Biosynthesis of aminocyclitol antibiotics.

Rinehart, Kenneth L.; Stroshane, Ronald M.

doi:10.7164/antibiotics.29.319

Cited by 101 publications

(39 citation statements)

References 120 publications

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“…Initially, feeding experiments with radioisotope and stable isotope-labeled primary metabolites such as glucose and glucosamine elucidated the origin of carbon atoms. 9 Idiotrophic mutants were also constructed and used to postulate the biosynthetic pathway through the determination of structures of accumulated intermediates. 10 Cosynthesis with blocked mutants was also effective to determine the order of biosynthetic steps.…”

Section: Introductionmentioning

confidence: 99%

Biosynthetic genes for aminoglycoside antibiotics

Kudo

Eguchi

2009

J Antibiot

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Biosynthetic studies of aminoglycoside antibiotics have progressed remarkably during the last decade. Many biosynthetic gene clusters for aminoglycoside antibiotics including streptomycin, kanamycin, butirosin, neomycin and gentamicin have been identified to date. In addition, most butirosin and neomycin biosynthetic enzymes have been functionally characterized using recombinant proteins. Herein, we reanalyze biosynthetic genes for structurally related 2-deoxystreptamine (2DOS)-containing aminoglycosides, such as kanamycin, gentamicin and istamycin, based on genetic information including characterized biosynthetic enzymes in neomycin and butirosin biosynthetic pathways. These proposed enzymatic functions for uncharacterized enzymes are expected to support investigation of the complex biosynthetic pathways for this important class of antibiotics.

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Section: Introductionmentioning

confidence: 99%

Biosynthetic genes for aminoglycoside antibiotics

Kudo

Eguchi

2009

J Antibiot

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“…A feeding experiment of D-[ 14 C]glucosamine into the kanamycin producer revealed that the labeled glucosamine was incorporated only into the 6-amino-6-deoxy-glucose moiety of kanamycin A, 16,17 which suggests that the deamination reaction at C-2 of the glucosamine moiety in kanamycin B is involved in the biosynthesis of Figure 1 Proposed biosynthetic pathway for kanamycin.…”

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confidence: 99%

Enzymatic activity of a glycosyltransferase KanM2 encoded in the kanamycin biosynthetic gene cluster

2009

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Kanamycin, discovered by Umezawa in 1957, is the most well-known 2-deoxystreptamine (2DOS)-containing aminoglycoside antibiotic. 1 Three structurally related kanamycins were identified from the producer Streptomyces kanamyceticus (Figure 1). Extensive biosynthetic studies of this class of aminoglycoside antibiotics, especially butirosin and neomycin, clarified that a unique aminocyclitol, 2DOS, is biosynthesized from D-glucose 6-phosphate by three crucial enzymes, 2-deoxy-scyllo-inosose (2DOI) synthase, L-glutamine (Gln):2DOI aminotransferase and 2-deoxy-scyllo-inosamine dehydrogenase. 2,3 After the 2DOS formation, uridine 5¢-diphospho-N-acetylglucosamine (UDP-GlcNAc):2DOS N-acetylglucosaminyltransferase catalyzes the glycosylation of 2DOS to give N-acetylparomamine, which is then deacetylated by N-acetylparomamine deacetylase to yield paromamine. 4 Paromamine is believed to be a branching biosynthetic intermediate, which is converted to either 4,6-disubstituted 2DOS aminoglycosides, such as kanamycin and gentamicin, or 4,5-disubstituted 2DOS aminoglycosides, such as neomycin and butirosin. Therefore, the regio-specificities and substrate specificities of glycosyltransferases that recognize paromamine as a glycosyl acceptor determine the core structures of aminoglycoside antibiotics.The biosynthetic gene cluster for kanamycin, comprising 24 open reading frames, was identified in 2004. 5 Two other research groups also deposited independently identical kanamycin biosynthetic genes by different symbols in the public DNA databases simultaneously. 6,7 To prevent confusion, herein we use the btr gene-based names, which were used systematically by the Piepersberg group and also in our recent review. 8,9 The entire kanamycin biosynthetic gene cluster was expressed in Streptomyces venezuelae and the resultant recombinant strain was reported to produce kanamycin A, which indicates that the kan genes are responsible for the biosynthesis of kanamycins. 10 The kanC, kanS1, kanE, kanM1 and kanN genes expressing Streptomyces lividans reportedly produce paromamine, confirming that these genes, respectively, encode 2DOI synthase, Gln:2DOI aminotransferase, 2-deoxy-scyllo-inosamine dehydrogenase, UDP-GlcNAc:2DOS N-acetylglucosaminyltransferase and N-acetylparomamine deacetylase (Figure 1). 11 Among these, the kanC gene was expressed in Escherichia coli and the recombinant KanC protein was confirmed to be 2DOI synthase. 6 Recombinant KanM1 protein was also reported to have weak glycosyltransferase activity with 2DOS as a glycosyl acceptor, and TDP-glucose or GDP-mannose as a glycosyl donor. 12 However, this KanM1 activity is contradictory to the presumed enzymatic function as suggested by the above-mentioned heterologous expression of UDP-GlcNAc:2DOS N-acetylglucosaminyltransferase in S. lividans. Detailed enzymatic analysis is thus necessary to elucidate the substrate specificity of KanM1 on using a pure enzyme.In this study, we heterologously expressed another glycosyltransferase gene, kanM2, in the kan gene cluster and investig...

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“…The streptomycin group of antibiotics e.g. streptomycin (1) and dihydrostreptomycin (2), is characterised by the presence of L-streptose or its reduced form, L-dihydrostreptose. The aglycone is an aminocyclitol streptidine.…”

Section: Total Synthesis Of Aminoglycoside Antibioticsmentioning

confidence: 99%

Recent advances in the synthesis of aminoglycoside antibiotics

Umezawa¹

1978

Pure and Applied Chemistry

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Abstract-Aminoglycoside antibiotics have established an important position in medicine and synthetic chemistry in this field has recently been developed. A review is provided of general synthetic schemes which we have developed for the total synthesis of streptomycin, dihydrostreptomycin, kanamycins, butirosin B, neomycin C, and others. Resistent bacteria are a serious subject in present chemotherapy and, the mechanisms of resistance have recently been revealed by medical microbiologists. ln the light of these mechanisms, an effort has been made to synthesise compounds, active against resistent bqcteria, by extension of the above mentioned synthetic schemes and by derivation from natural antibiotics.

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Biosynthesis of aminocyclitol antibiotics.

Cited by 101 publications

References 120 publications

Biosynthetic genes for aminoglycoside antibiotics

Biosynthetic genes for aminoglycoside antibiotics

Enzymatic activity of a glycosyltransferase KanM2 encoded in the kanamycin biosynthetic gene cluster

Recent advances in the synthesis of aminoglycoside antibiotics

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