A rhodanese‐like protein is highly overrepresented in the mutant <i>S. clavuligerus oppA2::aph</i>: effect on holomycin and other secondary metabolites production

Nárdiz, Nuria; Santamarta, Irene; Lorenzana, Luis M.; Martı́n, Juan F.; Liras, Paloma

doi:10.1111/j.1751-7915.2010.00222.x

Cited by 19 publications

(18 citation statements)

References 27 publications

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“…A connection between holomycin production and sulfur metabolism was reported previously. Interestingly, holomycin biosynthesis was stimulated by cysteine but inhibited by methionine and ethionine (4,40). RhlA was recently identified as a highly overexpressed protein in the holomycin-overproducing oppA2::aph mutant of S. clavuligerus (40), and the protein is indicated to be involved in the formation of a cysteine precursor for holomycin.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the rhodanese-like protein (SSCG_01126; RhlA [40]) was identified as a highly overproduced protein in CZR. The overexpression of cysteine synthase (SSCG_02363; CysM), thiamine S protein (SSCG_02362), and thioredoxin was also detected.…”

Section: Growth Phenotypes Of Argr Disruption Mutantsmentioning

confidence: 99%

“…In the cluster, a standalone nonribosomal peptide synthetase (SSCG_03488; hlmE) was postulated to catalyze the condensation of two cysteines to form the L-Cys-L-Cys dipeptide intermediate (31). Holomycin is not produced by the wild-type strain under the reported growth conditions (40), but it was produced by some CA mutants: de la Fuente et al reported that several CA mutants (ceaS2, bls2, and oat2) blocked in an early stage of CA biosynthesis before the formation of clavaminic acid could not produce holomycin, whereas mutants blocked in the second half of biosynthesis, after clavaminic acid formation, overproduced holomycin (11); they proposed a cross-regulation mechanism between the CA and holomycin pathways mediated by an intermediate of CA biosynthesis.…”

mentioning

confidence: 99%

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Induction of Holomycin Production and Complex Metabolic Changes by the argR Mutation in Streptomyces clavuligerus NP1

Yin¹,

Xiang²,

Zheng³

et al. 2012

Appl Environ Microbiol

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ABSTRACTIn bacteria, arginine biosynthesis is tightly regulated by a universally conserved regulator, ArgR, which regulates the expression of arginine biosynthetic genes, as well as other important genes. Disruption ofargRinStreptomyces clavuligerusNP1 resulted in complex phenotypic changes in growth and antibiotic production levels. To understand the metabolic changes underlying the phenotypes, comparative proteomic studies were carried out between NP1 and itsargRdisruption mutant (designated CZR). In CZR, enzymes involved in holomycin biosynthesis were overexpressed; this is consistent with its holomycin overproduction phenotype. The effects on clavulanic acid (CA) biosynthesis are more complex. Several proteins from the CA cluster were moderately overexpressed, whereas several proteins from the 5S clavam biosynthetic cluster and from the paralog cluster of CA and 5S clavam biosynthesis were severely downregulated. Obvious changes were also detected in primary metabolism, which are mainly reflected in the altered expression levels of proteins involved in acetyl-coenzyme A (CoA) and cysteine biosynthesis. Since acetyl-CoA and cysteine are precursors for holomycin synthesis, overexpression of these proteins is consistent with the holomycin overproduction phenotype. The complex interplay between primary and secondary metabolism and between secondary metabolic pathways were revealed by these analyses, and the insights will guide further efforts to improve production levels of CA and holomycin inS. clavuligerus.

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Section: Discussionmentioning

confidence: 99%

Section: Growth Phenotypes Of Argr Disruption Mutantsmentioning

confidence: 99%

mentioning

confidence: 99%

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Induction of Holomycin Production and Complex Metabolic Changes by the argR Mutation in Streptomyces clavuligerus NP1

Yin¹,

Xiang²,

Zheng³

et al. 2012

Appl Environ Microbiol

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“…Interestingly, a rhodanese-like enzyme RhlA was also found highly expressed in the proteome of holomycin overproducer strain oppA2 :: aph . 43 The rhodanese superfamily of enzymes typically contains one or more rhodanese structural modules and is thought to utilize persulfides to transfer sulfurs to other biosynthetic enzymes. 44,45 The role of RhlA in holomycin biosynthesis remains to be elucidated.…”

Section: Biosynthesis and Regulationmentioning

confidence: 99%

Dithiolopyrrolones: biosynthesis, synthesis, and activity of a unique class of disulfide-containing antibiotics

et al. 2014

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Dithiolopyrrolone (DTP) group antibiotics were first isolated in the early half of the 20th century, but only recently has research been reawakened by insights gained from the synthesis and biosynthesis of this structurally intriguing class of molecules. DTPs are characterized by an electronically unique bicyclic structure, which contains a compact disulfide bridge between two ene-thiols. Points of diversity within the compound class occur outside of the bicyclic core, at the two amide nitrogens. Such modifications distinguish three of the most well studied members of the class, holomycin, thiolutin, and aureothricin; the DTP core has also more recently been identified in the marine antibiotic thiomarinol, in which it is linked to a marinolic acid moiety, analog of the FDA-approved topical antibiotic Bactroban® (GlaxoSmithKline). Dithiolopyrrolones exhibit relatively broad-spectrum antibiotic activity against many Gram-positive and Gram-negative bacteria, as well as strains of Mycobacterium tuberculosis. Additionally, they have been shown to exhibit potent and selective anti-cancer activity. Despite this promising profile, there is still much unknown about the mechanisms of action for DTPs. Early reports suggested that they inhibit yeast growth at the level of transcription and that this effect is largely responsible for their distinctive microbial static properties; a similar mechanism is supported in bacteria. Elucidation of biosynthetic pathways for holomycin in Streptomyces clavuligerus and Yersinia ruckeri and thiomarinol in Alteromonas rava sp. nov. SANK 73390, have contributed evidence suggesting that multiple mechanisms may be operative in the activity of these compounds. This review will comprehensively cover the history and development of dithiolopyrrolones with particular emphasis on the biosynthesis, synthesis, biological activity and mechanism of action.

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“…Apenas uma rota biossintética para Hol foi proposta, com base em ferramentas da bioinformática, havendo ainda relatos sobre a identificação e a caracterização do agrupamento de genes responsável pela sua biossíntese (LI e WALSH, 2010). Quanto à biossíntese do composto por S. clavuligerus, há escassos estudos comparativos de capacidades produtivas e diferenças genéticas observadas entre a linhagem selvagem e mutantes melhores produtores (DE LA FUENTE et al, 2002;NÁRDIZ et al, 2011). Dados da literatura sempre associaram a produção de quantidades desprezíveis de Hol à linhagem selvagem S. clavuligerus ATCC 27064.…”

Section: Introductionunclassified

Bioprocesso De Produção Do Antitumoral Holomicina Por Streptomyces Clavuligerus

Baptista¹,

Cavallieri²,

Leite³

et al. 2015

Anais Do XX Congresso Brasileiro De Engenharia Química

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RESUMO -Streptomyces clavuligerus produz vários biocompostos de uso terapêutico, como os beta-lactâmicos ácido clavulânico e cefamicina C, e os não beta-lactâmicos holomicina e tunicamicina. Holomicina é conhecida por inibir a síntese de RNA polimerase de bactérias resistentes a rifamicina e é produzida em baixas concentrações (6 a 8 mgL -1 ) pela cepa selvagem (ATCC 27064) sob condições favoráveis à produção de beta-lactâmicos. Cultivos em biorreator convencional operado em batelada mostraram que a combinação de maltose e lisina promoveu a produção de cefamicina C e ácido clavulânico (90 a 100 mgL -1 ), sem produção de holomicina, e a mesma combinação (maltose e lisina) adicionada de glutamato estimulou a produção de holomicina (95 a 110 mgL -1 ), com produção de cefamicina C ou ácido clavulânico cerca de 65% menor para ambos. Os dados obtidos permitiram estimar parâmetros cinéticos e estequiométricos dos processos por meio de modelagem e simulação.

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A rhodanese‐like protein is highly overrepresented in the mutant S. clavuligerus oppA2::aph: effect on holomycin and other secondary metabolites production

Cited by 19 publications

References 27 publications

Induction of Holomycin Production and Complex Metabolic Changes by the argR Mutation in Streptomyces clavuligerus NP1

Induction of Holomycin Production and Complex Metabolic Changes by the argR Mutation in Streptomyces clavuligerus NP1

Dithiolopyrrolones: biosynthesis, synthesis, and activity of a unique class of disulfide-containing antibiotics

Bioprocesso De Produção Do Antitumoral Holomicina Por Streptomyces Clavuligerus

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