Biosynthetic origin of carbons 3 and 4 of leucomycin aglycone.

Ōmura, Satoshi; Tsuzuki, Kazuo; Nakagawa, Akira; Lukacs, Gabor

doi:10.7164/antibiotics.36.611

Cited by 34 publications

(34 citation statements)

References 7 publications

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“…The AT domain in module 6 also falls into the methylmalonyl family, but its activity results in a hydroxyl or perhaps a methoxy group at C-4. The biosynthesis of leucomycin, a 16-membered macrolide which contains a methoxy group at C-4, was examined by feeding the producing organism, Streptoverticillium kitasatoensis, 2-13 C-labeled precursors (23,24). Labeled malonate was not incorporated at carbons 3 and 4, indicating that malonylCoA was not a substrate for the corresponding AT.…”

Section: Resultsmentioning

confidence: 99%

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Identification and characterization of the niddamycin polyketide synthase genes from Streptomyces caelestis

1997

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The genes encoding the polyketide synthase (PKS) portion of the niddamycin biosynthetic pathway were isolated from a library of Streptomyces caelestis NRRL-2821 chromosomal DNA. Analysis of 40 kb of DNA revealed the presence of five large open reading frames (ORFs) encoding the seven modular sets of enzymatic activities required for the synthesis of a 16-membered lactone ring. The enzymatic motifs identified within each module were consistent with those predicted from the structure of niddamycin. Disruption of the second ORF of the PKS coding region eliminated niddamycin production, demonstrating that the cloned genes are involved in the biosynthesis of this compound.Niddamycin is a macrolide antibiotic which is able to bind 50S ribosomal subunits to inhibit protein synthesis. The compound was first discovered as a secondary metabolite of Streptomyces djakartensis (16) and was later found to be produced by Streptomyces caelestis NRRL-2821 (11a). The structure of niddamycin ( Fig. 1) suggests that the polyketide backbone of the macrolide ring is formed through the ordered condensation of carboxylic acid residues derived from acetate, propionate, butyrate, and perhaps glycolate (24). The disaccharide, mycaminose-isobutyrylmycarose, is attached to the macrolide ring at C-5.Macrolides belong to a class of molecules referred to as complex polyketides, which are synthesized on large, multifunctional enzymes called polyketide synthases (PKSs). The synthesis of polyketides is mechanistically similar to that of fatty acids; however, a greater variety of starter and extender carboxylic acid residues are incorporated into the growing polyketide chain, and the ␤-keto groups formed after each condensation step undergo various degrees of reduction (15,20).PKSs, in general, contain all of the enzymatic activities necessary for the sequential condensation of acyl thioesters (␤-ketoacyl acyl carrier protein synthases [KS]), acyltransferases [AT], and acyl carrier proteins [ACP]), the subsequent reduction of the ␤-keto groups (dehydratases [DH], enoylreductases [ER], and ketoreductases [KR]), and the release of the completed chain from the PKS (thioesterases [TE]). Analysis of the erythromycin PKS genes revealed that these enzymatic domains are organized into modules, each of which is responsible for one round of condensation and reduction (5, 7, 9, 10). As a result, there is a direct correlation between the number of modules contained within the erythromycin PKS and the length of the polyketide chain. In addition, the genetic order of the erythromycin PKS modules was found to be colinear with the order of biochemical reactions, allowing directed genetic alterations which produce predicted novel erythromycin derivatives (9, 11).The polyketide portion of the 16-membered macrolide niddamycin is predicted to be synthesized by a complex (type 1) PKS (15) comprising seven modules, each catalyzing one condensation reaction. It had previously been suggested that the choice of the extender coenzyme A (CoA)-thioester is determined by the ...

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Section: Resultsmentioning

confidence: 99%

“…The structure of niddamycin ( Fig. 1) suggests that the polyketide backbone of the macrolide ring is formed through the ordered condensation of carboxylic acid residues derived from acetate, propionate, butyrate, and perhaps glycolate (24). The disaccharide, mycaminose-isobutyrylmycarose, is attached to the macrolide ring at C-5.…”

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confidence: 99%

Identification and characterization of the niddamycin polyketide synthase genes from Streptomyces caelestis

1997

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“…Such ''glycolate'' units are found in a number of other antibiotics, such as geldanamycin (60), leucomycin (61), soraphen (62), FK520 and FK506 (63), and concanamycin A (64). Their origin is not clear from the various feeding experiments reported (17,(60)(61)(62)(63)(64)(65). The C-2 hydroxy group of this extender unit is usually but not always (65) methylated.…”

Section: Discussionmentioning

confidence: 99%

The biosynthetic gene cluster of the maytansinoid antitumor agent ansamitocin from Actinosynnema pretiosum

Bai

Clade

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

280

256

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Maytansinoids are potent antitumor agents found in plants and microorganisms. To elucidate their biosynthesis at the biochemical and genetic level and to set the stage for their structure modification through genetic engineering, we have cloned two gene clusters required for the biosynthesis of the maytansinoid, ansamitocin, from a cosmid library of Actinosynnema pretiosum ssp. auranticum ATCC 31565. This is a rare case in which the genes involved in the formation of a secondary metabolite are dispersed in separate regions in an Actinomycete. A set of genes, asm22-24, asm43-45, and asm47, was identified for the biosynthesis of the starter unit, 3-amino-5-hydroxybenzoic acid (AHBA). Remarkably, there are two AHBA synthase gene homologues, which may have different functions in AHBA formation. Four type I polyketide synthase genes, asmA-D, followed by the downloading asm9, together encode eight homologous sets of enzyme activities (modules), each catalyzing a specific round of chain initiation, elongation, or termination steps, which assemble the ansamitocin polyketide backbone. Another set of genes, asm13-17, encodes the formation of an unusual ''methoxymalonate'' polyketide chain extension unit that, notably, seems to be synthesized on a dedicated acyl carrier protein rather than as a CoA thioester. Additional ORFs are involved in postsynthetic modifications of the initial polyketide synthase product, which include methylations, an epoxidation, an aromatic chlorination, and the introduction of acyl and carbamoyl groups. Tentative functions of several asm genes were confirmed by inactivation and heterologous expression.

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“…123) Such "glycolate" extender units are also present in some other antibiotics, all presumably assembled on type I PKSs, such as geldanamycin, 124) leucomycin, 125) soraphen A, 126) FK520 and FK506, 127) concanamycin A, 128) aflastatin 129) and zwittermicin A. 130) Despite numerous feeding experiments their biochemical origin has, until recently, remained obscure.…”

Section: Building Blocksmentioning

confidence: 99%

“…The latter alternative takes account of the fact that in most natural products containing such "glycolate" extender units the extra oxygen is methylated. [124][125][126]128,129,159) This prediction was tested by synthesizing [1-…”

Section: Fig 20 Summary Of the Biosynthesis Of Ansamitocin P-3 By Tmentioning

confidence: 99%

Recent Developments in the Maytansinoid Antitumor Agents

et al. 2004

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Biosynthetic origin of carbons 3 and 4 of leucomycin aglycone.

Cited by 34 publications

References 7 publications

Identification and characterization of the niddamycin polyketide synthase genes from Streptomyces caelestis

Identification and characterization of the niddamycin polyketide synthase genes from Streptomyces caelestis

The biosynthetic gene cluster of the maytansinoid antitumor agent ansamitocin from Actinosynnema pretiosum

Recent Developments in the Maytansinoid Antitumor Agents

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