynthesis of peptide antibiotics. Biochem Pharmacol 1996, 52:177-186.
2. Marahiel MA, Stachelhaus T, Mootz HD: Modular peptide synthetases involved in nonribosomal peptide synthesis. Chem Rev 1997, in press. A comprehensive review focusing on the modular architecture of peptide synthetases, and possible future directions to produce novel compounds by genetic engineering of the protein templates. Includes a detailed description of the first peptide synthetase crystal structure. Also see the entire November 1997 issue of Chemical Reviews which is dedicated to polyketide and nonribosomal peptide synthesis.
3. Kleinkauf H, von Döhren H: A nonribosomal system of peptide biosynthesis. Eur J Biochem 1996, 236:335-351.
4. Stein T, Vater J: Amino acid activation and polymerization at modular multienzymes in nonribosomal peptide biosynthesis. Amino Acids 1996, 10:201-227. A clearly written review summarizing state of the art data on conserved residues within the distinct domains of peptide synthetases.
5. Zocher R, Keller U: Thiol template peptide synthesis systems in bacteria and fungi. Adv Microb Physiol 1997, 38:85-131.
6. Stachelhaus T, Schneider A, Marahiel MA: Rational design of peptide antibiotics by targeted replacement of bacterial and fungal domains. Science 1995, 269:69-72.
7. Turgay K, Krause M, Marahiel MA: Four homologous domains in the primary structure of GrsB are related to domains in a superfamily of adenylate-forming enzymes. Mol Microbiol 1992, 6:529-546.
8. Stachelhaus T, Marahiel MA: Modular structure of peptide synthetases revealed by dissection of the multifunctional enzyme GrsA. J Biol Chem 1995, 270:6163-6169.
9. Dieckmann R, Lee YO, van Liempt H, von Döhren H, Kleinkauf H: Expression of an active adenylate-forming domain of peptide synthetases corresponding to acyl-CoA-synthetases. FEBS Lett 1995, 357:212-216.
10. Haese A, Pieper R, von Ostrowski T, Zocher R: Bacterial expression of catalytically active fragments of the multifunctional enzyme enniatin synthetase. J Mol Biol 1994, 243:116-122.
11. Conti E, Franks NP, Brick P: Crystal structure of firefly luciferase throws light on a super-family of adenylate-forming enzymes. Structure 1996, 4:287-298. The authors describe the first crystal structure of an enzyme that belongs to the third superfamily of acyl adenylate-forming enzymes (the other two families are the class I and class II tRNA synthetases).
12. Eriani G, Delarue M, Poch O, Gangloff J, Moras D: Partition of tRNA synthetases into two classes based on mutually exclusive sets of sequence motifs. Nature 1990, 347:203-206.
13. Carter CW Jr: Cognition, mechanism, and evolutionary relationships in aminoacyl-tRNA synthetases. Annu Rev Biochem 1993, 62:715-748.
14. Conti E, Stachelhaus T, Marahiel MA, Brick P: Structural basis for the activation of phenylalanine in the nonribosomal biosynthesis of gramicidin S. EMBO J 1997, 16:4174-4183. The authors report the crystal structure of the adenylation domain (PheA) of the gramicidin S synthetase (GrsA) complexed with L-phenylalanine and AMP. The amino acyl adenylate has obviously been hydrolyzed. No electron density is found for the pyrophosphate. The protein folds into a large amino-terminal and a smaller carboxy-terminal domain and the substrates are bound at the interface. A strictly conserved lysine residue of the carboxy-terminal domain plays a key role by binding both the AMP and L-phenylanine. A stereo view of the amino acid specificity pocket is also presented.
15. Gocht M, Marahiel MA: Analysis of core sequences in the D-Phe activating domain of the multifunctional peptide synthetase TycA by site-directed mutagenesis. J Bacteriol 1994, 176:2654-2662.
16. Hamoen LW, Eshuis H, Jongbloed J, Venema G, van Sinderen D: A small gene, designated comS, located within the coding region of the fourth amino acid-activation domain of srfA, is required for competence development in Bacillus subtilis. Mol Microbiol 1995, 15:55-63.
17. Saito M, Hori K, Kurotsu T, Kanda M, Saito Y: Three conserved glycine residues in valine activation of gramicidin S synthetase 2 from Bacillus brevis. J Biochem (Tokyo) 1995, 117:276-282.
18. Pavela-Vrancic M, Pfeifer E, van Liempt H, Schöfer HJ, von Döhren H, Kleinkauf H: ATP binding in peptide synthetases: determination of contact sites of the adenine moiety by photoaffinity labeling of tyrocidine synthetase 1 with 2-azidoadenosine triphosphate. Biochemistry 1994, 33:6276-6283.
19. Pavela-Vrancic M, Pfeifer E, Schröder W, von Döhren H, Kleinkauf H: Identification of the ATP binding site in tyrocidine synthetase 1 by selective modification with fluorescein 5′-isothiocyanate. J Biol Chem 1994, 269:14962-14966.
20. Cosmina P, Rodriguez F, de Ferra F, Grandi G, Perego M, Venema G, van Sinderen D: Sequence and analysis of the genetic locus responsible for surfactin synthesis in Bacillus subtilis. Mol Microbiol 1993, 8:821-831.
21. Elsner A, Engert H, Saenger W, Hamoen L, Venema G, Bernhard F: Substrate specificity of hybrid modules from peptide synthetases. J Biol Chem 1997, 272:4814-4819. In this work hybrid modules of peptide synthetases were created by fusing the reading frames of two different modules at various highly conserved motifs within the adenylation domains. The results indicate the presence of a large amino-terminal and a small carboxy-terminal domain which are reciprocally interchangeable. The specificity determinants were found to be located in the large amino-terminal domain. The latter finding is in agreement with the PheA crystal structure, which was subsequently published. The fusion site reported here, however, does not correspond to the loop between the two domains described by Conti et al. (1997) [14••], suggesting a robust, conserved tertiary structure of adenylation domains.
22. Lipmann F, Gevers W, Kleinkauf H, Roskoski R Jr: Polypeptide synthesis on protein templates: the enzymatic synthesis of gramicidin S and tyrocidine. Adv Enzymol Relat Areas Mol Biol 1971, 35:1-34.
23. Schlumbohm W, Stein T, Ullrich C, Vater J, Krause M, Marahiel MA, Kruft V, Wittmann-Liebold B: An active serine is involved in covalent substrate amino acid binding at each reaction center of gramicidin S synthetase. J Biol Chem 1991, 266:23135-23141.
24. Stein T, Vater J, Kruft V, Otto A, Wittmann-Liebold B, Franke P, Panico M, McDowell R, Morris HR: The multiple carrier model of nonribosomal peptide biosynthesis at modular multienzymatic templates. J Biol Chem 1996, 271:15428-15435. The biochemical work presented here is clear evidence for the presence of the 4'-phosphopantetheine (P-pant) cofactor at the binding site of each module of the two gramicidin S synthetases. An exceptional system for labeling the five different thiolation centres and subsequently isolating the peptide fragments containing the P-pant binding site was developed. These findings have great impact on the current model of nonribosomal peptide synthesis, which is discussed in detail.
25. Lambalot RH, Walsh CT: Cloning, overproduction, and characterization of the Escherichia coli holo-acyl carrier protein synthase. J Biol Chem 1995, 270:24658-24661.
26. Lambalot RH, Gehring AM, Flugel RS, Zuber P, LaCelle M, Marahiel MA, Reid R, Khosla C, Walsh CT: A new enzyme superfamily - the phosphopantetheinyl transferases. Chem Biol 1996, 3:923-936. This paper describes the discovery of a new enzyme superfamily of phosphopantetheinyl transferases that were identified by low level similarity to the only know enzyme with 4′-phosphopantetheine (P-pant) transferring activity (see Lambalot and Walsh (1995) [25]). The findings are of immense importance for research on all enzymes requiring post-translational modification of their acyl carrier protein (ACP) domains - fatty acid and polyketide synthases in addition to nonribosomal peptide synthetases. In vitro data of three P-pant transferases of E. coli suggests the presence of three independent P-pant requiring pathways: for fatty acid and enterobactin synthesis. For the third P-pant transferase, identified from sequence homologies, the corresponding substrate is not yet known.
27. Gehring AM, Bradley KA, Walsh CT: Enterobactin biosynthesis in Escherichia coli: isochorismate lyase (EntB) is a bifunctional enzyme that is phosphopantetheinylated by EntD and then acylated by EntE using ATP and 2,3-dihydroxybenzoate. Biochemistry 1997, 36:8495-8503. This is the latest paper in a series about enterobactin biosynthesis. In this system, as in pristinamycin I and actinomycin D, the aryl acid activating starter module (here EntE) does not contain the 4′-phosphopantetheine co-factor because it lacks the thiolation domain. The obvious conflict with the multiple carrier model is reconciled by showing that EntE acylates EntB, the isochorismate lyase. EntB is found to be a bifunctional enzyme with a thiolation domain located at its carboxy-terminal. Peptide bond formation with L-serine activated by EntF is then thought to proceed from EntB. These findings might have important implications for the mysterious initiation of peptide bond formation in the actinomycin D and pristinamycin I systems [40•]).
28. Ku J, Mirmira RG, Liu L, Santi DV: Expression of a functional nonribosomal peptide synthetase module in Escherichia coli by co-expression with a phosphopantetheinyl transferase. Chem Biol 1997, 4:203-207. Heterologous expression of peptide synthetase modules in E. coli yields recombinant proteins deficient in 4′-phosphopentetheine (P-pant). Here it is shown that co-expression of a truncated module of gramicidin S synthetase GrsA with the P-pant transferase Gsp results in almost stoichiometric posttranslational modification of the peptide synthetase. This method might prove to be a useful general tool for producing functional peptide synthetase (fragments) for all kinds of applications.
29. De Crécy-Lagard V, Marlière P, Saurin W: Multienzymatic nonribosomal peptide biosynthesis: identification of the functional domains catalysing peptide elongation and epimerisation. C R Acad Sci Ser II Life Sci 1995, 318:927-936,
30. Stein T, Kluge B, Vater J, Franke P, Otto A, Wittmann-Liebold B: Gramicidin S synthetase 1 (phenylalanine racemase), a prototype of amino acid racemases containing the cofactor 4′-phosphopantetheine. Biochemistry 1995, 34:4633-4642.
31. Pospiech A, Bietenhader J, Schupp T: Two multifunctional peptide synthetases and an O-methyltransferase are involved in the biosynthesis of the DNA-binding antibiotic and antitumour agent saframycin Mx1 from Myxococcus xanthus. Microbiology 1996, 142:741-746. The sequence of two peptide synthetases involved in the synthesis of saframycin Mx1, probably via a linear tetrapeptide alanine-glycine-tyrosine-tyrosine intermediate, is reported. A putative reductase domain is found appended at the carboxyl terminus of one of the modules. This domain might be involved in the modification of the carboxy-terminal tyrosine residue. New domains increase the complexity of the natural systems and also the potential of targeted domain rearrangements.
32. Guilvout I, Mercereau-Puijalon O, Bonnefoy S, Pugsley AP, Carniel E: High-molecular-weight protein 2 of Yersinia enterocolitica is homologous to AngR of Vibrio anguillarum and belongs to a family of proteins involved in nonribosomal peptide synthesis. J Bacteriol 1993, 175:5488-5504.
33. Schwecke T, Aparicio J, Molnar I, König A, Khaw LE, Haydock SF, Oliynyk M, Caffrey P, Cortes J, Lester JB et al.: The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci USA 1995, 92:7839-7843.
34. Scotti C, Piatti M, Cuzzoni A, Perani P, Tognoni A, Grandi G, Galizzi A, Albertini AM: A Bacillus subtilis large ORF coding for a polypeptide highly similar to polyketide synthases. Gene 1993, 130:65-71.
35. Tacconi E, Scotti C, Gamba M, Valbuzzi A, Albertini AM: Structural and functional analysis of the pks locus for polyketide synthases in Bacillus subtilis. In 9th International conference on Bacilli: 1997 July 15-19: Lausanne. 1997: Abstract 70.
36. Meissner K, Dittmann E, Bsrner T: Toxic and non-toxic strains of the cyanobacterium Microcystis aeruginosa contain sequences homologous to peptide synthetase genes. FEMS Microbiol Lett 1996, 135:295-303,
37. Schwartz D, Alijah R, Nussbaumer B, Pelzer S, Wohlleben W: The peptide synthetase gene phsA from Streptomyces viridochromogenes is not juxtaposed with other genes involved in nonribosomal biosynthesis of peptides. Appl Environ Microbiol 1996, 2:570-577.
38. Bernhard F, Demel G, Soltani K, von Döhren H, Blinov V: Identification of genes encoding for peptide synthetases in the Gram-negative bacterium Lysobacter sp. ATCC 53042 and the fungus Cylindrotrichum oligospermum. DNA Seq 1996, 6:319-330.
39. Gaisser S, Hughes C: A locus coding for putative nonribosomal peptide/polyketide synthase functions is mutated in a swarming-defective Proteus mirabilis strain. Mol Gen Genet 1997, 253:415-427.
40. De Crécy-Lagard V, Blanc V, Gil P, Naudin L, Lorenzon S, Famechon A, Bamas-Jacques N, Crouzet J, Thibaut D: Pristinamycin I biosynthesis in Streptomyces pristinaespiralis: molecular characterization of the first two structural peptide synthetase genes. J Bacteriol 1997, 179:705-713. The sequences of the first two peptide synthetases involved in the synthesis of pristinamycin I are reported (see de Crécy-Lagard et al. (1997) [41] for the last synthetase). The paper discusses similarities to the actinomycin D system, for which no sequence data, but detailed biochemical information is available. Since the starter synthetase SnbA lacks the thiolation domain an alternative model of peptide bond formation including the presence of a waiting position is presented (see also recent advances in another similar system [27•]).
41. de Crécy-Lagard V, Saurin W, Thibaut D, Gil P, Naudin L, Crouzet J, Blanc V: Streptogramin B biosynthesis in Streptomyces pristinaespiralis and Streptomyces virginiae: Molecular characterization of the last structural peptide synthetase gene. Antimicrob Agents Chemother 1997, 41:1904-1909.
42. Tognoni A, Franchi E, Magistrelli C, Colombo E, Cosmina P, Grandi G: A putative new peptide synthase operon in Bacillus subtilis: partial characterization. Microbiology 1995, 141:645-648.
43. Chen CL, Chang LK, Chang YS, Liu ST, Tschen JS: Transposon mutagenesis and cloning of the genes encoding the enzymes of fengycin biosynthesis in Bacillus subtilis. Mol Gen Genet 1995, 248:121-125.
44. Philipp WJ, Poulet S, Eiglmeier K, Pascopella L, Balasubramanian V, Heym B, Bergh S, Bloom BR, Jacobs WR Jr, Cole ST: An integrated map of the genome of the tubercle bacillus, Mycobacterium tuberculosis H37Rv, and comparison with Mycobacterium leprae. Proc Natl Acad Sci USA 1996, 93:3132-3137.
45. See the TIGR webpage for proceedings of the genome project: http://www.tigr.org.
46. Merriman TR, Merriman ME, Lamont IL: Nucleotide sequence of pvdD, a pyoverdine biosynthetic gene from Pseudomonas aeruginosa: PvdD has similarity to peptide synthetases. J Bacteriol 1995, 177:252-258.
47. Chambers CE, McIntyre DD, Mouck M, Sokol PA: Physical and structural characterization of yersiniophore, a siderophore produced by clinical isolates of Yersinina enterocolitica. Biometals 1996, 9:157-167.
48. Feignier C, Besson F, Michel G: Characterization of iturin synthetase in the wild type Bacillus subtilis strain producing iturin and in an iturin-deficient mutant FEMS Microbiol Lett 1996, 136:117-122.
49. Wessels P, von Döhren H, Kleinkauf H: Biosynthesis of acylpeptidolactones of the daptomycin type. A comparative analysis of peptide synthetases forming A21978C and AS4145. Eur J Biochem 1996, 242:665-673.
50. Thibaut D, Bisch D, Ratet N, Maton L, Couder M, Debussche L, Blanche F: Purification of peptide synthetases involved in pristinamycin I biosynthesis. J Bacteriol 1997, 179:697-704.
51. Riederer B, Han M, Keller U: D-Lysergyl peptide synthetase from the ergot fungus Claviceps purpurea. J Biol Chem 1996, 271:27524-27530.
52. Walzel B, Riederer B, Keller U: Mechanism of alkaloid cyclopeptide synthesis in the ergot fungus Claviceps purpurea. Chem Biol 1997, 4:223-230. The authors present detailed biochemical data on the formation of ergopeptine precursors (see Figure 1). The sequential formation of all intermediates up to the final tetrapeptide was monitored by omitting the respective next substrate amino acid and thin layer chromatography ptoduct analysis. See this excellent work as the recent example for the ordered process of successive acyl transfers on peptide synthetase templates. Similar work on the first systems investigated has largely contributed to the present multiple carrier model.
53. Stachelhaus T, Hüser A, Marahiel MA: Biochemical characterization of peptidyl carrier protein (PCP), the thiolation domain of multifunctional peptide synthetases. Chem Biol 1996, 3:913-921. In this work the integrated architecture of a peptide synthetase modules was dissected to investigate a possible interaction between artificially isolated domains, which normally act in concert according to their position in the protein template. The adenylation domain of gramacidin S synthetase GrsA and the thiolated domain of tyrocidin synthetase TycA were incubated. The thiolation domain was indeed acylated in trans. These results raise the question if all necessary kinds of domains incubated together as distinct proteins would yield a positive interaction resulting in random peptide products.
54. Mootz HD, Marahiel MA: The tyrocidine biosynthesis operon of Bacillus brevis: Complete nucleotide sequence and biochemical characterization of functional internal adenylation domains. J Bacteriol 1997, 21:6843-6850. The entire nucleotide sequence of the ten modules comprising tyrocidine operon is reported. Probably transcribed in the operon, a thioesterase and two tandem ABC-transporters, which may be involved in tyrocidine secretion, were also found. Internal adenylation domains were expressed as distinct proteins and their enzymatic properties were investigated. These findings strongly support the catalytic independence of single domains within multi-modular peptide synthetases.