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Chapter 16 : Biosynthesis of Polyketide Antibiotics

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Biosynthesis of Polyketide Antibiotics, Page 1 of 2

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Abstract:

Several of the antibiotics noted in earlier chapters—mupirocin (targeting Ile-tRNA synthetase); tetracycline (30S ribosomal subunit); erythromycin, tylosin, and carbomycin (50S ribosomal subunit); and fidaxomicin and myxopyronin A (RNA polymerase)—are members of the large natural product class known as polyketides (PKs) (Fig. 16.1). The name derives from the fact that these metabolites, and also fatty acids, are assembled by enzymatic machinery that generates β-ketone intermediates. In some of the assembly lines there are tethered poly-β-ketone intermediates; hence the historical name. At first glance, the scaffolds of the antibiotics shown in Fig. 16.1 do not look to have a similar origin, but there is common underlying chemical logic and enzymatic machinery. They all arise from acetate as a key building block.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Figures

Image of Figure 16.0
Figure 16.0

Azithromycin, doxycycline, and mupirocin are approved antibiotics, all of polyketide origin. These structures illustrate the diversity of mature scaffolds available from polyketide synthase biosynthetic pathways.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.1
Figure 16.1

Structure of some representative polyketide antibiotics: mupirocin and myxopyronin A have six-membered pyrone rings. Oxytetracycline is representative of a large class of fused polyaromatic polyketide scaffolds. Macrolactone-containing polyketides are also known as macrolides and can be subclassified by the number of atoms in the macrolactone: erythromycin is a 14-membered ring and fidaxomicin an 18-membered macrolactone. Abyssomicin has a 5,11,6-tricyclic framework.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.2
Figure 16.2

Growth and translocation of a triketide chain on three successive thiolation domains. The starter acyl chain is propionyl rather than the more common acetyl thioester. The chain elongation monomers are a malonyl group in the diketide-forming step and a methylmalonyl in the triketide-forming chain elongation. The elongating 10-carbon thioester chain has three ketones, each in a 1,3 relation to each other. The phosphopantetheinyl arm is represented by the shorthand squiggle-SH notation.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.3
Figure 16.3

The first committed step in fatty acid and polyketide biosynthesis is carboxylation of acetyl-CoA to 2-malonyl-CoA. This is an unfavorable reaction and is driven in the biosynthetic direction by cleavage of ATP. The ATP cleavage activates the bicarbonate cosubstrate and then allows its transfer to the biotin cofactor to give -carboxy-biotin as the proximal donor of CO. The C carbanion of acetyl-CoA is kinetically accessible because it is stabilized by resonance with the thioester enolate form.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.4
Figure 16.4

Fatty acid synthases use the thio-Claisen condensation in every chain elongation step. Subsequent four-electron reduction of the β-keto group to the saturated CH group is carried out before the next condensation/elongation/chain transfer step. Seven chain elongations yield the most common C saturated fatty acyl thioester as major product.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.5
Figure 16.5

A hallmark difference between FAS and PKS assembly lines is that polyketide chains can escape complete reduction of the β-keto thioester in any elongation cycle. Step 1 shows the consequences of a defective (or absent) KR, step 2 shows a cycle with a defective (or absent) DH, and step 3 highlights a defective or absent ER domain in three consecutive cycles. The elongated chain contains three functional groups, in contrast to a fully saturated fatty acyl chain.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.6
Figure 16.6

Five elongation cycles on a PKS assembly line that lacks any functional KR domains would yield a pentaketonic C thioester chain tethered to the sixth ACP of the PKS assembly line. This will be highly reactive and needs to be protected from off-pathway side reactions, one of which is shown.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.7
Figure 16.7

(a) Different arrangements of proteins in FAS and PKS assembly lines. Iterative type I assembly line organization is exemplified by mammalian fatty acid synthases and fungal iterative polyketide synthases. Type II bacterial PKS and FAS minimal machinery involves only four proteins as shown, while the KS-β is an inactive homolog of the active KS-α and serves as a chain length determining factor. The three-protein, seven-module assembly line in the erythromycin pathway releases 6-deoxyerythronolide B (DEB) and is known as DEB synthase. (b) There are seven modules, each with an ACP domain, so the growing chain is passed down the assembly line. The different complement of KR, DH, and ER domains in each module allows prediction of the degree of incomplete processing of the β-ketoacyl thioester intermediate in each of the seven catalytic cycles of chain growth.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.8
Figure 16.8

Macrocyclization as a chain release mechanism. (a) In the macrolide series, the TE domains are the most downstream catalytic domains in the PKS assembly lines. After the full-length PK chain has been transferred to the active-site serine of the TE domain, it catalyzes intramolecular attack of a particular OH group internal to the chain. The regiospecific ring closure must reflect a specific reactive conformer of the bound substrate chain in the active site. DEBS gives a 14-membered macrolide, while the tylactone and fidaxomicin synthases give 16- and 18-membered macrolides, respectively. (b) The -bridged macrolactams of the rifamycin family likewise arise by a macrocyclizing release from the constituent PKS assembly lines. In this case, though, the intramolecular nucleophile is an amine, yielding a macrolactam. The amine derives from the starter unit in the first modules, a 3-amino-5-hydroxybenzoyl-CoA.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.9
Figure 16.9

Aromatic polyketide structures include bicyclic (tetrahydronaphthalene), tricyclic (frenolicin), and tetracyclic (tetracycline, tetracenomycin, and daunomycin) frameworks that are linear or angular (rabelomycin) and more complex scaffolds (fredericamycin A).

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.10
Figure 16.10

The polyketonic species in the oxytetracycline PKS assembly line built up by the OxyABC subunits undergoes regiospecific reduction of the C keto group by action of OxyJ. This in turn is substrate for cyclodehydration and aromatization of the A ring by OxyK. The B and C rings are formed by aldol condensations catalyzed by OxyN. Cyclization of the D ring effects chain release of a tetracyclic nascent product, pretetramid (Zhang et al., 2007).

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.11
Figure 16.11

(a) Unusual starter units for PKS assembly lines. (b) Two unusual chain extender units, aminomalonyl- and hydroxymalonyl-, are utilized by the PKS assembly line for zwittermicin.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.12
Figure 16.12

Post-assembly line modifications yield the final active metabolites in polyketide antibiotic maturation: a series of methylations and oxygenations convert pretetramide to anhydrotetracycline to oxytetracycline. SAH, -adenosylhomocysteine; SAM, -adenosylmethionine.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.13
Figure 16.13

Five post-assembly line modifications convert DEB to erythromycin A. These involve two deoxy-sugar transferases, a sugar -methyltransferase, and two cytochrome P450-mediated hydroxylations of the macrolide at C and C.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.14
Figure 16.14

The biosynthesis of mupirocin involves two PKS assembly lines to yield products coupled in the last step to give the antibiotic. (a) The 9-OH-nonanoic acid moiety is assembled by a fatty acid synthase type of iterative PKS that yields the fully saturated chain. (b) The hydroxypyran half of mupirocin arises from a second PKS assembling a hexaketidyl chain with epoxidation and subsequent rearrangement to the pyran ring.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.15
Figure 16.15

Biosynthesis of abyssomicin and its atropisomer. A 16-carbon thioester intermediate on one PKS assembly line is intercepted by a glycerol thioester on a second assembly line to create the tetramic acid moiety of abyssomicin. A possible Diels-Alder condensation would yield the 5,6,12-tricyclic scaffold in which rotation in the 12-membered ring is restricted such that the ketone is above or below the plane. Regiospecific epoxygenation of one of three double bonds sets up an intramolecular attack to create the mature tetracyclic framework.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.16
Figure 16.16

The pathway to the fungal aflatoxins involves an iterative PKS that releases the tricyclic norsolorinic acid anthrone as nascent product from a tethered heptaketonic thioester.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.17
Figure 16.17

Three hybrid nonribosomal peptide/polyketide metabolites: the antitumor antibiotic bleomycin A2, the plague bacterium siderophore yersiniabactin, and the pristinamycin PII component of the ribosome-targeting Synercid combination. The moieties derived from PKS action are shown in red.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.18
Figure 16.18

Key junction points in hybrid assembly lines. At a PKS-NRPS junction, the condensation domain of the downstream NRPS module must recognize the upstream PK chain as an acyl donor substrate. At an NRPS-PKS junction, it is the ketosynthase domain on the downstream PKS module that must accept the upstream peptidyl thioester as an acyl donor. The growing chains are transferred from ACP to PCP and vice versa.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Figure 16.19
Figure 16.19

(a) Pristinamycin IA is built as a heptapeptidyl intermediate on an NRPS assembly line and released as a cyclic macrolactone. Five of the seven building block amino acids are nonproteinogenic. (b) Pristinamycin IIA is built on a hybrid assembly line with two junctions between PKS and NRPS modules.

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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Image of Vignette 16.1
Vignette 16.1

A Bioinformatic Cornucopia of Unexamined PKS, NRPS, and PK-NRP Hybrid Biosynthetic Enzymes

Citation: Walsh C, Wencewicz T. 2016. Biosynthesis of Polyketide Antibiotics, p 320-342. In Antibiotics: Challenges, Mechanisms, Opportunities. ASM Press, Washington, DC. doi: 10.1128/9781555819316.ch16
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