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Biosynthesis of the anti‐parasitic agent megalomicin: transformation of erythromycin to megalomicin in Saccharopolyspora erythraea
Author(s) -
Volchegursky Yanina,
Hu Zhihao,
Katz Leonard,
McDaniel Robert
Publication year - 2000
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1046/j.1365-2958.2000.02059.x
Subject(s) - biology , polyketide synthase , gene cluster , polyketide , erythromycin , micromonospora , streptomyces , streptomycetaceae , transformation (genetics) , gene , heterologous expression , phytoene desaturase , biosynthesis , biochemistry , microbiology and biotechnology , actinomycetales , genetics , bacteria , antibiotics , recombinant dna
Megalomicin is a therapeutically diverse compound which possesses antiparasitic, antiviral and antibacterial properties. It is produced by Micromonospora megalomicea and differs from the well‐known macrolide antibiotic erythromycin by the addition of a unique deoxyamino sugar, megosamine, to the C‐6 hydroxyl. We have cloned and sequenced a 48 kb segment of the megalomicin ( meg ) biosynthetic gene cluster which contains the modular polyketide synthase (PKS) and the complete pathway for megosamine biosynthesis. The similarities and distinctions between the related megalomicin and erythromycin gene clusters are discussed. Heterologous expression of the megalomicin PKS in Streptomyces lividans led to production of 6‐deoxyerythronolide B, the same macrolactone intermediate for erythromycin. A 12 kb fragment harbouring the putative megosamine pathway was expressed in Saccharopolyspora erythraea , resulting in the conversion of erythromycin to megalomicin. Considering the extensive knowledge surrounding the genetic engineering of the erythromycin PKS and the familiarity with genetic manipulation and fermentation of S. erythraea , the ability to produce megalomicin in this strain should allow the engineering of novel megalomicin analogues with potentially improved therapeutic activities.