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9783540220923

Biocombinatorial Approaches For Drug Finding

by ; ; ;
  • ISBN13:

    9783540220923

  • ISBN10:

    3540220925

  • Format: Hardcover
  • Copyright: 2005-01-15
  • Publisher: Springer Verlag
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Summary

Genome- and proteome-based research is generating a significant increase in the number of available drug targets. Correspondingly there is an increasing need for novel, diverse compounds, particularly based on natural compounds, as screening resource. The purpose of the Ernst Schering Research Foundation Workshop 51 was to provide a forum for an open exchange on perspectives and limitations of biocombinatorial synthesis and the significance of this technology for future drug discovery in light of this challenge. Experts from academia and industry provided contributions covering: the significance of natural compounds for state-of-the-art drug discovery; the underlying basic principle for the biosynthesis of highly complex compounds; and the scope and limitations of combinatorial biosynthesis regarding formation, identification, optimisation, isolation and manufacturing of novel biologically active entities.

Table of Contents

1 Protein Domain Fold Similarity and Natural Product Structure as Guiding Principles for Compound Library Design
M.A. Koch, H. Waldmann
1(18)
1.1 Introduction
1(2)
1.2 Protein Folds and Protein Function
3(1)
1.3 Implications for Library Design
4(1)
1.4 Same Fold - Same Function: Development of Kinase Inhibitors
4(3)
1.5 Same Fold - Different Function: Development of LTA4H and Sulfotransferase Inhibitors
7(6)
1.5.1 Example 1: Leukotriene A4 Hydrolase
7(2)
1.5.2 Example 2: Sulfotransferases
9(4)
1.6 Conclusion: A New Guiding Principle for Chemical Genomics?
13(2)
References
15(4)
2 Sources of Polyketides and Non-ribosomal Peptides
S. Donadio, E. Busti, P. Monciardini, R. Bamonte, P. Mazza, M. Sosio, L. Cavaletti
19(24)
2.1 The Search for New Drug Leads
19(1)
2.2 Chemical Diversity from Microbial Sources
20(2)
2.3 Increasing the Odds
22(3)
2.4 Developing Tools for Strain Isolation
25(2)
2.5 Exploiting the Uncultured World
27(7)
2.5.1 Accessing Uncultured Actinomycetes
28(4)
2.5.2 Genetic Potential of Novel Strains
32(2)
2.6 Integrating Tools for Bioprospecting
34(2)
2.7 Outlook
36(1)
References
37(6)
3 Polyketide Synthases: Mechanisms and Models
K.J. Weissman
43(36)
3.1 Combinatorial Biosynthesis: The Tools
46(1)
3.2 Combinatorial Biosynthesis: The Instructions
47(2)
3.3 Evaluating the Combinatorial Potential of PKSs
49(1)
3.4 PKS Domains: Mechanism, Structure and Mutagenesis
50(11)
3.4.1 Ketosynthases
50(4)
3.4.2 Acyltransferases
54(1)
3.4.3 Ketoreductases
54(4)
3.4.4 Dehydratases and Enoylreductases
58(1)
3.4.5 Thioesterases
59(2)
3.5 PKS Structure
61(8)
3.5.1 A Note of Caution
62(1)
3.5.2 Interdomain and Intermodular Linkers
63(2)
3.5.3 Interprotein 'Docking Domains'
65(4)
3.6 Combinatorial Biosynthesis: How to Proceed?
69(1)
3.7 Conclusions
70(1)
References
71(8)
4 Functional and Structural Basis for Targeted Modification of Non-Ribosomal Peptide Synthetases
T. Dürfahrt, M.A. Marahiel
79(28)
4.1 Introduction
79(2)
4.2 Core Domains
81(4)
4.2.1 Adenylation-(A)-domains
81(1)
4.2.2 Carrier Proteins
82(2)
4.2.3 Condensation-(C)-domain
84(1)
4.3 Peptide Synthesis
85(2)
4.4 Tailoring Enzymes
87(6)
4.4.1 Online Tailoring
88(4)
4.4.2 Postsynthetic Tailoring
92(1)
4.5 Biosynthesis Strategies
93(1)
4.6 Development of Hybrid NRPSs
94(5)
4.6.1 Module and Domain Fusions
96(2)
4.6.2 Modifying Domains in Hybrid Synthetases
98(1)
4.6.3 Manipulation of the Selectivity of A-domains
99(1)
4.7 Chemoenzymatic Approaches
99(1)
4.8 Conclusion
100(1)
References
100(7)
5 Prerequisites for Combinatorial Biosynthesis: Evolution of Hybrid NRPS-PKS Gene Clusters
B. Shen, M. Chen, Y. Cheng, L. Du, D.J. Edwards, N.P. George, Y. Huang, T. Oh, C. Sanchez, G. Tang, E. Wendt-Pienkowski, F. Yi
107(20)
5.1 Introduction
107(3)
5.2 Phosphopantetheinyl Transferases with Broad Substrate Specificity Toward Both Apo-ACP and Apo-PCP
110(3)
5.3 Switch Between Peptide and Polyketide Biosynthesis by Active Site Alteration and Linker-Pairing at the Hybrid NRPS-PKS Interface
113(6)
5.4 Type II Thioesterase with Broad Substrate Specificity Toward Acyl-S-ACP, AcyI-S-PCP, and Aminoacyl-S-PCP
119(4)
5.5 Conclusion
123(1)
References
124(3)
6 Engineering Glycosylation in Bioactive Compounds by Combinatorial Biosynthesis
C. Méndez, J.A. Salas
127(20)
6.1 Characterization of Deoxysugar Biosynthetic Gene Clusters
129(6)
6.2 The Use of 'Sugar Cassette Plasmids' in Combinatorial Biosynthesis
135(1)
6.3 The Elloramycin E1mGT Glycosyltransferase as an Example of a Broad Sugar Substrate Flexibility
136(5)
6.3.1 Single Gene Replacement: Generation of D-Olivose
139(1)
6.3.2 Gene Replacement and Gene Addition: Generation of L-Rhodinose
140(1)
6.3.3 Deletion of Two Genes: Generation of L-Rhamnose
140(1)
References
141(6)
7 Glycotransferases and Other Tailoring Enzymes as Tools for the Generation of Novel Compounds
A. Bechthold, G. Weitnauer, A. Luzhetskyy, M. Berner, C. Bihlmeier, R. Boll, C. Dürr, A. Frerich, C. Hofmann, A. Mayer, I. Treede, A. Vente, M. Luzhetskyy
147(18)
7.1 Introduction
147(3)
7.2 Glycosyltransferases Targeting a Polyketide Derived Aglycon
150(3)
7.3 Glycosyltransferases Involved in the Biosynthesis of Saccharide Side Chains
153(3)
7.4 Alteration of the Substrate Specificity of Glycosyltransferases
156(2)
7.5 Generation of a Glycosyltransferase Tool Box
158(1)
7.6 Enzymes Involved in Deoxysugar Modification
158(2)
7.7 Conclusion
160(1)
References
161(4)
8 Enzymatic Incorporation of Halogen Atoms into Natural Compounds
E. Kling, C. Schmid, S. Unversucht, T. Wage, S. Zehner, K.-H. van Pée
165(30)
8.1 Introduction
165(5)
8.2 Halogenating Enzymes
170(18)
8.2.1 Haloperoxidases
170(4)
8.2.2 Perhydrolases
174(3)
8.2.3 FADH2-Dependent Halogenases
177(10)
8.2.4 Combinatorial Biosynthesis Using Tryptophan Halogenases
187(1)
8.3 Perspectives
188(2)
References
190(5)
9 From Glucose to Antibiotics: What Controls the Fluxes?
J. Nielsen, A. Eliasson
195(20)
9.1 Metabolic Engineering of Antibiotic-Producing Microorganisms
195(2)
9.2 The Role of the Central Carbon Metabolism
197(10)
9.2.1 Precursor Demand
198(2)
9.2.2 The Function of Metabolic Networks
200(2)
9.2.3 How to Quantify Fluxes
202(3)
9.2.4 Flux Analysis of Antibiotic-Producing Microorganisms
205(2)
9.3 Control of Flux
207(5)
9.4 Impact of Functional Genomics
212(1)
References
213(2)
10 Precursor-Directed Biosynthesis for the Generation of Novel Glycopeptides
E. Stegmann, D. Bischoff, C. Kittel, S. Pelzer, O. Puk, J. Recktenwald, S. Weist, R. Süßmuth, W. Wohlleben
215(18)
10.1 Introduction
215(3)
10.2 Biosynthesis of Balhimycin in A. balhimycina
218(8)
10.2.1 Biosynthetic Gene Cluster and Genetic Tools for A. balhimycina
218(1)
10.2.2 Biosynthesis of the Non-proteinogenic Amino Acids
218(4)
10.2.3 Assembling of the Heptapetide Backbone
222(1)
10.2.4 Modifying Reactions
223(3)
10.2.5 'Additional' Genes of the Balhimycin Biosynthetic Pathway
226(1)
10.3 Novel Glycopeptides by Precursor-Directed Biosynthesis
226(2)
10.4 Outlook
228(2)
References
230(3)
11 Tool-Box: Tailoring Enzymes for Bio-Combinatorial Lead Development and as Markers for Genome-Based Natural Product Lead Discovery
S. Pelzer, S.-E. Wohlert, A. Vente
233(28)
11.1 Introduction
233(4)
11.2 Establishment of a Technology Platform to Exploit the Genetic Potential of Actinomycetes for the Synthesis of Novel Natural Compounds
237(4)
11.3 Tool-Box: An Enzyme Collection Developed by Genome-Based Enzyme Discovery
241(12)
11.3.1 Impact and Application of Tailoring Enzymes in Combinatorial Biosynthesis
241(2)
11.3.2 General Work Flow of Genome-Based Enzyme Discovery
243(2)
11.3.3 Genome-Based Discovery of Methyltransferases
245(3)
11.3.4 Use of Enzyme Sequence Similarities as a Tool for the Discovery of Novel Natural Compound Producers
248(5)
References
253(8)
12 Natural Product Biosynthetic Assembly Lines: Prospects and Challenges for Reprogramming
D.A. Vosburg, C.T. Walsh
261(24)
12.1 Introduction
261(2)
12.2 Heterocyclization During Chain Elongation
263(2)
12.3 Macrocyclization as Chain Termination
265(5)
12.4 Evaluation of Assembly Line Flux
270(1)
12.5 Linking Heterologous Modules to Create New Assembly Lines
271(1)
12.6 Post Assembly Line Tailoring Enzymes
272(3)
12.7 Nontraditional Assembly Lines
275(2)
12.8 Conclusions
277(1)
References
278(7)
Previous Volumes Published in This Series 285

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