Fluorinated tryptophans as substrates and inhibitors of the ATP‐[<sup>32</sup>P] PP<sub>i</sub> exchange reaction catalysed by tryptophanyl tRNA synthetase

Nevinsky, G.A.; Фаворова, О. О.; Lavrik, Olga I.; Petrova, T. D.; Kochkina, L.L.; Савченко, Т. И.

doi:10.1016/0014-5793(74)80985-3

Cited by 21 publications

(11 citation statements)

References 11 publications

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“…. [28][29][30] Yet, fluorotryptophans showed different affinities towards tryptophanyl-tRNA synthetase from both beef pancreas [28] and Bacillus subtilis. [29] In both cases d,l-(4-F)Trp showed the highest affinity, followed by d,l-(6-F)Trp and d,l-(5-F)Trp.…”

Section: C]a C H T U N G T R E N N U N G (6-f)trp Was Quantified In Tmentioning

confidence: 99%

Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells

et al. 2008

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Nonproteinogenic amino acids that either occur naturally or are synthesized chemically are becoming important tools in modern drug discovery. In this context, fluorinated amino acids have great potential in the development of novel pharmaceuticals and drugs. To assess whether different fluorinated aromatic amino acid analogues of phenylalanine, tyrosine, and tryptophan are potentially interesting as therapeutic drugs, we examined their cytostatic and cytotoxic effects on the growth of the human breast cancer cell line MCF-7. Of all the tested analogues L-4-fluorotryptophan, L-6-fluorotryptophan and L-p-fluorophenylalanine effectively and irreversibly inhibited cell growth with IC(50) values in the low micromolar range (3-15 microM). Additionally, using L-4-[14C]fluorotryptophan, and L-6-[14C]fluorotryptophan, we discovered that the cellular uptake of these fluorinated amino acids occurs through active transport with a 70-fold excess of intracellular over extracellular concentrations. We identified system L as the responsible amino acid transporter. Our findings fully support the idea that fluorinated aromatic amino acid analogues are promising chemotherapeutics with the potential for use in combination with classical cancer therapy, and as new cytotoxic drugs for certain tumor types such as melanoma.

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Section: C]a C H T U N G T R E N N U N G (6-f)trp Was Quantified In Tmentioning

confidence: 99%

Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells

et al. 2008

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“…We demonstrated the substrate inhibition (50–90%) of human TrpRS by Trp at physiological concentrations 10–50 µM [ 3 ]. Trp is an essential amino acid with K m for purified bovine pancreatic TrpRS 1.4 ± 0.2 × 10 −7 M in Trp-dependent ATP–PP i exchange reaction [ 37 ]. The Michaelis constant K m is the substrate, such as tryptophan concentration at which the reaction rate is half of V max , denoting a dose of a naturally occurring agent such as tryptophan that is within the range of concentrations or potencies that would occur naturally.…”

Section: Resultsmentioning

confidence: 99%

“… a In the reaction of ATP[ 32 P]pyrophosphate exchange; b In the reaction of tRNA trp charging; # Note, the Km value of purified bovine pancreatic TrpRS for tryptophan in ATP-[ 32 P]pyrophosphate exchange (0.9 × 10 −7 M) is six times lower than Ki for tryptamine (6.0 × 10 −7 M) as reported [ 7 , 44 ]. In other studies, the tryptophan K m for purified bovine pancreatic TrpRS is 1.4 ± 0.2 × 10 −7 M [ 37 ] and 1.14 × 10 −6 M for bovine kidney TrpRS in the cell extract [ 44 ] in the reaction of ATP-[ 32 P]pyrophosphate exchange. …”

Section: Figurementioning

confidence: 99%

Towards an Integrative Understanding of tRNA Aminoacylation–Diet–Host–Gut Microbiome Interactions in Neurodegeneration

Paley

Perry

2018

Nutrients

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Transgenic mice used for Alzheimer’s disease (AD) preclinical experiments do not recapitulate the human disease. In our models, the dietary tryptophan metabolite tryptamine produced by human gut microbiome induces tryptophanyl-tRNA synthetase (TrpRS) deficiency with consequent neurodegeneration in cells and mice. Dietary supplements, antibiotics and certain drugs increase tryptamine content in vivo. TrpRS catalyzes tryptophan attachment to tRNAtrp at initial step of protein biosynthesis. Tryptamine that easily crosses the blood–brain barrier induces vasculopathies, neurodegeneration and cell death via TrpRS competitive inhibition. TrpRS inhibitor tryptophanol produced by gut microbiome also induces neurodegeneration. TrpRS inhibition by tryptamine and its metabolites preventing tryptophan incorporation into proteins lead to protein biosynthesis impairment. Tryptophan, a least amino acid in food and proteins that cannot be synthesized by humans competes with frequent amino acids for the transport from blood to brain. Tryptophan is a vulnerable amino acid, which can be easily lost to protein biosynthesis. Some proteins marking neurodegenerative pathology, such as tau lack tryptophan. TrpRS exists in cytoplasmic (WARS) and mitochondrial (WARS2) forms. Pathogenic gene variants of both forms cause TrpRS deficiency with consequent intellectual and motor disabilities in humans. The diminished tryptophan-dependent protein biosynthesis in AD patients is a proof of our model-based disease concept.

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“…The product was characterized by elementary analysis and IR and W spectroscopy. L-6-Fluoro-Trp was isolated by means of D-amino acid oxidase [7]. All reagents were from the same sources as earlier [6].…”

Section: Methodsmentioning

confidence: 99%

“…This type of analysis has been discussed by Wong and Hanes [5] . We used the reaction of ATP-[32 P] pyrophosphate exchange catalyzed by tryptophan:tRNAligase from beef pancreas in the presence of tryptophan (Trp) and its 6-fluorinated analog (6-fluoro-Trp) demonstrated earlier to be a substrate of the enzyme [6,7].…”

Section: Introductionmentioning

confidence: 99%

Kinetic parameters of tryptophan: tRNA ligase catalyzed ATP‐[³²P] pyrophosphate exchange as an approach to estimation of the order of substrate binding

et al. 1975

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Fluorinated tryptophans as substrates and inhibitors of the ATP‐[³²P] PP_i exchange reaction catalysed by tryptophanyl tRNA synthetase

Cited by 21 publications

References 11 publications

Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells

Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells

Towards an Integrative Understanding of tRNA Aminoacylation–Diet–Host–Gut Microbiome Interactions in Neurodegeneration

Kinetic parameters of tryptophan: tRNA ligase catalyzed ATP‐[³²P] pyrophosphate exchange as an approach to estimation of the order of substrate binding

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Fluorinated tryptophans as substrates and inhibitors of the ATP‐[32P] PPi exchange reaction catalysed by tryptophanyl tRNA synthetase

Cited by 21 publications

References 11 publications

Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells

Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells

Towards an Integrative Understanding of tRNA Aminoacylation–Diet–Host–Gut Microbiome Interactions in Neurodegeneration

Kinetic parameters of tryptophan: tRNA ligase catalyzed ATP‐[32P] pyrophosphate exchange as an approach to estimation of the order of substrate binding

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Fluorinated tryptophans as substrates and inhibitors of the ATP‐[³²P] PP_i exchange reaction catalysed by tryptophanyl tRNA synthetase

Kinetic parameters of tryptophan: tRNA ligase catalyzed ATP‐[³²P] pyrophosphate exchange as an approach to estimation of the order of substrate binding