Biosynthesis and pathway engineering of antifungal polyene macrolides in actinomycetes
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REVIEW
Biosynthesis and pathway engineering of antifungal polyene macrolides in actinomycetes Dekun Kong • Mi-Jin Lee • Shuangjun Lin Eung-Soo Kim
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Received: 22 January 2013 / Accepted: 4 March 2013 / Published online: 21 March 2013 Ó Society for Industrial Microbiology and Biotechnology 2013
Abstract Polyene macrolides are a large family of natural products typically produced by soil actinomycetes. Polyene macrolides are usually biosynthesized by modular and large type I polyketide synthases (PKSs), followed by several steps of sequential post-PKS modifications such as regionspecific oxidations and glycosylations. Although known as powerful antibiotics containing potent antifungal activities (along with additional activities against parasites, enveloped viruses and prion diseases), their high toxicity toward mammalian cells and poor distribution in tissues have led to the continuous identification and structural modification of polyene macrolides to expand their general uses. Advances in in-depth investigations of the biosynthetic mechanism of polyene macrolides and the genetic manipulations of the polyene biosynthetic pathways provide great opportunities to generate new analogues. Recently, a novel class of polyene antibiotics was discovered (a disaccharide-containing NPP) that displays better pharmacological properties such as improved water-solubility and reduced hemolysis. In this review, we summarize the recent advances in the biosynthesis, pathway engineering, and regulation of polyene antibiotics in actinomycetes.
Dekun Kong and Mi-Jin Lee contributed equally to this work. D. Kong S. Lin (&) State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, P. R. China e-mail: [email protected] M.-J. Lee E.-S. Kim (&) Department of Biological Engineering, Inha University, Incheon 402-751, Korea e-mail: [email protected]
Keywords Polyene Polyketide biosynthesis Pathway engineering Glycosylation Oxidation
Introduction Polyene macrolides are a large family of polyketides with potent antifungal activities. They include antibiotics such as nystatin A1 (1), amphotericin A and B (2 and 3), pimaricin (4), candicidin/FR-008 (5), and CE-108/rimocidin (6 and 7) (Fig. 1). Polyene antibiotics are structurally characterized by polyhydroxylated macrocyclic lactones comprised of 20–40 carbons with three to eight conjugated double bonds [34, 87]. The macrolactone typically contains a six-membered hemiketal ring with a carboxyl group derived from a methyl branch via an oxidation. Another structural characteristic of polyene antibiotics is a deoxyaminosugar residue attached to the macrolactone core through a glycoside bond. The primary antifungal mechanism of the polyene antibiotics involves the interaction of polyenes with ergosterol in the fungus to form transmembrane channels [7, 8, 76]. These channels cause the leakage of cellular K? and Mg2?, eventually leading to the death of the fungal cells. The interactions between polyene molecu
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