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PanG, a new ketopantoate reductase involved in pantothenate synthesis.

ABSTRACT: Pantothenate, commonly referred to as vitamin B(5), is an essential molecule in the metabolism of living organisms and forms the core of coenzyme A. Unlike humans, some bacteria and plants are capable of de novo biosynthesis of pantothenate, making this pathway a potential target for drug development. Francisella tularensis subsp. tularensis Schu S4 is a zoonotic bacterial pathogen that is able to synthesize pantothenate but is lacking the known ketopantoate reductase (KPR) genes, panE and ilvC, found in the canonical Escherichia coli pathway. Described herein is a gene encoding a novel KPR, for which we propose the name panG (FTT1388), which is conserved in all sequenced Francisella species and is the sole KPR in Schu S4. Homologs of this KPR are present in other pathogenic bacteria such as Enterococcus faecalis, Coxiella burnetii, and Clostridium difficile. Both the homologous gene from E. faecalis V583 (EF1861) and E. coli panE functionally complemented Francisella novicida lacking any KPR. Furthermore, panG from F. novicida can complement an E. coli KPR double mutant. A Schu S4 ?panG strain is a pantothenate auxotroph and was genetically and chemically complemented with panG in trans or with the addition of pantolactone. There was no virulence defect in the Schu S4 ?panG strain compared to the wild type in a mouse model of pneumonic tularemia. In summary, we characterized the pantothenate pathway in Francisella novicida and F. tularensis and identified an unknown and previously uncharacterized KPR that can convert 2-dehydropantoate to pantoate, PanG.

SUBMITTER: Miller CN

PROVIDER: S-EPMC3571331 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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PanG, a new ketopantoate reductase involved in pantothenate synthesis.

Miller Cheryl N CN LoVullo Eric D ED Kijek Todd M TM Fuller James R JR Brunton Jason C JC Steele Shaun P SP Taft-Benz Sharon A SA Richardson Anthony R AR Kawula Thomas H TH

Journal of bacteriology 20121214 5

Pantothenate, commonly referred to as vitamin B(5), is an essential molecule in the metabolism of living organisms and forms the core of coenzyme A. Unlike humans, some bacteria and plants are capable of de novo biosynthesis of pantothenate, making this pathway a potential target for drug development. Francisella tularensis subsp. tularensis Schu S4 is a zoonotic bacterial pathogen that is able to synthesize pantothenate but is lacking the known ketopantoate reductase (KPR) genes, panE and ilvC, ...[more]

PMID: 23243306

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Project description:UNLABELLED:The trxB2 gene, which is annotated as a thioredoxin reductase, was found to be essential for growth of Lactococcus lactis in the presence of oxygen. The corresponding protein (TrxB2) showed a high similarity with Bacillus subtilis YumC (E value = 4.0E-88), and YumC was able to fully complement the ΔtrxB2 mutant phenotype. YumC represents a novel type of ferredoxin (flavodoxin) reductase (FdR) with hitherto-unknown biological function. We adaptively evolved the ΔtrxB2 mutant under aerobic conditions to find suppressor mutations that could help elucidate the involvement of TrxB2 in aerobic growth. Genome sequencing of two independent isolates, which were able to grow as well as the wild-type strain under aerated conditions, revealed the importance of mutations in nrdI, encoding a flavodoxin involved in aerobic ribonucleotide reduction. We suggest a role for TrxB2 in nucleotide metabolism, where the flavodoxin (NrdI) serves as its redox partner, and we support this hypothesis by showing the beneficial effect of deoxynucleosides on aerobic growth of the ΔtrxB2 mutant. Finally, we demonstrate, by heterologous expression, that the TrxB2 protein functionally can substitute for YumC in B. subtilis but that the addition of deoxynucleosides cannot compensate for the lethal phenotype displayed by the B. subtilis yumC knockout mutant. IMPORTANCE:Ferredoxin (flavodoxin) reductase (FdR) is involved in many important reactions in both eukaryotes and prokaryotes, such as photosynthesis, nitrate reduction, etc. The recently identified bacterial YumC-type FdR belongs to a novel type, the biological function of which still remains elusive. We found that the YumC-like FdR (TrxB2) is essential for aerobic growth of Lactococcus lactis. We suggest that the YumC-type FdR is involved in the ribonucleotide reduction by the class Ib ribonucleotide reductase, which represents the workhorse for the bioconversion of nucleotides to deoxynucleotides in many prokaryotes and eukaryotic pathogens under aerobic conditions. As the partner of the flavodoxin (NrdI), the key FdR is missing in the current model describing the class Ib system in Escherichia coli. With this study, we have established a role for this novel type of FdR and in addition found the missing link needed to explain how ribonucleotide reduction is carried out under aerobic conditions.

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PanG, a new ketopantoate reductase involved in pantothenate synthesis.

Publications

PanG, a new ketopantoate reductase involved in pantothenate synthesis.

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