Mechanistic and Structural Basis of Stereospecific Cβ-Hydroxylation in Calcium-Dependent Antibiotic, a Daptomycin-Type Lipopeptide

Strieker, Matthias; Kopp, Florian; Mahlert, Christoph; Essen, Lars‐Oliver; Marahiel, Mohamed A.

doi:10.1021/cb700012y

Cited by 106 publications

(145 citation statements)

References 46 publications

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“…Natural peptides often incorporate hydroxylated amino acids. 16,17,19,20 In chromophore biosynthesis, the producing strains utilize similar b-hydroxylation system consisting of cytochrome P-450, non-ribosomal peptide synthetase, and discrete thioesterase for conversion of L-tryptophan to 3. 16,17 Chromophore biosynthetic clusters for 1 and 2 consist of genes encoding enzymes for tryptophan metabolism, such as kynurenic acid 21 acid, 22,23 which are presumably different from the constitutive enzymes (Scheme 2).…”

Section: Cloning Expression and Purification Of Swb1 And Swb2mentioning

confidence: 99%

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

et al. 2010

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Quinomycin antibiotics, represented by echinomycin, are an important class of antitumor antibiotics. We have recently succeeded in identification of biosynthetic gene clusters of echinomycin and SW-163D, and have achieved heterologous production of echinomycin in Escherichia coil. In addition, we have engineered echinomycin nonribosomal peptide synthetase (NRPS) to generate echinomycin derivatives. However, the biosynthetic pathways of intercalative chromophores quinoxaline-2-carboxylic acid (QXC) and 3-hydroxyquinaldic acid (HQA), which are important for biological activity, were not fully elucidated. Here, we report experiments involving incorporation of a putative advanced precursor, (2S, 3R)-[6'-2H]-3-hydroxy-L-kynurenine, and functional analysis of the enzymes Swb1 and Swb2 responsible for late-stage biosynthesis of HQA. Based on these experimental results, we propose biosynthetic pathways for both QXC and HQA via the common intermediate 3-hydroxy-L-kynurenine

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Section: Cloning Expression and Purification Of Swb1 And Swb2mentioning

confidence: 99%

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

et al. 2010

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“…The study by Strieker et al 27 have shown that AsnO converts the free L-Asn to L-hAsn before incorporation into the growing peptide. According to their model, L-hAsn binds to the adenylation (A)-domain of the CA hAsn9 TE module of CdaPS2, in which it is converted to D-hAsn and incorporated into the growing peptide chain.…”

Section: Discussionmentioning

confidence: 99%

“…The AsnO protein was crystallized, and the catalytic binding pocket for L-Asn has been defined as a 10 letter code: EQNHENDHR at positions 125, 144, 146, 155, 157, 158, 241, 287 and 305. 27 The LptL protein has an identical L-Asn catalytic binding pocket displaced by eight amino acids relative to AsnO, and starting at position E117. Therefore, even though the lptL and asnO genes and their protein products have diverged considerably (47% identical amino acids), they have conserved the L-Asn binding pocket 100%.…”

Section: Discussionmentioning

confidence: 99%

“…26,27 Furthermore, LptL has a binding pocket for the oxygenation of Asn identical to that of AsnO, EQNHENDHR (Table 4). 27 LptL and AsnO homologs with amino acid sequences ranging from 47 to 60% identities were observed in Saccharopolyspora erythraea, Streptomyces scabies, Streptomyces sp. SPB78, Streptomyces sp.…”

Section: Antibacterial Properties Of A54145 Derivativesmentioning

confidence: 99%

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Production of novel lipopeptide antibiotics related to A54145 by Streptomyces fradiae mutants blocked in biosynthesis of modified amino acids and assignment of lptJ, lptK and lptL gene functions

Alexander

Rock

et al. 2010

J Antibiot

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A54145 is a complex of lipopeptide antibiotics produced by Streptomyces fradiae. A54145 factors are structurally related to daptomycin, with four modified amino acids, only one of which is present in daptomycin. We generated three mutants defective in lptJ, lptK or lptL, whose gene products are involved in the formation of hydroxy-Asn 3 (hAsn 3 ) and methoxy-Asp 9 (moAsp 9 ). Each of the mutants produced novel lipopeptides related to A54145 and the profiles allowed assignment of functions for those genes. We constructed strains carrying different combinations of these genes coupled with a mutation in the lptI gene involved in the biosynthesis of 3-methyl-Glu 12 (3mGlu 12 ), and all recombinants produced novel lipopeptides. One of the compounds displayed very good antibacterial activity in the presence of bovine surfactant, which interacts with daptomycin or A54145E to inhibit their antibacterial activities. (Figure 1) is a complex of calcium-dependent lipodepsipeptide antibiotics produced by Streptomyces fradiae NRRL 18160. 1,2 A54145 has a cyclic depsipeptide ring containing 10 amino acids and an exocyclic tail of three amino acids, and it is similar in overall structure to daptomycin. Like A21987C and daptomycin, 3,4 the Nterminal Trp 1 of the exocyclic peptide is coupled to long-chain length fatty acids, the most common being iso-decanoyl, n-decanoyl and anteiso-undecanoyl in A54145 factors. 1,2 A54145 factors also vary at positions 12 and 13, in which different factors have different combinations of Glu 12 , L-3-methyl-Glu 12 (3mGlu 12 ), Ile 13 , or Val 13 . The most prevalent factors produced during the S. fradiae fermentation are shown in Figure 1. Typically, A54145 factors containing Glu 12 accumulate early in fermentation and those containing 3mGlu 12 accumulate later, with final yields of about 60% of factors containing Glu 12 . 1 The study by Boeck et al. 5 demonstrated that the distribution of A54145 factors can be manipulated by adding certain amino acids or lipids to the fermentation. For instance, feeding L-Ile, enriched for factors containing Ile 13 from 89 to 98%, whereas feeding L-Val (which inhibited overall lipopeptide production by about 70%) enriched for compounds containing Val 13 from 11 to 56%, almost exclusively in

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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). This reactivity is suited to orthoester linkage and methylenedioxy bridge biosynthesis.…”

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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Mechanistic and Structural Basis of Stereospecific Cβ-Hydroxylation in Calcium-Dependent Antibiotic, a Daptomycin-Type Lipopeptide

Cited by 106 publications

References 46 publications

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

Production of novel lipopeptide antibiotics related to A54145 by Streptomyces fradiae mutants blocked in biosynthesis of modified amino acids and assignment of lptJ, lptK and lptL gene functions

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

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