Abstract
BackgroundStreptomyces albus J1074 produces glycosylated antibiotics paulomycin A, B and E that derive from chorismate and contain an isothiocyanate residue in form of paulic acid. Paulomycins biosynthesis pathway involves two glycosyltransferases, three acyltransferases, enzymes required for paulic acid biosynthesis (in particular an aminotransferase and a sulfotransferase), and enzymes involved in the biosynthesis of two deoxysugar moieties: D-allose and L-paulomycose.ResultsInactivation of genes encoding enzymes involved in deoxysugar biosynthesis, paulic acid biosynthesis, deoxysugar transfer, and acyl moieties transfer has allowed the identification of several biosynthetic intermediates and shunt products, derived from paulomycin intermediates, and to propose a refined version of the paulomycin biosynthesis pathway. Furthermore, several novel bioactive derivatives of paulomycins carrying modifications in the L-paulomycose moiety have been generated by combinatorial biosynthesis using different plasmids that direct the biosynthesis of alternative deoxyhexoses.ConclusionsThe paulomycins biosynthesis pathway has been defined by inactivation of genes encoding glycosyltransferases, acyltransferases and enzymes involved in paulic acid and L-paulomycose biosynthesis. These experiments have allowed the assignment of each of these genes to specific paulomycin biosynthesis steps based on characterization of products accumulated by the corresponding mutant strains. In addition, novel derivatives of paulomycin A and B containing L-paulomycose modified moieties were generated by combinatorial biosynthesis. The production of such derivatives shows that L-paulomycosyl glycosyltransferase Plm12 possesses a certain degree of flexibility for the transfer of different deoxysugars. In addition, the pyruvate dehydrogenase system form by Plm8 and Plm9 is also flexible to catalyze the attachment of a two-carbon side chain, derived from pyruvate, into both 2,6-dideoxyhexoses and 2,3,6-trideoxyhexoses. The activity of the novel paulomycin derivatives carrying modifications in the L-paulomycose moiety is lower than the original compounds pointing to some interesting structure–activity relationships.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0452-4) contains supplementary material, which is available to authorized users.
Highlights
Streptomyces albus J1074 produces glycosylated antibiotics paulomycin A, B and E that derive from chorismate and contain an isothiocyanate residue in form of paulic acid
Boundaries of the cluster have been further defined by RT-PCR gene expression analysis using S. albus J1074 total RNA as a template, isolated at 48 h from cultures grown in R5A that were producing paulomycins and paulomenols
The first set of mutant strains are affected in genes coding for: acyltransferase Plm19, which we propose to be involved in the incorporation of paulic acid while Li and coworkers [33] proposed to be performed by 3-oxoacylACP synthase III Pau29 (Plm27); C-glycosyltrasferase Plm23; sulfotransferase Plm28; and aminotransferase Plm29, the last two enzymes likely involved in paulic acid biosynthesis
Summary
Streptomyces albus J1074 produces glycosylated antibiotics paulomycin A, B and E that derive from chorismate and contain an isothiocyanate residue in form of paulic acid. S. albus J1074 produces glycosylated compounds paulomycin A, B and E, and their derivatives paulomenol A and B (Fig. 1) [14], generated by the spontaneous loss of the paulic acid moiety. Paulomycins A and B antibiotics containing an isothiocyanate group (paulic acid) and mainly active against Gram-positive bacteria, were initially isolated from Streptomyces paulus strain 273 [17, 18]. The gene cluster involved in paulomycins biosynthesis has been recently reported in S. albus J1074 [14], S. paulus NRRL8115 and Streptomyces sp. A pathway for paulomycin biosynthesis in S. paulus NRRL8115, based on in silico gene analysis, has been recently proposed [33]
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