Bioactive oligosaccharide natural products

Abstract

Covering up to December 2013. Oligosaccharide natural products target a wide spectrum of biological processes including disruption of cell wall biosynthesis, interference of bacterial translation, and inhibition of human α-amylase. Correspondingly, oligosaccharides possess the potential for development as treatments of such diverse diseases as bacterial infections and type II diabetes. Despite their potent and selective activities and potential clinical relevance, isolated bioactive secondary metabolic oligosaccharides are less prevalent than other classes of natural products and their biosynthesis has received comparatively less attention. This review highlights the unique modes of action and biosynthesis of four classes of bioactive oligosaccharides: the orthosomycins, moenomycins, saccharomicins, and acarviostatins.

Figure 1

Representative members of the families of bioactive oligosaccharide natural products discussed in this review.

Figure 2

Naturally occurring everninomicins and avilamycins.

Figure 3

Ribosomal binding site of orthosomycin antibiotics. Small ribosomal subunit (PDB 2J00) is shown in dark grey and large subunit (PDB 2J01) is shown in lighter grey. The A and P sites are shown in salmon. Ribosomal protein L16 is shown in green (chain Q), helix 89 (chain A, residues 2454-2498) in blue, and helix 91 (chain A, residues 2520-2545) in magenta. Amino acid residues and nucleotides known to interact with everninomicin and avilamycin are highlighted in yellow.

Figure 4

Orthosomycin biosynthesis. Structure of avilamycin A and everninomicin A. Avi gene cluster from S. viridichromogenes Tü57 and Eve gene cluster from M. carbonacea var africana. Genes are color-coded according to putative functions.

Figure 5

Naturally occurring moenomycins. Adapted from Ostash 2010.

Figure 6

Site of moenomycin interaction with glycosyltransferases. A) Crystal structure of moenomycin (yellow) bound to S. aureus monofunctional transglycosylase (PDB 3HZS). Only 15 carbons of the lipid tail are ordered in this structure. B) Crystal structures of membrane-bound monofunctional glycosyltransferase with moenomycin (yellow; PDB 3VMR) and a lipid II analog (blue; PDB 3VMT). Note: 3VMR and 3VMT were aligned, and the surface of 3VMR was subsequently hidden for clarity. Moenomycin binds in the channel where the growing glycan chain binds thereby disrupting transglycosylation activity. Under normal biological conditions, lipid II would be transferred to the growing glycan chain forming a new β1-4 glycosidic linkage.

Figure 7

Moenomycin biosynthetic gene cluster from Streptomyces ghanaensis. Genes are color-coded according to function.

Figure 8

Naturally occurring saccharomicins and corresponding gene cluster from Saccharothrix espanaensis LL-C19004. Genes are color-coded according to putative function.

Figure 9

Acarbose and the six original naturally-occurring acarviostatins.

Figure 10

Human pancreatic amylase in complex (A) acarbose (PDB 1B2Y) and (B) the hydrolysis product of acarviostatin III03 (PDB 3OLG). Both acarbose and the acarviostatins are competitive inhibitors of human pancreatic amylase by acting as transition-state analogs.

Figure 11

Acarbose biosynthetic gene cluster from S. glaucescens and putative acarviostatin biosynthetic gene cluster from S. coelicoflavus ZG0656. Genes are color-coded according to putative function.

Scheme 1

Orthosomycin biosynthesis. A) Proposed scheme for formation of ring G, L-lyxose. AviE2 has been shown to catalyze the decarboxylation of UDP-D-glucuronic acid to UDP-D-xylose. B) Scheme for formation of 2,6-di-O-methyl-D-mannose from 6-O-methyl-D-glucose. AviX12 catalyzes a unique radical epimerization reaction while AviG6 methylates the 2-hydroxyl presumably after epimerization. C) Formation of L-evernitrose from L-epi-vancosamine. ORF36 catalyzes the oxidation of the nitrogen from the amino to the nitroso oxidation state. It is likely spontaneous oxidation of the nitroso congener which leads to the nitro form.

Scheme 2

Experimentally determined order of moenomycin biosynthesis. P = phosphate; C₁₅ = 15-carbon lipid chain; C₂₅ = 25-carbon lipid chain; B-F indicate ring systems of moenomycin. Enzymes are color-coded to match the gene cluster in figure 7.

Scheme 3

Biosynthesis of the saccharomicin aglycone beginning with L-tyrosine. Four enzymes have been shown to be sufficient to catalyze the formation of the saccharomicin aglycone.

Scheme 4

Proposed biosynthetic pathway to the acarviostatins beginning with sedo-heptulose-7-phosphate and D-glucose-1-phosphate. Sct genes correspond to those from the putative acarviostatin pathway while Gac genes are their corresponding homologs found in the acarbose gene cluster from S. glaucescens. Adapted from Guo 2012.