Biosynthesis of viomycin. II. Origin of β-lysine and viomycidine

Carter, James; Bus, Rene H. Du; Dyer, John; Floyd, J. C.; Rice, Kenner C.; Shaw, Paul D.

doi:10.1021/bi00703a027

Cited by 26 publications

(14 citation statements)

References 22 publications

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“…Unlike the substrate uncertainty exhibited by SbnB, the substrate for SbnA homologs have been defined through precursor labeling studies [37,38]. Since, an SbnA homologue is involved in L-Dap production for viomycin (Table 4), then it is very likely that L-serine (or the O -acetylated derivative) is also the substrate for SbnA.…”

Section: Discussionmentioning

confidence: 99%

Mutation of L-2,3-diaminopropionic acid synthase genes blocks staphyloferrin B synthesis in Staphylococcus aureus

2011

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BackgroundStaphylococcus aureus synthesizes two siderophores, staphyloferrin A and staphyloferrin B, that promote iron-restricted growth. Previous work on the biosynthesis of staphyloferrin B has focused on the role of the synthetase enzymes, encoded from within the sbnA-I operon, which build the siderophore from the precursor molecules citrate, alpha-ketoglutarate and L-2,3-diaminopropionic acid. However, no information yet exists on several other enzymes, expressed from the biosynthetic cluster, that are thought to be involved in the synthesis of the precursors (or synthetase substrates) themselves.ResultsUsing mutants carrying insertions in sbnA and sbnB, we show that these two genes are essential for the synthesis of staphyloferrin B, and that supplementation of the growth medium with L-2,3-diaminopropionic acid can bypass the block in staphyloferrin B synthesis displayed by the mutants. Several mechanisms are proposed for how the enzymes SbnA, with similarity to cysteine synthase enzymes, and SbnB, with similarity to amino acid dehydrogenases and ornithine cyclodeaminases, function together in the synthesis of this unusual nonproteinogenic amino acid L-2,3-diaminopropionic acid.ConclusionsMutation of either sbnA or sbnB result in abrogation of synthesis of staphyloferrin B, a siderophore that contributes to iron-restricted growth of S. aureus. The loss of staphyloferrin B synthesis is due to an inability to synthesize the unusual amino acid L-2,3-diaminopropionic acid which is an important, iron-liganding component of the siderophore structure. It is proposed that SbnA and SbnB function together as an L-Dap synthase in the S. aureus cell.

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Section: Discussionmentioning

confidence: 99%

Mutation of L-2,3-diaminopropionic acid synthase genes blocks staphyloferrin B synthesis in Staphylococcus aureus

2011

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“…1). 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).…”

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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

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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“…[5,6] This amino acid is either (2S,3R)-capreomycidine (3) or its hydroxylated derivative (2S,3R)-tuberactidine (Scheme 1). Based on the results of precursor-labeling studies, [7,8] these nonproteinogenic amino acids are derived from the novel intramolecular cyclization of the side chain of (2S)-arginine (4), which generates the 2-iminohexahydro-2-pyrimidyl ring. It is reasonable to presume that (2S,3R)-tuberactidine is formed by the subsequent hydroxylation of 3.…”

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confidence: 99%

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

Ozanick

Shen

et al. 2004

ChemBioChem

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Biosynthesis of viomycin. II. Origin of β-lysine and viomycidine

Cited by 26 publications

References 22 publications

Mutation of L-2,3-diaminopropionic acid synthase genes blocks staphyloferrin B synthesis in Staphylococcus aureus

Mutation of L-2,3-diaminopropionic acid synthase genes blocks staphyloferrin B synthesis in Staphylococcus aureus

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

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

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