An alternative pathway for reduced folate biosynthesis in bacteria and halophilic archaea

Levin, Itay; Giladi, Moshe; Altman-Price, Neta; Ortenberg, Ron; Mevarech, Moshe

doi:10.1111/j.1365-2958.2004.04339.x

Cited by 50 publications

(42 citation statements)

References 28 publications

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“…Alternatively, the intracellular concentration of dihydrofolate might reach a level at which enzymes with low DHFR reductase activity and insensitivity to TMP are sufficiently active to recycle the dihydrofolate pool and to sustain bacterial growth. Indeed, it has been shown that short-chain dehydrogenases, such as FolM in E. coli (11) or the dihydropteroate synthase from Helicobacter pylori, have TMP-independent DHFR activity (22). In agreement with this model, strain CCH290 is only weakly resistant to the combination of both antibiotics (SXT) ( Table 3), SU decreasing the synthesis of dihydrofolate and rendering the strain sensitive to TMP.…”

Section: Discussionsupporting

confidence: 66%

A Naturally Occurring Gene Amplification Leading to Sulfonamide and Trimethoprim Resistance in Streptococcus agalactiae

et al. 2008

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Gene amplifications have been detected as a transitory phenomenon in bacterial cultures. They are predicted to contribute to rapid adaptation by simultaneously increasing the expression of genes clustered on the chromosome. However, genome amplifications have rarely been described in natural isolates. Through DNA array analysis, we have identified two Streptococcus agalactiae strains carrying tandem genome amplifications: a fourfold amplification of 13.5 kb and a duplication of 92 kb. Both amplifications were located close to the terminus of replication and originated independently from any long repeated sequence. They probably arose in the human host and showed different stabilities, the 13.5-kb amplification being lost at a frequency of 0.003 per generation and the 92-kb tandem duplication at a frequency of 0.035 per generation. The 13.5-kb tandem amplification carried the five genes required for dihydrofolate biosynthesis and led to both trimethoprim (TMP) and sulfonamide (SU) resistance. Resistance to SU probably resulted from the increased synthesis of dihydropteroate synthase, the target of this antibiotic, whereas the amplification of the whole pathway was responsible for TMP resistance. This revealed a new mechanism of resistance to TMP involving an increased dihydrofolate biosynthesis. This is, to our knowledge, the first reported case of naturally occurring antibiotic resistance resulting from genome amplification in bacteria. The low stability of DNA segment amplifications suggests that their role in antibiotic resistance might have been underestimated.

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Section: Discussionsupporting

confidence: 66%

A Naturally Occurring Gene Amplification Leading to Sulfonamide and Trimethoprim Resistance in Streptococcus agalactiae

et al. 2008

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“…As in H. volcanii, tetrahydrofolate derivatives are essential methyl donors for several metabolic reactions, the predicted phenotype for HVO_2348 deletion strains (VDC3234, VDC 3235 and VDC 3236) is the requirement for dT, hypoxanthine and pantothenate on Hv-CA (minimal medium supplemented with casaminoacids (Levin et al 2004)). As predicted, the mutant strains were auxotrophic for dT ( Figure 5).…”

Section: A Gateway Platform For Gene Deletion In H Volcaniimentioning

confidence: 99%

A Gateway platform for functional genomics in Haloferax volcanii: deletion of three tRNA modification genes

Yacoubi

Phillips

Blaby‐Haas

et al. 2009

Archaea

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SummaryIn part due to the existence of simple methods for its cultivation and genetic manipulation, Haloferax volcanii is a major archaeal model organism. It is the only archaeon for which the whole set of post-transcriptionally modified tRNAs has been sequenced, allowing for an in silico prediction of all RNA modification genes present in the organism. One approach to check these predictions experimentally is via the construction of targeted gene deletion mutants. Toward this goal, an integrative "Gateway vector" that allows gene deletion in H. volcanii uracil auxotrophs was constructed. The vector was used to delete three predicted tRNA modification genes: HVO_2001 (encoding an archaeal transglycosyl tranferase or arcTGT), which is involved in archeosine biosynthesis; HVO_2348 (encoding a newly discovered GTP cyclohydrolase I), which catalyzes the first step common to archaeosine and folate biosynthesis; and HVO_2736 (encoding a member of the COG1444 family), which is involved in N 4 -acetylcytidine (ac 4 C) formation. Preliminary phenotypic analysis of the deletion mutants was conducted, and confirmed all three predictions.

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“…A very interesting additional application of designed mutants with an inactivated essential function has been reported recently. They can be used to identify novel non-homologous proteins from other species that are able to complement the missing reaction, and that were hitherto annotated as hypothetical proteins (Levin et al, 2004).…”

Section: Genetics and Functional Genomicsmentioning

confidence: 99%

From genomes to function: haloarchaea as model organisms

Soppa

2006

Microbiology

123

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Haloarchaea are adapted to high-salt environments and accumulate equally high salt concentrations in the cytoplasm. The genomes of representatives of six haloarchaeal genera have been fully or partially sequenced, allowing the analysis of haloarchaeal properties in silico. Transcriptome and proteome analyses have been established for Halobacterium salinarum and Haloferax volcanii. Genetic systems are available including methods that allow the fast in-frame deletion or modification of chromosomal genes. The high-efficiency transformation system of Hf. volcanii allows the isolation of genes essential for a biological process by complementation of loss-of-function mutants. For the analysis of haloarchaeal biology many molecular genetic, biochemical, structural and cell biological methods have been adapted to application at high salt concentrations. Recently it has become clear that several different mechanisms allow the adaptation of proteins to the high salt concentration of the cytoplasm. Taken together, the wealth of techniques available make haloarchaea excellent archaeal model species.

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An alternative pathway for reduced folate biosynthesis in bacteria and halophilic archaea

Cited by 50 publications

References 28 publications

A Naturally Occurring Gene Amplification Leading to Sulfonamide and Trimethoprim Resistance in Streptococcus agalactiae

A Naturally Occurring Gene Amplification Leading to Sulfonamide and Trimethoprim Resistance in Streptococcus agalactiae

A Gateway platform for functional genomics in Haloferax volcanii: deletion of three tRNA modification genes

From genomes to function: haloarchaea as model organisms

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