Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

Nunes, J.; Duque, Mario A; Freitas, Talita Freitas de; Galina, Luiza; Timmers, Luís Fernando Saraiva Macedo; Bizarro, Cristiano Valim; Machado, Pablo; Basso, Luiz Augusto; Ducati, Rodrigo G.

doi:10.3390/molecules25061259

Cited by 44 publications

(21 citation statements)

References 165 publications

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“…The shikimate pathway is considered an attractive target for developing new rational-based antimicrobial agents ( 11 ). It is essential for bacterial growth but absent in most animals, including mammals, favoring the development of selective inhibitors for pathogenic bacteria ( 12 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

EPSP Synthase-Depleted Cells Are Aromatic Amino Acid Auxotrophs in Mycobacterium smegmatis

et al. 2021

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We found that cells from Mycobacterium smegmatis , a model organism safer and easier to study than the disease-causing mycobacterial species, when depleted of an enzyme from the shikimate pathway, are auxotrophic for the three aromatic amino acids (AroAAs) that serve as building blocks of cellular proteins: l- tryptophan, l -phenylalanine, and l -tyrosine. That supplementation with only AroAAs is sufficient to rescue viable cells with the shikimate pathway inactivated was unexpected, since this pathway produces an end product, chorismate, that is the starting compound of essential pathways other than the ones that produce AroAAs.

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Section: Introductionmentioning

confidence: 99%

EPSP Synthase-Depleted Cells Are Aromatic Amino Acid Auxotrophs in Mycobacterium smegmatis

et al. 2021

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“…A model allosteric protein for evaluating these factors is Saccharomyces cerevisiae chorismate mutase (ScCM). CM enzymes are important regulatory enzymes in the shikimate pathway, which is responsible for the production of the amino acids Phe, Tyr, and Trp as well as other aromatic compounds such as ubiquinone and folate. , There is interest in developing shikimate pathway inhibitors as novel antimicrobials as well as engineering this pathway to help in the production of food flavorings, preservatives, and other compounds . Chorismate mutases catalyze the pericyclic [3,3]-sigmatropic rearrangement of chorismate to prephenate by stabilizing the chair conformation of chorismate, which resembles the transition state (Figure S1).…”

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confidence: 99%

Different Solvent and Conformational Entropy Contributions to the Allosteric Activation and Inhibition Mechanisms of Yeast Chorismate Mutase

et al. 2020

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Allosteric regulation is important in many biological processes, including cell signaling, gene regulation, and metabolism. Saccharomyces cerevisiae chorismate mutase (ScCM) is a key homodimeric enzyme in the shikimate pathway responsible for the generation of aromatic amino acids, where it is allosterically inhibited and activated by Tyr and Trp, respectively. Our previous studies indicated that binding of both allosteric effectors is negatively cooperative, that is binding at one allosteric binding site discourages binding at the other, due to the entropic penalty of binding the second allosteric effector. We utilized variable temperature isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) experiments to better understand the entropic contributions to allosteric effector binding, including changes to solvent entropy and protein conformational entropy. Upon binding either Tyr or Trp, ScCM experiences a quenching of motions on the picosecond-to-nanosecond time scale, which we could relate to a loss of protein conformational entropy. Further ITC and NMR studies were consistent with the Tyr-bound form of ScCM being associated with more water molecules compared to the Trp-bound form and Tyr binding being associated with a less positive solvent entropy change. These studies provide insight into the role of structural dynamics in ScCM function and highlight the importance of solvent entropy changes in allosteric regulation, a historically underappreciated concept.

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“…Biosynthesis of flavonols from p-coumaroyl-CoA and malonyl-CoA. Enzymatic reaction catalyzed by DAHPS: 3-deoxy-D-arabino-heptulosonate-7-phosphate-synthase; DHQS: 3-dexydroquinate synthase; SDO: shikimate dehydrogenase; PAL: phenylalanine ammonia-lyase; TAL: tyrosine ammonia lyase; C4H: cinnamate 4-hydroxylase; CHI: chalcone isomerase, FHT: flavanone 3β-hydroxylase; FNS Ι: flavone synthase Ι; FLS: flavonol synthase; FMO: flavonoid 3′-monooxygenase; CPR: cytochrome P450reductase [ 8 , 9 , 10 ].…”

Section: Figurementioning

confidence: 99%

Anticancer Potential of Selected Flavonols: Fisetin, Kaempferol, and Quercetin on Head and Neck Cancers

Kubina

Kabała‐Dzik

2021

Nutrients

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Flavonols are ones of the most common phytochemicals found in diets rich in fruit and vegetables. Research suggests that molecular functions of flavonoids may bring a number of health benefits to people, including the following: decrease inflammation, change disease activity, and alleviate resistance to antibiotics as well as chemotherapeutics. Their antiproliferative, antioxidant, anti-inflammatory, and antineoplastic activity has been proved. They may act as antioxidants, while preventing DNA damage by scavenging reactive oxygen radicals, reinforcing DNA repair, disrupting chemical damages by induction of phase II enzymes, and modifying signal transduction pathways. One of such research areas is a potential effect of flavonoids on the risk of developing cancer. The aim of our paper is to present a systematic review of antineoplastic activity of flavonols in general. Special attention was paid to selected flavonols: fisetin, kaempferol, and quercetin in preclinical and in vitro studies. Study results prove antiproliferative and proapoptotic properties of flavonols with regard to head and neck cancer. However, few study papers evaluate specific activities during various processes associated with cancer progression. Moreover, an attempt was made to collect the majority of substantive studies on bioactive potential of the selected flavonols, especially with regard to modulation of a range of signal transduction pathways that participate in cancer development.

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Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

Cited by 44 publications

References 165 publications

EPSP Synthase-Depleted Cells Are Aromatic Amino Acid Auxotrophs in Mycobacterium smegmatis

EPSP Synthase-Depleted Cells Are Aromatic Amino Acid Auxotrophs in Mycobacterium smegmatis

Different Solvent and Conformational Entropy Contributions to the Allosteric Activation and Inhibition Mechanisms of Yeast Chorismate Mutase

Anticancer Potential of Selected Flavonols: Fisetin, Kaempferol, and Quercetin on Head and Neck Cancers

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