Genetic engineering of macrolide biosynthesis: past advances, current state, and future prospects.
Polyketides comprise one of the major families of natural products. They are found in a wide variety of bacteria, fungi, and plants and include a large number of medically important compounds. Polyketides are biosynthesized by polyketide synthases (PKSs). One of the major groups of polyketides are the macrolides, the activities of which are derived from the presence of a macrolactone ring to which one or more 6-deoxysugars are attached. The core macrocyclic ring is biosynthesized from acyl-CoA precursors by PKS. Genetic manipulation of PKS-encoding genes can result in predictable changes in the structure of the macrolactone component, many of which are not easily achieved through standard chemical derivatization or total synthesis. Furthermore, many of the changes, including post-PKS modifications such as glycosylation and oxidation, can be combined for further structural diversification. This review highlights the current state of novel macrolide production with a focus on the genetic engineering of PKS and post-PKS tailoring genes. Such engineering of the metabolic pathways for macrolide biosynthesis provides attractive alternatives for the production of diverse non-natural compounds. Other issues of importance, including the engineering of precursor pathways and heterologous expression of macrolide biosynthetic genes, are also considered.
Park
Sung Ryeol
SR
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Republic of Korea.
Han
Ah Reum
AR
Ban
Yeon-Hee
YH
Yoo
Young Ji
YJ
Kim
Eun Ji
EJ
Yoon
Yeo Joon
YJ
D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D001419:Bacteria / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D005798:Genes, Bacterial; D005818:Genetic Engineering; D006031:Glycosylation; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D048630:Polyketide Synthases / Q000235:genetics* / Q000378:metabolism; D015202:Protein Engineering; D013379:Substrate Specificity
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D018942:Macrolides; D048630:Polyketide Synthases