Conversion of (2S)‐Arginine to (2S,3R)‐Capreomycidine by VioC and VioD from the Viomycin Biosynthetic Pathway of Streptomyces sp. Strain ATCC11861

Ju, Jing; Ozanick, Sarah G.; Shen, Ben; Thomas, Michael G.

doi:10.1002/cbic.200400136

Cited by 72 publications

(81 citation statements)

References 19 publications

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“…Thus, the asymmetric hydroxylation of L-Pip was achieved in the biotransformation by taking advantage of the high regio-and stereoselectivity of FoPip4H. lysine, L-arginine, L-Leu, and L-isoleucine (23)(24)(25)(26). Until recently, all Fe/␣KG-DOs had been found in bacteria; however, an L-proline hydroxylase was identified to be the first Fe/␣KG-DO from a fungus, Glarea lozoyensis (27).…”

Section: Figmentioning

confidence: 99%

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Hibi

Mori

Miyake

et al. 2016

Appl Environ Microbiol

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Hydroxypipecolic acids are bioactive compounds widely distributed in nature and are valuable building blocks for the organic synthesis of pharmaceuticals. We have found a novel hydroxylating enzyme with activity toward L-pipecolic acid (L-Pip) in a filamentous fungus, Fusarium oxysporum c8D. The enzyme L-Pip trans-4-hydroxylase (Pip4H) of F. oxysporum (FoPip4H) belongs to the Fe(II)/␣-ketoglutarate-dependent dioxygenase superfamily, catalyzes the regio-and stereoselective hydroxylation of L-Pip, and produces optically pure trans-4-hydroxy-L-pipecolic acid (trans-4-L-HyPip). Amino acid sequence analysis revealed several fungal enzymes homologous with FoPip4H, and five of these also had L-Pip trans-4-hydroxylation activity. In particular, the homologous Pip4H enzyme derived from Aspergillus nidulans FGSC A4 (AnPip4H) had a broader substrate specificity spectrum than other homologues and reacted with the L and D forms of various cyclic and aliphatic amino acids. Using FoPip4H as a biocatalyst, a system for the preparative-scale production of chiral trans-4-L-HyPip was successfully developed. Thus, we report a fungal family of L-Pip hydroxylases and the enzymatic preparation of trans-4-L-HyPip, a bioactive compound and a constituent of secondary metabolites with useful physiological activities.H ydroxypipecolic acids (HyPips) are naturally occurring sixmembered heterocyclic hydroxy amino acids that are widely distributed in nature. For instance, 4-hydroxy-, 5-hydroxy-, and 4,5-dihydroxypipecolic acids have been found in various members of the plant family (1-4). Likewise, 5-hydroxypipecolic acid was found to be present in mammalian brain and blood (5). HyPips are also components of some peptide antibiotics, terpenoids, and alkaloids, for example, Thus, the enzymatic hydroxylation of L-Pip was achieved as a side reaction of L-proline hydroxylase. To date, specific L-Piphydroxylating enzymes have not been reported, despite the fact that HyPips are important metabolites found in plants and mammals. In the present study, we identified and characterized L-Pip hydroxylases broadly conserved in some filamentous fungi. We found that the newly discovered L-Pip hydroxylases were particularly suitable biocatalysts for the asymmetric hydroxylation of cyclic amino acids, such as pipecolic acids and prolines. Moreover, the widespread distribution of genes encoding L-Pip hydroxylases indicates some important physiological roles of fungal secondary metabolites related to trans-4-L-HyPip. MATERIALS AND METHODSStrains and culture. Microorganisms isolated from soil and plant samples were cultured in GP medium comprised of 0.15% (wt/vol) KH 2 PO 4 , 0.05% (wt/vol) K 2 HPO 4 , 0.1% (wt/vol) NH 4 Cl, 0.03% (wt/vol) MgSO 4 ·7H 2 O, 0.01% (wt/vol) yeast extract, 0.025% (wt/vol) glucose, and 0.1% (wt/vol) L-Pip (pH 7.0) and grown at 28°C with shaking. Escherichia coli JM109 and Rosetta2(DE3) (Novagen, WI, USA) were used as host strains for the overexpression of the recombinant enzymes and cultured at 28°C in LB medium, comprised of 1% (wt/v...

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Section: Figmentioning

confidence: 99%

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Hibi

Mori

Miyake

et al. 2016

Appl Environ Microbiol

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“…A series of precursor labeling studies of CMN and VIO have been performed to investigate how these unusual antibiotics are assembled by the producing bacteria (4,5,12,35). Our group has previously proposed a biosynthetic mechanism for the assembly of VIO using these labeling experiment results in combination with data from bioinformatic and biochemical analyses of the VIO biosynthetic gene cluster and the enzymes it encodes (19,34). At the time, we also proposed that CMN biosynthesis would incorporate similar mechanisms with subtle differences to account for the structural differences between these antibiotics.…”

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confidence: 99%

Identification of the Biosynthetic Gene Cluster and an Additional Gene for Resistance to the Antituberculosis Drug Capreomycin

Felnagle

Rondon²,

Berti

et al. 2007

Appl Environ Microbiol

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100

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Capreomycin (CMN) belongs to the tuberactinomycin family of nonribosomal peptide antibiotics that are essential components of the drug arsenal for the treatment of multidrug-resistant tuberculosis. Members of this antibiotic family target the ribosomes of sensitive bacteria and disrupt the function of both subunits of the ribosome. Resistance to these antibiotics in Mycobacterium species arises due to mutations in the genes coding for the 16S or 23S rRNA but can also arise due to mutations in a gene coding for an rRNA-modifying enzyme, TlyA. While Mycobacterium species develop resistance due to alterations in the drug target, it has been proposed that the CMN-producing bacterium, Saccharothrix mutabilis subsp. capreolus, uses CMN modification as a mechanism for resistance rather than ribosome modification. To better understand CMN biosynthesis and resistance in S. mutabilis subsp. capreolus, we focused on the identification of the CMN biosynthetic gene cluster in this bacterium. Here, we describe the cloning and sequence analysis of the CMN biosynthetic gene cluster from S. mutabilis subsp. capreolus ATCC 23892. We provide evidence for the heterologous production of CMN in the genetically tractable bacterium Streptomyces lividans 1326. Finally, we present data supporting the existence of an additional CMN resistance gene. Initial work suggests that this resistance gene codes for an rRNA-modifying enzyme that results in the formation of CMN-resistant ribosomes that are also resistant to the aminoglycoside antibiotic kanamycin. Thus, S. mutabilis subsp. capreolus may also use ribosome modification as a mechanism for CMN resistance.Mycobacterium tuberculosis, the causative agent of tuberculosis, has been causing disease in humans since the beginning of civilization (8). Despite more than 50 years of vaccine and antibiotic development, it has been estimated that 225 million new cases of tuberculosis will arise between the years 1998 and 2030, with 79 million tuberculosis-related deaths (25). One of the challenges in treating this disease is the widespread development of multidrug-resistant tuberculosis (MDR-TB), defined as an infection that does not respond to treatment with either of the first-line drugs isoniazid and rifampin (9). The development of MDR-TB has resulted in an increased emphasis on the use of second-line drugs to treat these infections. One of these second-line drugs is capreomycin (CMN), a collection of four structurally related peptide antibiotics (Fig. 1). For simplicity, throughout this report the individual derivatives are identified as CMN IA, IB, IIA, and IIB and are referred to collectively as CMN. The importance of CMN for the treatment of MDR-TB is reflected in this drug's being included on the World Health Organization's list of essential medicines (36). There is additional interest in CMN because of the recent finding that this drug is bactericidal for nonreplicating M. tuberculosis, suggesting the potential use of CMN to treat latent tuberculosis infections (15).CMN and a structural ana...

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“…Indeed the subsequent processing of the amino acid b-hydroxyl groups by further oxidation (Chen et al, 2002), glycosylation (Lu et al, 2004), macrolactonization (Kato et al, 1988;Walker et al, 2005;McCafferty et al, 2002), methylation (Miao et al, 2006) or in the case of CDA, phosphorylation, serves to increase the structural diversity of nonribosomal peptides and related products, resulting in a wide range of biological activities. Of the many bhydroxylated amino acids and derivatives found in nonribosomal peptides, some arise as a result of the oxidation of free amino acids prior to peptide assembly (Yin & Zabriskie, 2004;Ju et al, 2004;Haltli et al, 2005). For example, in the biosynthesis of viomycin and mannopeptimycin, L-Arg and the non-proteinogenic amino acid L-enduracididine are hydroxylated as free amino acids by non-haem Fe(II)/2-oxoglutarate-dependent oxygenases VioC (Yin & Zabriskie, 2004;Ju et al, 2004) and MppO (Haltli et al, 2005), respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Of the many bhydroxylated amino acids and derivatives found in nonribosomal peptides, some arise as a result of the oxidation of free amino acids prior to peptide assembly (Yin & Zabriskie, 2004;Ju et al, 2004;Haltli et al, 2005). For example, in the biosynthesis of viomycin and mannopeptimycin, L-Arg and the non-proteinogenic amino acid L-enduracididine are hydroxylated as free amino acids by non-haem Fe(II)/2-oxoglutarate-dependent oxygenases VioC (Yin & Zabriskie, 2004;Ju et al, 2004) and MppO (Haltli et al, 2005), respectively. In addition, there are a number of other nonhaem Fe(II)/2-oxoglutarate-dependent oxygenases which are known to hydroxylate specific amino acid residues within ribosomal polypeptides.…”

Section: Introductionmentioning

confidence: 99%

“…For example, LptL possesses 45 % identity across 310 out of 330 amino acid residues, and is predicted to be involved in the hydroxylation of the Asn residue at position 3 of A54145 in Streptomyces fradiae (Miao et al, 2006). In addition Lenduracididine hydroxylase, VioC (Yin & Zabriskie, 2004;Ju et al, 2004), exhibits 33 % identity across a 292 amino acid alignment with AsnO, and the L-arginine hydroxylase MppO (Haltli et al, 2005) possesses 31 % identity across 300 amino acid residues. All of these proteins possess the His-1 (HXE) and the C-terminal His-3 (DNXXXXH) motifs which make up the Fe(II) coordination sphere, which supports their known or putative function as Fe(II)/2-oxoglutarate-dependent oxygenase enzymes (Haltli et al, 2005;Khaleeli et al, 2000).…”

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confidence: 99%

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An asparagine oxygenase (AsnO) and a 3-hydroxyasparaginyl phosphotransferase (HasP) are involved in the biosynthesis of calcium-dependent lipopeptide antibiotics

et al. 2007

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Nonribosomal peptides contain a wide range of unusual non-proteinogenic amino acid residues. As a result, these complex natural products are amongst the most structurally diverse secondary metabolites in nature, and possess a broad spectrum of biological activities. b-Hydroxylation of amino acid precursors or peptidyl residues and their subsequent processing by downstream tailoring enzymes are some of the most common themes in the biosynthetic diversification of these therapeutically important peptides. Identification and characterization of the biosynthetic intermediates and enzymes involved in these processes are thus pivotal in understanding nonribosomal peptide assembly and modification. To this end, the putative asparaginyl oxygenase-and 3-hydroxyasparaginyl phosphotransferase-encoding genes hasP and asnO were separately deleted from the calcium-dependent antibiotic (CDA) biosynthetic gene cluster of Streptomyces coelicolor. Whilst the parent strains produce a number of 3-hydroxyasparagine-and 3-phosphohydroxyasparagine-containing CDAs, the DhasP mutants produce exclusively non-phosphorylated CDAs. On the other hand, DasnO mutants produce several new Asn-containing CDAs not present in the wild-type, which retain calcium-dependent antimicrobial activity. This confirms that AsnO and HasP are required for the b-hydroxylation and phosphorylation of the Asn residue within CDA. INTRODUCTIONThe calcium-dependent antibiotics (CDAs) from Streptomyces coelicolor (Hojati et al., 2002;Kempter et al., 1997) belong to the group of structurally related acidic lipopetide antibiotics, which include A54145 (Fukuda et al., 1990; Miao et al., 2006), daptomycin (Baltz et al., 2005;Miao et al., 2005;Raja et al., 2003), friulimicins and amphomycins (Vértesy et al., 2000). All of these nonribosomally biosynthesized lipopeptides contain N-terminal fatty acid side chains, which is a trans-2,3-epoxyhexanoyl moiety in the case of CDA (Fig. 1), along with decapeptide lactone or lactam cores. Within the decapeptide cores are a number of conserved amino acids, including acidic residues responsible for co-ordination of calcium ions, which are essential for antimicrobial activity. Notably, daptomycin was recently approved for clinical use, becoming the first new structural class of natural antibiotic to reach the clinic in over 30 years (Baltz et al., 2005;Raja et al., 2003). As a result of this, there has been considerable interest in establishing the biosynthetic origins of the acidic lipopeptide group of antibiotics, with the specific aim of engineering new lipopeptide variants with improved therapeutic properties. To this end we have focused on engineering the biosynthesis of CDAs, using adenylation domain active site modifications to replace Asp In addition to D-HPG, CDA contains a number of other non-proteinogenic amino acids, including L-3-methylglutamic acid (3-MeGlu; at position 10), which is also present at the same relative position in the decapeptide cores of daptomycin and A54145 (Milne et al., 2006), and a Cterminal Z-dehydro...

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Conversion of (2S)‐Arginine to (2S,3R)‐Capreomycidine by VioC and VioD from the Viomycin Biosynthetic Pathway of Streptomyces sp. Strain ATCC11861

Cited by 72 publications

References 19 publications

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Novel Enzyme Family Found in Filamentous Fungi Catalyzing trans -4-Hydroxylation of l -Pipecolic Acid

Identification of the Biosynthetic Gene Cluster and an Additional Gene for Resistance to the Antituberculosis Drug Capreomycin

An asparagine oxygenase (AsnO) and a 3-hydroxyasparaginyl phosphotransferase (HasP) are involved in the biosynthesis of calcium-dependent lipopeptide antibiotics

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