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Chapter 17 : Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes

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Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, Page 1 of 2

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Abstract:

In addition to the nonribosomal and polyketide scaffolds of natural antibiotics examined in the previous two chapters, organisms have assembled other molecular frameworks that serve as effective antibiotic classes. The aminoglycosides, of which streptomycin can be viewed as a founding member, were among the earliest classes of natural antibiotics isolated from soil bacterial samples. More recently, the semisynthetic versions of the pleuromutilins, scaffolds built by the isoprene pathway, have been approved clinically for topical use. Neither of these two classes uses the carrier protein assembly line machinery. The chemical logic of oligosaccharide and terpenoid antibiotic biosynthetic assembly as well as antibiotics containing an unusual direct C-P bond are illustrated in this chapter.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.0
Figure 17.0

The three approved antibiotics shown represent aminoglycoside (kanamycin), pleuromutilin (retapamulin), and phosphonate (fosfomycin) families, respectively.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.1
Figure 17.1

Glucose with its all-equatorial configuration of hydroxyl groups at carbons 2 to 6 is the most prominent hexose in cellular metabolism. (a) Glucose in aqueous solutions is a rapidly equilibrating mixture of α- and β-anomers, via the open-chain aldehyde form (not shown). (b) Once glucose has diffused into cells, it is trapped by phosphorylation at C. (c) The phosphoryl group can be transferred between C and C by phosphoglucomutase action. The glucose-1-P is the α-isomer and is the starting point for conversion to NDP-sugars as sugar donors in metabolism.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.2
Figure 17.2

NDP-sugars as glycosyl donors. (a) Conversion of glucose-1-P to UDP-glucose, a major glucosyl donor. (b) Transfer of glucosyl group from dTDP-glucose to the phenol-OH of PheGly in the vancomycin aglycone yields a monoglucosyl product. (c) Generation of a 1,3-β-disaccharyl linkage by attack of the C-OH of a glucosyl moiety as nucleophile.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.3
Figure 17.3

Three naturally occurring aminoglycoside antibiotics: streptomycin, an aminocyclitol derived from myoinositol; and kanamycin and tobramycin, with a core 2-deoxystreptose unit.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.4
Figure 17.4

Biosynthesis of the trisaccharide framework in kanamycin: (a) glucose-6-P to the diamino sugar 2-deoxystreptose; (b) formation of the paromamine disaccharide; (c) formation of kanamycin B.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.5
Figure 17.5

(a) Dehydroxylation of kanamycin generates tobramycin. (b) Conversion of paromamine to ribostamycin and neomycin.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.6
Figure 17.6

Biosynthesis of streptomycin-6-P. Glucose-6-P is the source of streptidine-6-P; glucose-1-P is the source of dTDP-dihydrostreptose and CDP--Me--glucosamine. The three building blocks are joined to give dihydrostreptomycin-6-P. The alcohol on the central sugar is then dehydrogenated to the aldehyde in streptomycin-6-P, which is secreted by the producing cells.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.7
Figure 17.7

Export and activation of streptomycin-6-P. Enzymatic dephosphorylation to the active antibiotic occurs in the extracellular medium by a phosphatase also secreted by the producer (Sugiyama et al., 1981).

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.8
Figure 17.8

The pleuromutilins and abyssomicins are of isoprenoid origin.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.9
Figure 17.9

(a) The Δ- and Δ-isoprenyl diphosphates are the biological isoprene reagents. (b) In head-to-tail chain elongation, the Δ-isoprenyl-PP acts as the electrophile via an S1-type dissociation to the allyl cation, while the Δ partner acts as the nucleophile through the π-electrons of its double bond. (c) The C, C, and C prenyl diphosphates known as geranyl, farnesyl, and geranylgeranyl diphosphates are then entryways to hundreds to thousands of natural isoprene scaffolds.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.10
Figure 17.10

Geranyl diphosphate as a central substrate for many variants of monoterpene scaffolds via S1 ionization and cyclization to the tertiary terpinyl cation.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Vignette 17.1
Vignette 17.1

So Many Natural Isoprenoids, So Few Antibiotics.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.11
Figure 17.11

The C geranylgeranyl diphosphate is the entryway to the platencin and platensimycin class of antibiotics. (a) Cyclization and cation rearrangements via beyeran-16-yl cation generate -kaurene, the enantiomer of the plant terpene kaurene. (b) Oxidation of -kaurene and coupling to aminohydroxybenzoate yields platensimycin. (c) Rearrangement of the beyeran-16-yl cation instead produces -atiserene on the way to platencin.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.12
Figure 17.12

Moenomycin, an isoprenyl-phosphoglyceryl pentasaccharide antibiotic. The terpenoid moenocinyl 25-carbon side chain is shown in red.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.13
Figure 17.13

Biosynthetic pathway for moenomycin. (a) Reaction of farnesyl diphosphate with the 2-OH of 3-phosphoglycerate. (b) Three glycosyl transfers generate the farnesyl-glycerate-P-trisaccharide intermediate; then the isoprene chain is elongated and rearranged to the C moenocinyl before addition of the last two hexoses and the C5N unit.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.14
Figure 17.14

Naturally occurring antibiotics with direct C-P bonds at both the phosphonate and phosphinate oxidation states. The phosphinate moiety is shown in red.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.15
Figure 17.15

C-P-containing antibiotic biosynthesis. (a) Phosphonomutase catalyzes the first committed step, forming the C-P bond via rearrangement of PEP; the unfavorable equilibrium is managed by subsequent decarboxylation to phosphonoacetaldehyde. Rearrangement and the orientation of the enolpyruvate and metaphosphate ion are presumed to occur in the active site to go on to C-P bond formation. (b) Generation of the phosphonate antibiotic fosfomycin and (c) of the phosphonate antibiotic FR900098.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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Image of Figure 17.16
Figure 17.16

Biosynthesis of the antimetabolite phosphinothricin as the protected tripeptide.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Oligosaccharide, Isoprenoid, and C-P Antibiotic Classes, p 344-362. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch17
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