Leaky Pantothenate and Thiamin Mutations of Salmonella typhimurium Conferring Sulphometuron Methyl Sensitivity

LaRossa, Robert A.; Dyk, Tina K. Van

doi:10.1099/00221287-135-8-2209

Cited by 18 publications

(20 citation statements)

References 31 publications

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“…In the literature, several references have been made to a phenotypic connection between pantothenate and thiamine (9,11,19). Results presented herein demonstrate that the nutritional requirement of panE mutants results from reduced flux through the purine biosynthetic pathway.…”

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confidence: 87%

Reduced Flux through the Purine Biosynthetic Pathway Results in an Increased Requirement for Coenzyme A in Thiamine Synthesis in Salmonella enterica Serovar Typhimurium

2000

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Work presented here establishes a connection between cellular coenzyme A (CoA) levels and thiamine biosynthesis in Salmonella enterica serovar Typhimurium. Prior work showed that panE mutants (panE encodes ketopantoate reductase) had a conditional requirement for thiamine or pantothenate. Data presented herein show that the nutritional requirement of panE mutants for either thiamine or pantothenate is manifest only when flux through the purine biosynthetic pathway is reduced. Further, the data show that under the above conditions it is the lack of thiamine pyrophosphate, and not decreased CoA levels, that directly prevents growth.

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mentioning

confidence: 87%

Reduced Flux through the Purine Biosynthetic Pathway Results in an Increased Requirement for Coenzyme A in Thiamine Synthesis in Salmonella enterica Serovar Typhimurium

2000

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“…The particular efficacy of AHAS inhibitors has been ascribed to the buildup of ketobutyrate to toxic levels (23)(24)(25). Pioneering experiments used labeled threonine to study the effect of SMM on the buildup and fate of ketobutyrate in S. typhimurium (25).…”

Section: Discussionmentioning

confidence: 99%

“…As the analog 2-keto-4-hydroxybutyrolactone (compound 3) is a very potent inhibitor of the next enzyme on the coenzyme A pathway, ketopantoate reductase (17), compound 2 might well also be an inhibitor. There have been suggestions that other metabolic fates of ketobutyrate further affect the coenzyme A pool and other biosynthetic activities (24,46). FIG.…”

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confidence: 99%

Metabolic effects of inhibitors of two enzymes of the branched-chain amino acid pathway in Salmonella typhimurium

1996

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The metabolic effects of inhibitors of two enzymes in the pathway for biosynthesis of branched-chain amino acids were examined in Salmonella typhimurium mutant strain TV105, expressing a single isozyme of acetohydroxy acid synthase (AHAS), AHAS isozyme II. One inhibitor was the sulfonylurea herbicide sulfometuron methyl (SMM), which inhibits this isozyme and AHAS of other organisms, and the other was N-isopropyl oxalylhydroxamate (IpOHA), which inhibits ketol-acid reductoisomerase (KARI). The effects of the inhibitors on growth, levels of several enzymes of the pathway, and levels of intermediates of the pathway were measured. The intracellular concentration of the AHAS substrate 2-ketobutyrate increased on addition of SMM, but a lack of correlation between increased ketobutyrate and growth inhibition suggests that the former is not the immediate cause of the latter. The levels of the keto acid precursor of valine, but not of the precursor of isoleucine, were drastically decreased by SMM, and valine, but not isoleucine, partially overcame SMM inhibition. This apparent stronger effect of SMM on the flux into the valine arm, as opposed to the isoleucine arm, of the branched-chain amino acid pathway is explained by the kinetics of the AHAS reaction, as well as by the different roles of pyruvate, ketobutyrate, and the valine precursor in metabolism. The organization of the pathway thus potentiates the inhibitory effect of SMM. IpOHA has strong initial effects at lower concentrations than does SMM and leads to increases both in the acetohydroxy acid substrates of KARI and, surprisingly, in ketobutyrate. Valine completely protected strain TV105 from IpOHA at the MIC. A number of explanations for this effect can be ruled out, so that some unknown arrangement of the enzymes involved must be suggested. IpOHA led to initial cessation of growth, with partial recovery after a time whose duration increased with the inhibitor concentration. The recovery is apparently due to induction of new KARI synthesis, as well as disappearance of IpOHA from the medium.Enzymes that participate in biosynthetic pathways of essential amino acids have been recognized as targets for a number of safe and effective herbicides (18). The biosynthetic pathway to the branched-chain amino acids valine, leucine, and isoleucine is of special importance in this respect. At least three classes of very potent and extensively used herbicides, the sulfonylureas, the imidazolinones, and the sulfonanilides (26,30,39), are known to inhibit the first common enzyme in this pathway (Fig. 1), acetohydroxy acid synthase (AHAS; EC 4.1.3.18). The second common enzyme in the pathway (Fig. 1), ketol-acid reductoisomerase (KARI; EC 1.1.1.86), is the target for two additional inhibitors with potential herbicidal activity, 2-dimethylphosphinoyl-2-hydroxyacetate (42) and N-isopropyl oxalylhydroxamate (IpOHA) (3).Sulfometuron methyl (SMM), which belongs to the sulfonylurea class of herbicides and inhibits AHAS activity, is an extremely potent herbicide and bacteriostatic age...

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“…A connection between the biosynthesis of thiamine and that of pantothenate has been previously noted (8,21,42). The finding that exogenous pantothenate replaced the requirement for thiamine in a number of mutant strains of S. enterica serovar Typhimurium (9,26) reemphasized the need to understand the connection between these two biosynthetic pathways.…”

mentioning

confidence: 99%

Elevated Levels of Ketopantoate Hydroxymethyltransferase (PanB) Lead to a Physiologically Significant Coenzyme A Elevation in Salmonella enterica Serovar Typhimurium

Rubio

Downs

2002

J Bacteriol

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Pantothenate is the product of the ATP-dependent condensation of pantoate and ␤-alanine and is a direct precursor of coenzyme A. A connection exists between pantothenate biosynthesis and thiamine biosynthesis in Salmonella enterica serovar Typhimurium since derivatives of a purF mutant that can grow (on glucose medium) in the absence of thiamine excrete pantothenate. We show here that the causative mutation in three such mutants was the addition of a CG base pair upstream of the panB gene. This base addition brings the spacing between the ؊10 and ؊35 hexamers of the promoter to a consensus spacing of 17 bp and results in increased transcription of the pan operon. Furthermore, overexpression of PanB caused by this mutation, or by other means, was necessary and sufficient to increase pantothenate production and allow PurF-independent thiamine synthesis on glucose medium.

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Leaky Pantothenate and Thiamin Mutations of Salmonella typhimurium Conferring Sulphometuron Methyl Sensitivity

Cited by 18 publications

References 31 publications

Reduced Flux through the Purine Biosynthetic Pathway Results in an Increased Requirement for Coenzyme A in Thiamine Synthesis in Salmonella enterica Serovar Typhimurium

Reduced Flux through the Purine Biosynthetic Pathway Results in an Increased Requirement for Coenzyme A in Thiamine Synthesis in Salmonella enterica Serovar Typhimurium

Metabolic effects of inhibitors of two enzymes of the branched-chain amino acid pathway in Salmonella typhimurium

Elevated Levels of Ketopantoate Hydroxymethyltransferase (PanB) Lead to a Physiologically Significant Coenzyme A Elevation in Salmonella enterica Serovar Typhimurium

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