Biosynthesis of the orthosomycin antibiotic avilamycin A: deductions from the molecular analysis of the avi biosynthetic gene cluster of Streptomyces viridochromogenes Tü57 and production of new antibiotics

Weitnauer, Gabriele; Mühlenweg, Agnes; Trefzer, Axel; Hoffmeister, Dirk; Süßmuth, Roderich D.; Jung, Günther; Welzel, Katrin; Vente, Andreas; Girreser, Ulrich; Bechthold, Andreas

doi:10.1016/s1074-5521(01)00040-0

Cited by 120 publications

(124 citation statements)

References 54 publications

(61 reference statements)

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“…The amino acid sequence deduced from cpz23 shows highest overall homology to several hypothetical proteins from Streptomyces including AviX9 of the avilamycin gene cluster from Streptomyces viridochromogenes (50). According to the conserved protein domain search the C terminus of Cpz23 is similar to SGNH-hydrolases, a diverse family of lipases and carboxyesterases (51).…”

Section: Identification and Cloning Of The Caprazamycin Gene Cluster-mentioning

confidence: 99%

Identification and Manipulation of the Caprazamycin Gene Cluster Lead to New Simplified Liponucleoside Antibiotics and Give Insights into the Biosynthetic Pathway

Kaysser

Lutsch

Siebenberg

et al. 2009

Journal of Biological Chemistry

127

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Section: Identification and Cloning Of The Caprazamycin Gene Cluster-mentioning

confidence: 99%

Identification and Manipulation of the Caprazamycin Gene Cluster Lead to New Simplified Liponucleoside Antibiotics and Give Insights into the Biosynthetic Pathway

Kaysser

Lutsch

Siebenberg

et al. 2009

Journal of Biological Chemistry

127

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“…calO4, aviN and evrI, are also found in the biosynthetic clusters of calicheamicin (Ahlert et al, 2002), avilamycin A (Weitnauer et al, 2001) and evernimicin (Hosted et al, 2001), respectively. It has been proposed that they may control the starter unit for orsellenic acid biosynthesis, based on their sequence similarity to dpsC (Hosted et al, 2001;Weitnauer et al, 2001). However, their function has not been proven experimentally.…”

Section: Discussionmentioning

confidence: 99%

“…calO4 of the calicheamicin biosynthetic gene cluster in Micromonospora echinospora subsp. calichensis (47 % identity at the amino acid level) (Ahlert et al, 2002), aviN of the avilamycin A cluster in Streptomyces viridochromogenes (45 % identity) (Weitnauer et al, 2001) and evrI of the evernimicin cluster in Micromonospora carbonacea var. africana ATCC 39149 (44 % identity) (Hosted et al, 2001).…”

Section: Sequence Analysis Of Clon2mentioning

confidence: 99%

“…DpsC was shown to catalyse the transfer of propionate to an acyl carrier protein in daunorubicin biosynthesis (Bao et al, 1999a, b). CalO4, AviN and EvrI were proposed to be involved in orsellenic acid biosynthesis and to control the nature of the starter unit of the biosynthesis (Ahlert et al, 2002;Weitnauer et al, 2001), but no experimental evidence has been yet published for the function of these enzymes.…”

Section: Sequence Analysis Of Clon2mentioning

confidence: 99%

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CloN2, a novel acyltransferase involved in the attachment of the pyrrole-2-carboxyl moiety to the deoxysugar of clorobiocin

Kahlich

Kammerer

et al. 2003

Microbiology

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The aminocoumarin antibiotic clorobiocin contains a 5-methylpyrrole-2-carboxylic acid unit, attached via an ester bond to the 3-OH group of the deoxysugar moiety. To investigate candidate genes responsible for the formation of this ester bond, a gene inactivation experiment was carried out in the clorobiocin producer Streptomyces roseochromogenes var. oscitans DS 12.976. An in-frame deletion was created in the coding sequence of the gene cloN2. The production of secondary metabolites in the wild-type and in the cloN2 mutant was analysed. The wild-type showed clorobiocin as the main product, whereas the cloN2 mutant accumulated a new aminocoumarin derivative, novclobiocin 104, lacking the pyrrole moiety at the 3-OH of the deoxysugar. In addition, free pyrrole-2-carboxylic acid accumulated in the culture extract of the cloN2 mutant. The structures of the metabolites were confirmed by NMR and LC-MS analysis. Clorobiocin production was successfully restored in the cloN2 mutant by introducing a replicative plasmid containing the cloN2 sequence. These results prove an involvement of cloN2 in the formation of the ester bond between the pyrrole moiety and the deoxysugar in clorobiocin biosynthesis. Furthermore, they indicate that the C-methylation at position 5 of the pyrrole moiety occurs after the attachment of pyrrole-2-carboxylic acid unit to the deoxysugar moiety.

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“…It has been suggested that within the avilamycin biosynthetic cluster in Streptomyces viridochromogenes, a set of putative α-ketoglutarate, nonheme iron-dependent [AKG/Fe(II)-dependent] oxygenases may be capable of catalyzing both orthoester linkage and methylenedioxy bridge formation (9,10). AKG/Fe(II)-dependent oxygenases are powerful oxidants that catalyze a range of reactions, including oxidative cyclizations, hydroxylations, peroxidations, epoxidations, desaturations, and halogenations (11)(12)(13)(14).…”

mentioning

confidence: 99%

Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily

McCulloch

McCranie

Smith

et al. 2015

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

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Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. We have identified a conserved group of nonheme iron, α-ketoglutarate-dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics.antibiotic biosynthesis | oxidative cyclization | crystal structure | nonheme iron α-ketoglutarate-dependent oxygenases

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Biosynthesis of the orthosomycin antibiotic avilamycin A: deductions from the molecular analysis of the avi biosynthetic gene cluster of Streptomyces viridochromogenes Tü57 and production of new antibiotics

Cited by 120 publications

References 54 publications

Identification and Manipulation of the Caprazamycin Gene Cluster Lead to New Simplified Liponucleoside Antibiotics and Give Insights into the Biosynthetic Pathway

Identification and Manipulation of the Caprazamycin Gene Cluster Lead to New Simplified Liponucleoside Antibiotics and Give Insights into the Biosynthetic Pathway

CloN2, a novel acyltransferase involved in the attachment of the pyrrole-2-carboxyl moiety to the deoxysugar of clorobiocin

Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily

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