Folate Biosynthesis Pathway: Mechanisms and Insights into Drug Design for Infectious Diseases

Dias, M.V.B.; Santos, Jademilson Celestino dos; Libreros-Zúñiga, Gerardo Andrés; Ribeiro, J.A.; Chavez-Pacheco, S.M.

doi:10.4155/fmc-2017-0168

Cited by 49 publications

(27 citation statements)

References 144 publications

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“…Trimethoprim inhibits the synthesis of tetrahydrofolic acid, a carbon unit carrier, by affecting the activity of dihydrofolate reductase, thereby affecting the growth and metabolism of bacteria (Bertacine Dias et al, 2018). The products of purine metabolism will be reduced under the inadequate condition of one carbon unit (Sah et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

SmpB and tmRNA Orchestrate Purine Pathway for the Trimethoprim Resistance in Aeromonas veronii

Wang

Khan

et al. 2020

Front. Cell. Infect. Microbiol.

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Small protein B(SmpB) cooperates with transfer-messenger RNA (tmRNA) for trans-translation to ensure the quality control of protein synthesis in prokaryotes. Furthermore, they regulate cell metabolism separately. According to research, SmpB functions as a transcription factor, and tmRNA acts as a small RNA. Purine pathway has been reported to be related to trimethoprim resistance, including hypoxanthine synthesis, adenosine metabolism and guanosine metabolism. Another reason of drug tolerance is the efflux pump of the bacterium. In transcriptomic data, it was shown that the expression of some related enzymes in adenosine metabolism were raised significantly in smpB deletion strain than that of wild type, which led to the differential trimethoprim resistance of Aeromonas veronii (A. veronii). Furthermore, the metabolic products of adenosine AMP, cAMP, and deoxyadenosine were accumulated significantly. However, the expressions of the enzymes related to hypoxanthine synthesis and guanosine metabolism were elevated significantly in ssrA (small stable RNA, tmRNA) deletion strain, which eventually caused an augmented metabolic product xanthine. In addition, the deletion of ssrA also affected the significant downregulations of efflux pump acrA/acrB. The minimal inhibitory concentrations (MIC) were overall decreased after the trimethoprim treatment to the wild type, smpB and ssrA. And the difference in sensitivity between smpB and ssrA was evident. The MIC of smpB was descended significantly than those of wild type and ssrA in M9 medium supplemented with 1 mM adenosine, illustrating that the adenosine metabolism pathway was principally influenced by SmpB. Likewise, the strain ssrA conferred more sensitivity than wild type and smpB in M9 medium supplemented with 1mM guanosine. By overexpressing acrA/acrB, the tolerance to trimethoprim was partially recovered in ssrA. These results revealed that SmpB and tmRNA acted on different branches in purine metabolism, conferring the diverse trimethoprim resistance to A. veronii. This study suggests that the trans-translation system might be an effective target in clinical treatment of A. veronii and other multi-antibiotic resistance bacteria with trimethoprim.

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Section: Discussionmentioning

confidence: 99%

SmpB and tmRNA Orchestrate Purine Pathway for the Trimethoprim Resistance in Aeromonas veronii

Wang

Khan

et al. 2020

Front. Cell. Infect. Microbiol.

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“…These observations are reminiscent of the impact of the number of side chain glutamate residues of tetrahydrofolate (H 4 folate) ( Fig. 1B) on the cellular metabolism and effectiveness of certain anticancer agents (33)(34)(35)(36)(37)(38)(39)(40)(41)(42). Tetrahydrofolate carries one to nine glutamate residues in its side chain and the state of this polyglutamylation is controlled through well-coordinated actions of folylpolyglutamate synthetases and ␥-glutamyl hydrolases (33)(34)(35).…”

mentioning

confidence: 89%

“…For last 55 years, it has been known that folate or vitamin B 9 must be reduced to the H 4 folate stage before folylpolyglutamate synthetases can introduce more than one glutamate residues in the side chain of this coenzyme (53). However, the mechanistic basis for this requirement remains to be elucidated (33,34,36,37,53,54). This is an important knowledge gap in biochemistry, as the variation in the length of the polyglutamylate side chain of H 4 folate impacts the metabolism of a broad range of organisms and has implications in the development of major human diseases such as cancer and resistance to anticancer drugs (33, 34, 37-41, 53, 54).…”

Section: Figmentioning

confidence: 99%

Coenzyme F ₄₂₀ -Dependent Glucose-6-Phosphate Dehydrogenase-Coupled Polyglutamylation of Coenzyme F ₄₂₀ in Mycobacteria

2018

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Coenzyme F420 plays a key role in the redox metabolisms of various archaea and bacteria, including Mycobacterium tuberculosis. In M. tuberculosis, F420-dependent reactions have been linked to several virulence factors. F420 carries multiple glutamate residues in the side chain, forming F420-n species (n, number of glutamate residues), and the length of this side chain impacts cellular physiology. M. tuberculosis strains with F420 species carrying shorter side chains exhibit resistance to delamanid and pretomanid, two new tuberculosis (TB) drugs. Thus, the process of polyglutamylation of F420 is of great interest. It has been known from genetic analysis that in mycobacteria an F420-0 γ-glutamyl ligase (FbiB) introduces up to seven glutamate residues into F420. However, purified FbiB of M. tuberculosis (MtbFbiB) is either inefficient or incapable of incorporating more than two glutamates. We found that, in vitro, MtbFbiB synthesized side chains containing up to seven glutamate residues if F420 was presented to the enzyme in a two-electron reduced state (F420H2). Our genetic analysis in Mycobacterium bovis BCG and Mycobacterium smegmatis and an analysis of literature data on M. tuberculosis revealed that in these mycobacteria the polyglutamylation process requires the assistance of F420-dependent glucose-6-phosphate dehydrogenase (Fgd) which reduces F420 to F420H2. We hypothesize that, starting with F420-0H2, the amino-terminal domain of FbiB builds F420-2H2, which is then transferred to the carboxy-terminal domain for further glutamylation; F420-2H2 modifies the carboxy-terminal domain structurally to accommodate longer glutamyl chains. This system is analogous to folylpolyglutamate synthase, which introduces more than one glutamate residue into folate only after this vitamin is reduced to tetrahydrofolate. IMPORTANCE Coenzyme F420-dependent reactions of Mycobacterium tuberculosis, which causes tuberculosis, potentially contributes to the virulence of this bacterium. The coenzyme carries a glutamic acid-derived tail, the length of which influences the metabolism of M. tuberculosis. Mutations that eliminate the production of F420 with longer tails make M. tuberculosis resistant to two new tuberculosis drugs. This report describes that the synthesis of longer glutamyl tails of F420 requires concerted actions of two enzymes, one of which reduces the coenzyme prior to the action of the other, which catalyzes polyglutamylation. This knowledge will help to develop more effective tuberculosis (TB) drugs. Remarkably, the introduction of multiple glutamate residues into the sidechain of folate (vitamin B9) requires similar concerted actions, where one enzyme reduces the vitamin to tetrahydrofolate and the other catalyzes polyglutamylation; folate is required for DNA and amino acid synthesis. Thus, the reported research has also revealed a key similarity between two important cellular systems.

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“…Folate (folic acid) is a designation for cofactors that consist of three moieties: para -aminobenzoic acid (PABA), pterin and glutamates (Bertacine Dias et al 2018 ). Tetrahydrofolate (a pterin ring) has an essential role in the biosynthesis of purines, thymidylate, pantothenate, RNA and amino acids (Bertacine Dias et al 2018 ). Among folic acid synthesis inhibitors, sulfamethoxazole and trimethoprim were the most similar to evernic acid compounds.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial and antioxidant activity of Evernia prunastri extracts and their isolates

Shcherbakova

Göransson

Гнездилов

et al. 2021

World J Microbiol Biotechnol

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Lichens are symbiotic organisms formed by a fungus and one or more photosynthetic partners which are usually alga or cyanobacterium. Their diverse and scarcely studied metabolites facilitate adaptability to extreme living conditions. We investigated Evernia prunastri (L.) Ach., a widely distributed lichen, for its antimicrobial and antioxidant potential. E. prunastri was sequentially extracted by hexane (Hex), dichloromethane (DCM) and acetonitrile (ACN) that were screened for their antioxidant and antimicrobial (against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Candida albicans) activities. The Hex extract possessed the highest antioxidant capacity (87 mg ascorbic acid/g extract) corresponding to the highest content of phenols (73 mg gallic acid/g extract). The DCM and Hex extracts were both active against S. aureus (MICs of 4 and 21 µg/ml, respectively) but were less active against Gram-negative bacteria and yeast. The ACN extract exhibited activity on both S. aureus (MIC 14 µg/ml) and C. albicans (MIC 38 µg/ml) and was therefore further fractionated by silica gel column chromatography. The active compound of the most potent fraction was subsequently characterized by 1H and 13C-NMR spectroscopy and identified as evernic acid. Structural similarity analyses were performed between compounds from E. prunastri and known antibiotics from different classes. The structural similarity was not present. Antioxidant and antimicrobial activities of E. prunastri extracts originate from multiple chemical compounds; besides usnic acid, most notably evernic acid and derivatives thereof. Evernic acid and its derivatives represent possible candidates for a new class of antibiotics. Graphic abstract

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Folate Biosynthesis Pathway: Mechanisms and Insights into Drug Design for Infectious Diseases

Cited by 49 publications

References 144 publications

SmpB and tmRNA Orchestrate Purine Pathway for the Trimethoprim Resistance in Aeromonas veronii

SmpB and tmRNA Orchestrate Purine Pathway for the Trimethoprim Resistance in Aeromonas veronii

Coenzyme F ₄₂₀ -Dependent Glucose-6-Phosphate Dehydrogenase-Coupled Polyglutamylation of Coenzyme F ₄₂₀ in Mycobacteria

Antimicrobial and antioxidant activity of Evernia prunastri extracts and their isolates

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Folate Biosynthesis Pathway: Mechanisms and Insights into Drug Design for Infectious Diseases

Cited by 49 publications

References 144 publications

SmpB and tmRNA Orchestrate Purine Pathway for the Trimethoprim Resistance in Aeromonas veronii

SmpB and tmRNA Orchestrate Purine Pathway for the Trimethoprim Resistance in Aeromonas veronii

Coenzyme F 420 -Dependent Glucose-6-Phosphate Dehydrogenase-Coupled Polyglutamylation of Coenzyme F 420 in Mycobacteria

Antimicrobial and antioxidant activity of Evernia prunastri extracts and their isolates

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Resources

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Coenzyme F ₄₂₀ -Dependent Glucose-6-Phosphate Dehydrogenase-Coupled Polyglutamylation of Coenzyme F ₄₂₀ in Mycobacteria