Mining and engineering natural-product biosynthetic pathways

被引:154
作者
Wilkinson, Barrie
Micklefield, Jason
机构
[1] Biotica, Saffron Walden CB10 1XL, Essex, England
[2] Univ Manchester, Sch Chem, Manchester M1 7ND, Lancs, England
[3] Univ Manchester, Manchester Interdisciplinary Bioctr, Manchester M1 7ND, Lancs, England
基金
英国生物技术与生命科学研究理事会;
关键词
D O I
10.1038/nchembio.2007.7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Natural products continue to fulfill an important role in the development of therapeutic agents. In addition, with the advent of chemical genetics and high-throughput screening platforms, these molecules have become increasingly valuable as tools for interrogating fundamental aspects of biological systems. To access the vast portion of natural-product structural diversity that remains unexploited for these and other applications, genome mining and microbial metagenomic approaches are proving particularly powerful. When these are coupled with recombineering and related genetic tools, large biosynthetic gene clusters that remain intractable or cryptic in the native host can be more efficiently cloned and expressed in a suitable heterologous system. For lead optimization and the further structural diversification of natural-product libraries, combinatorial biosynthetic engineering has also become indispensable. However, our ability to rationally redesign biosynthetic pathways is often limited by our lack of understanding of the structure, dynamics and interplay between the many enzymes involved in complex biosynthetic pathways. Despite this, recent structures of fatty acid synthases should allow a more accurate prediction of the likely architecture of related polyketide synthase and nonribosomal peptide synthetase multienzymes.
引用
收藏
页码:379 / 386
页数:8
相关论文
共 67 条
[11]   Hydroxymalonyl-acyl carrier protein (ACP) and aminomalonyl-ACP are two additional type I polyketide synthase extender units [J].
Chan, Yolande A. ;
Boyne, Michael T., II ;
Podevels, Angela M. ;
Klimowicz, Amy K. ;
Handelsman, Jo ;
Kelleher, Neil L. ;
Thomas, Michael G. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (39) :14349-14354
[12]   Redesign of a central enzyme in alkaloid biosynthesis [J].
Chen, Shi ;
Galan, M. Carmen ;
Coltharp, Carla ;
O'Connor, Sarah E. .
CHEMISTRY & BIOLOGY, 2006, 13 (11) :1137-1141
[13]   REPOSITIONING OF A DOMAIN IN A MODULAR POLYKETIDE SYNTHASE TO PROMOTE SPECIFIC CHAIN CLEAVAGE [J].
CORTES, J ;
WIESMANN, KEH ;
ROBERTS, GA ;
BROWN, MJB ;
STAUNTON, J ;
LEADLAY, PF .
SCIENCE, 1995, 268 (5216) :1487-1489
[14]   Active-site residue, domain and module swaps in modular polyketide synthases [J].
Del Vecchio, F ;
Petkovic, H ;
Kendrew, SG ;
Low, L ;
Wilkinson, B ;
Lill, R ;
Cortés, J ;
Rudd, BAM ;
Staunton, J ;
Leadlay, PF .
JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY, 2003, 30 (08) :489-494
[15]   MODULAR ORGANIZATION OF GENES REQUIRED FOR COMPLEX POLYKETIDE BIOSYNTHESIS [J].
DONADIO, S ;
STAVER, MJ ;
MCALPINE, JB ;
SWANSON, SJ ;
KATZ, L .
SCIENCE, 1991, 252 (5006) :675-679
[16]   Metabolic engineering of Pseudomonas putida for methylmalonyl-CoA biosynthesis to enable complex heterologous secondary metabolite formation [J].
Gross, Frank ;
Ring, Michael W. ;
Perlova, Olena ;
Fu, Jun ;
Schneider, Susan ;
Gerth, Klaus ;
Kuhlmann, Silvia ;
Stewart, A. Francis ;
Zhang, Youming ;
Mueller, Rolf .
CHEMISTRY & BIOLOGY, 2006, 13 (12) :1253-1264
[17]   Harnessing the potential of communication-mediating domains for the biocombinatorial synthesis of nonribosomal peptides [J].
Hahn, M ;
Stachelhaus, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (02) :275-280
[18]   Role of type II thioesterases: evidence for removal of short acyl chains produced by aberrant decarboxylation of chain extender units [J].
Heathcole, ML ;
Staunton, J ;
Leadlay, PF .
CHEMISTRY & BIOLOGY, 2001, 8 (02) :207-220
[19]   Engineered urdamycin glycosyltransferases are broadened and altered in substrate specificity [J].
Hoffmeister, D ;
Wilkinson, B ;
Foster, G ;
Sidebottom, PJ ;
Ichinose, K ;
Bechthold, A .
CHEMISTRY & BIOLOGY, 2002, 9 (03) :287-295
[20]   Architecture of a fungal fatty acid synthase at 5 Å resolution [J].
Jenni, S ;
Leibundgut, M ;
Maier, T ;
Ban, N .
SCIENCE, 2006, 311 (5765) :1263-1267