Inhibition of Folate Biosynthesis and Function as a Basis for Chemotherapy

Hitchings, George H.; Burchall, James J.

doi:10.1002/9780470122723.ch9

Cited by 172 publications

(52 citation statements)

References 170 publications

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“…While it may seem surprising that FolD served as a major source of NADPH under the conditions used here, a more recent study using a human cell line has also shown that oxidation of 5,10-CH 2 -THF to N 10 -fTHF makes a major contribution to NADPH production (40). A consequence of the THF deficiency of the ⌬folD strain was its hypersensitivity to trimethoprim (TMP), a known inhibitor of dihydrofolate reductase (41). TMP binds with high affinity to bacterial DHFRs compared to vertebrate DHFRs (41).…”

Section: Discussionmentioning

confidence: 99%

“…A consequence of the THF deficiency of the ⌬folD strain was its hypersensitivity to trimethoprim (TMP), a known inhibitor of dihydrofolate reductase (41). TMP binds with high affinity to bacterial DHFRs compared to vertebrate DHFRs (41). Importantly, the hypersensitivity of the ⌬folD strain suggests that the absence of FolD potentiates the role of TMP and may even overcome the resistance to TMP that results from dhfr gene amplification (e.g., in the experiment shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

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One-Carbon Metabolic Pathway Rewiring in Escherichia coli Reveals an Evolutionary Advantage of 10-Formyltetrahydrofolate Synthetase (Fhs) in Survival under Hypoxia

et al. 2015

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bIn cells, N 10 -formyltetrahydrofolate (N 10 -fTHF) is required for formylation of eubacterial/organellar initiator tRNA and purine nucleotide biosynthesis. Biosynthesis of N 10 -fTHF is catalyzed by 5,10-methylene-tetrahydrofolate dehydrogenase/cyclohydrolase (FolD) and/or 10-formyltetrahydrofolate synthetase (Fhs). All eubacteria possess FolD, but some possess both FolD and Fhs. However, the reasons for possessing Fhs in addition to FolD have remained unclear. We used Escherichia coli, which naturally lacks fhs, as our model. We show that in E. coli, the essential function of folD could be replaced by Clostridium perfringens fhs when it was provided on a medium-copy-number plasmid or integrated as a single-copy gene in the chromosome. The fhs-supported folD deletion (⌬folD) strains grow well in a complex medium. However, these strains require purines and glycine as supplements for growth in M9 minimal medium. The in vivo levels of N 10 -fTHF in the ⌬folD strain (supported by plasmid-borne fhs) were limiting despite the high capacity of the available Fhs to synthesize N 10 -fTHF in vitro. Auxotrophy for purines could be alleviated by supplementing formate to the medium, and that for glycine was alleviated by engineering THF import into the cells. The ⌬folD strain (harboring fhs on the chromosome) showed a high NADP ؉ -to-NADPH ratio and hypersensitivity to trimethoprim. The presence of fhs in E. coli was disadvantageous for its aerobic growth. However, under hypoxia, E. coli strains harboring fhs outcompeted those lacking it. The computational analysis revealed a predominant natural occurrence of fhs in anaerobic and facultative anaerobic bacteria.T he pathway of one-carbon metabolism is central to the synthesis of purine nucleotides, thymidylate, glycine, and methionine (Fig. 1). The enzymes that catalyze interconversions of the pathway intermediates are highly conserved across the three domains of life (1-6). Serine hydroxymethyltransferase (GlyA) catalyzes the reversible reaction of conversion of serine and tetrahydrofolate (THF) to glycine and 5,10-methylene-tetrahydrofolate (5,10-CH 2 -THF) (7). FolD, a bifunctional enzyme, carries out sequential steps of reversible conversions of 5,10-CH 2 -THF to 5,10-methenyltetrahydrofolate (5,10-CH ϩ -THF), followed by the conversion of the latter to N 10 -formyltetrahydrofolate (N 10 -fTHF) by its dehydrogenase and cyclohydrolase activities, respectively (8). Availability of N 10 -fTHF is crucial for the de novo pathway of purine nucleotide biosynthesis and formylation of the initiator tRNA (tRNA fMet ) to initiate protein synthesis in eubacteria and eukaryotic organelles (9). N 10 -fTHF can also be synthesized by formyltetrahydrofolate synthetase, Fhs (also known as formate-tetrahydrofolate ligase), by utilizing THF, formate, and ATP (Fig. 1). The dual scheme of N 10 -fTHF synthesis is conserved in eukaryotes and some archaea (6). Many eukaryotic organisms possess FolD with trifunctional activities of dehydrogenase-cyclohydrolase-synthetase (10, 11). Among eubacter...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

One-Carbon Metabolic Pathway Rewiring in Escherichia coli Reveals an Evolutionary Advantage of 10-Formyltetrahydrofolate Synthetase (Fhs) in Survival under Hypoxia

et al. 2015

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“…Trimethoprim (TMP) is among the most important antibacterial agents (synthetic antibiotics) used in human and veterinary medicine worldwide acting as an inhibitor in the chemotherapy treatment due to its antifolate effect by interaction with dihydroflate coenzymes [11,12]. In respect of many articles, TMP was detected at 0.6-7.6 g L −1 level in hospital sewage water in Sweden [13], at 0.12 and 0.16 g L −1 levels in wastewater effluents from East Aurora and Holland, respectively [2], and 12.4 mg/kg level in manure and soil in a German farming area [14], and at 40-705 ng L −1 in two municipal wastewater treatment plants in USA [15], and 0.013-0.15 g L −1 in US streams [5].…”

Section: Introductionmentioning

confidence: 99%

Equilibrium studies for trimethoprim adsorption on montmorillonite KSF

Bekçi

Seki

Yurdakoç

2006

Journal of Hazardous Materials

122

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“…3) TMP binds bacterial DHFR with several thousand times higher affinity than that seen for mammalian DHFR 3,4) and is currently in clinical use. In addition, since DHFR is widely conserved in pathogenic bacteria, it is a useful target for the discovery of novel antibacterial agents with a broad spectrum of activity.…”

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confidence: 99%

The Lactone Form of Stachybotrydial: A New Inhibitor of Dihydrofolate Reductase from <i>Stachybotrys</i> sp. FN298

Kwon

Sohn

Kim

et al. 2014

Biological & Pharmaceutical Bulletin

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Dihydrofolate reductase (DHFR) has been confirmed to be a novel target for antibacterial drug development. In this study, we determined that a fungal metabolite from Stachybotrys sp. FN298 can inhibit the DHFR of Staphylococcus aureus. Its structure was identified as a lactone form of stachybotrydial using mass spectrometry and nuclear magnetic resonance analysis. This compound inhibited S. aureus DHFR with a half-maximal inhibitory concentration of 41 µM. It also prevented the growth of S. aureus and methicillinresistant S. aureus (MRSA) with a minimum inhibitory concentration of 32 µg·mL 1 . To our knowledge, this is the first description of a DHFR inhibitor of microbial origin. The inhibitory function of the lactone form of stachybotrydial highlights its potential for development into a new broad-spectrum antibacterial agent and as an agent against MRSA.

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Inhibition of Folate Biosynthesis and Function as a Basis for Chemotherapy

Cited by 172 publications

References 170 publications

One-Carbon Metabolic Pathway Rewiring in Escherichia coli Reveals an Evolutionary Advantage of 10-Formyltetrahydrofolate Synthetase (Fhs) in Survival under Hypoxia

One-Carbon Metabolic Pathway Rewiring in Escherichia coli Reveals an Evolutionary Advantage of 10-Formyltetrahydrofolate Synthetase (Fhs) in Survival under Hypoxia

Equilibrium studies for trimethoprim adsorption on montmorillonite KSF

The Lactone Form of Stachybotrydial: A New Inhibitor of Dihydrofolate Reductase from <i>Stachybotrys</i> sp. FN298

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