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Microbiology 143 (1997), 3251-3262; DOI  10.1099/00221287-143-10-3251
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Sequencing and mutagenesis of genes from the erythromycin biosynthetic gene cluster of Saccharopolyspora erythraea that are involved in L-mycarose and D-desosamine production

Richard G. Summers1, Stefano Donadio1,{dagger}, Michael J. Staver1, Evelyn Wendt-Pienkowski2, C. Richard Hutchinson2 and Leonard Katz1,1

Antibacterial Discovery Research Division, Abbott Laboratories, D-47P AP9A, 100 Abbott Park Road, Abbott Park, IL 60064, USA
School of Pharmacy, University of Wisconsin, Madison, WI 53706, USA

1 Author for correspondence: Leonard Katz. Tel: + 1 847 937 4132. Fax: +1 847 938 3403. e-mail: leonard.katz@.abbott.com

ABSTRACT

The nucleotide sequence on both sides of the eryA polyketide synthase gene of the erythromycin-producing bacterium Saccharopolyspora erythraea reve the presence of ten genes that are involved in L-mycarose (eryB) and D-desosamine (eryC) biosynthesis or attachment. Mutant strains carrying targeted lesions in eight of these genes indicate that three (eryBIV, eryBV an eryBVI) act in L-mycairose biosynthesis or attachment, while the other five (eryCII, eryCIII, eryCIV, eryCV and eryCVI) are devoted to D-desosamine biosynthesis or attachment. The remaining two genes (eryBII and eryBVII) appear to function in L-mycarose biosynthesis based on computer analysis an earlier genetic data. Three of these genes, eryBII, eryCIII and eryCII, lie between the eryAIII and eryG genes on one side of the polyketide synthase genes, while the remaining seven, eryBIV, eryBV, eryCVI, eryBVI, eryCIV, eryC and eryBVII lie upstream of the eryAI gene on the other side of the gene cluster. The deduced products of these genes show similarities to: aldohexos 4-ketoreductases (eryBIV), aldoketo reductases (eryBII), aldohexose 5-epimerases (eryBVII), the dnmT gene of the daunomycin biosynthetic pathwa of Streptomyces peucetius (eryBVI), glycosyltransferases (eryBV and eryCIII), the AscC 3,4-dehydratase from the ascarylose biosynthetic pathway of Yersin pseudotuberculosis (eryCIV), and mammalian N-methyltransferases (eryCVI). The eryCII gene resembles a cytochrome P450, but lacks the conserved cysteir residue responsible for coordination of the haem iron, while the eryCV gene displays no meaningful similarity to other known sequences. From the predicted function of these and other known eryB and eryC genes, pathways for the biosynthesis of L-mycarose and D-desosamine have been deduced.

Keywords: desosamine, erythromycin, mycarose, sugar biosynthesis, Saccharopolyspora

{ddagger} Present address: BioSearch Italia SpA, via R. Lepetit 34, 21040 Gerenzano (Varese), Italy.




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