Inhibition of tRNA Gene Transcription by the Immunosuppressant Mycophenolic Acid

Jurkiewicz, Aneta; Leśniewska, Ewa; Cieśla, Małgorzata; Gorjão, Neuton; Kantidakis, Theodoros; White, Robert J.; Boguta, Magdalena; Graczyk, Damian

doi:10.1128/mcb.00294-19

Cited by 8 publications

(4 citation statements)

References 38 publications

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“…The mechanism of action of MPA was elucidated by Allison and Eugui 22 and has been described in detail in several publications. [23][24][25][26][27] The key effect responsible for the immunosuppressive action of MPA is a potent, noncompetitive, and reversible inhibition of the enzyme IMPDH. This enzyme catalyzes the conversion of IMP to xanthosine-5 0 -monophosphate (XMP) in the presence of the cofactor nicotinamide adenine dinucleotide (NAD+), and this is the rate-limiting step in the de novo purine synthesis pathway.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…This enzyme catalyzes the conversion of IMP to xanthosine-5 0 -monophosphate (XMP) in the presence of the cofactor nicotinamide adenine dinucleotide (NAD+), and this is the rate-limiting step in the de novo purine synthesis pathway. This results in the depletion of the intracellular pool of guanosine and deoxyguanosine, imbalance between precursors of mRNA, rRNA, and tRNA, nuclear stress, arrest in cell cycle progression at the G0/G1 phase of their cell cycle and thus preventing cell proliferation 24,27 T and B lymphocytes, as well as fibroblasts, are primarily affected because they are strongly dependent on the de novo pathway of purine synthesis in contrast to most other cells that can sustain their purine nucleotide pool through the salvage pathway.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

See 1 more Smart Citation

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

Bergan¹,

Brunet²,

Hesselink³

et al. 2021

Therapeutic Drug Monitoring

118

237

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When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and

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Section: Mechanism Of Actionmentioning

confidence: 99%

Section: Mechanism Of Actionmentioning

confidence: 99%

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

Bergan¹,

Brunet²,

Hesselink³

et al. 2021

Therapeutic Drug Monitoring

118

237

View full text Add to dashboard Cite

show abstract

“…3 ). MPA reportedly interferes with translational processes in yeast 97 and inhibits RNA polymerase III (Pol III) in mammalian cells, which is required for transcription of 5 S ribosomal RNA, transfer RNA 98 and other small RNAs 99 , 100 . Pol III inhibition can lead to ribosomal disturbances and a rapid decline of transfer RNA, which is crucial to the correct translation of mRNA codons; rapamycin can also suppress Pol III activity 101 .…”

Section: Risk Factors For Impaired Vaccine Responsesmentioning

confidence: 99%

Vaccination in patients with kidney failure: lessons from COVID-19

2022

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Infection is the second leading cause of death in patients with chronic kidney disease (CKD). Adequate humoral (antibody) and cellular (T cell-driven) immunity are required to minimize pathogen entry and promote pathogen clearance to enable infection control. Vaccination can generate cellular and humoral immunity against specific pathogens and is used to prevent many life-threatening infectious diseases. However, vaccination efficacy is diminished in patients with CKD. Premature ageing of the immune system and chronic systemic low-grade inflammation are the main causes of immune alteration in these patients. In the case of SARS-CoV-2 infection, COVID-19 can have considerable detrimental effects in patients with CKD, especially in those with kidney failure. COVID-19 prevention through successful vaccination is therefore paramount in this vulnerable population. Although patients receiving dialysis have seroconversion rates comparable to those of patients with normal kidney function, most kidney transplant recipients could not generate humoral immunity after two doses of the COVID-19 vaccine. Importantly, some patients who were not able to produce antibodies still had a detectable vaccine-specific T cell response, which might be sufficient to prevent severe COVID-19. Correlates of protection against SARS-CoV-2 have not been established for patients with kidney failure, but they are urgently needed to enable personalized vaccination regimens.

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“…It is conceivable that in the context of RNA polymerase supramolecular complex, the DNA single-strand binding activity of IMPDH plays a role in adjusting the transcription machinery and DNA topology at these supercoiling-dependent gene promoters. In addition, IMPDH has been associated with transcription elongation and translation [56][57][58].…”

Section: Figurementioning

confidence: 99%

Composition of Transcription Machinery and Its Crosstalk with Nucleoid-Associated Proteins and Global Transcription Factors

et al. 2021

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The coordination of bacterial genomic transcription involves an intricate network of interdependent genes encoding nucleoid-associated proteins (NAPs), DNA topoisomerases, RNA polymerase subunits and modulators of transcription machinery. The central element of this homeostatic regulatory system, integrating the information on cellular physiological state and producing a corresponding transcriptional response, is the multi-subunit RNA polymerase (RNAP) holoenzyme. In this review article, we argue that recent observations revealing DNA topoisomerases and metabolic enzymes associated with RNAP supramolecular complex support the notion of structural coupling between transcription machinery, DNA topology and cellular metabolism as a fundamental device coordinating the spatiotemporal genomic transcription. We analyse the impacts of various combinations of RNAP holoenzymes and global transcriptional regulators such as abundant NAPs, on genomic transcription from this viewpoint, monitoring the spatiotemporal patterns of couplons—overlapping subsets of the regulons of NAPs and RNAP sigma factors. We show that the temporal expression of regulons is by and large, correlated with that of cognate regulatory genes, whereas both the spatial organization and temporal expression of couplons is distinctly impacted by the regulons of NAPs and sigma factors. We propose that the coordination of the growth phase-dependent concentration gradients of global regulators with chromosome configurational dynamics determines the spatiotemporal patterns of genomic expression.

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Inhibition of tRNA Gene Transcription by the Immunosuppressant Mycophenolic Acid

Cited by 8 publications

References 38 publications

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

Vaccination in patients with kidney failure: lessons from COVID-19

Composition of Transcription Machinery and Its Crosstalk with Nucleoid-Associated Proteins and Global Transcription Factors

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