Extracellular 5′-methylthioadenosine inhibits intracellular symmetric dimethylarginine protein methylation of FUSE-binding proteins

Tang, Baiqing; Lee, Hyung‐Ok; Gupta, Sapna; Wang, Liqun; Kurimchak, Alison; Duncan, James S.; Kruger, Warren D.

doi:10.1016/j.jbc.2022.102367

Cited by 4 publications

(3 citation statements)

References 35 publications

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“…To confirm the activity of the compounds against PRMT9, we then used a radioisotope-based assay as a secondary screening approach. , In these experiments, Hs PRMT9 was incubated with 3 H-SAM and SF3B2 (401–550) peptide with and without inhibitors 1a – c at the reported concentrations, and then the reaction products were analyzed by SDS gel electrophoresis followed by fluorography and densitometric analysis. 5′-Deoxy-5′-(methylthio)adenosine (methylthioadenosine, MTA), the polyamine byproduct in the methionine salvage pathway that is reported to be a SAM-competitive inhibitor of PRMTs, − and the PRMT5 inhibitor EPZ015666 (GSK3235025) , were used as reference drugs. As shown in Figure a and consistent with the results of the AlphaLISA assay, all three compounds induced half inhibition of PRMT9 at a concentration lower than 5 μM.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Feoli,

Iannelli,

Cipriano

et al. 2023

J. Med. Chem.

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Less studied than the other protein arginine methyltransferase isoforms, PRMT7 and PRMT9 have recently been identified as important therapeutic targets. Yet, most of their biological roles and functions are still to be defined, as well as the structural requirements that could drive the identification of selective modulators of their activity. We recently described the structural requirements that led to the identification of potent and selective PRMT4 inhibitors spanning both the substrate and the cosubstrate pockets. The reanalysis of the data suggested a PRMT7 preferential binding for shorter derivatives and prompted us to extend these structural studies to PRMT9. Here, we report the identification of the first potent PRMT7/9 inhibitor and its binding mode to the two PRMT enzymes. Label-free quantification mass spectrometry confirmed significant inhibition of PRMT activity in cells. We also report the setup of an effective AlphaLISA assay to screen small molecule inhibitors of PRMT9.

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Section: Resultsmentioning

confidence: 99%

Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Feoli,

Iannelli,

Cipriano

et al. 2023

J. Med. Chem.

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“…This is facilitated by methionine adenosyl-transferase 2 (MAT2), which catalyzes the final step of AdoMet synthesis by facilitating the ATP-dependent transfer of an adenosyl group to methionine. MTAP deficiency results in the inability of endogenous MTA to salvage methionine or adenine, resulting in impaired polyamine biosynthesis and the accumulation of dcAdoMet and 5'-MTA [ 31 ].…”

Section: The Source and Metabolism Of Polyaminementioning

confidence: 99%

Polyamines: their significance for maintaining health and contributing to diseases

Xuan,

Gu,

et al. 2023

Cell Commun Signal

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Polyamines are essential for the growth and proliferation of mammalian cells and are intimately involved in biological mechanisms such as DNA replication, RNA transcription, protein synthesis, and post-translational modification. These mechanisms regulate cellular proliferation, differentiation, programmed cell death, and the formation of tumors. Several studies have confirmed the positive effect of polyamines on the maintenance of health, while others have demonstrated that their activity may promote the occurrence and progression of diseases. This review examines a variety of topics, such as polyamine source and metabolism, including metabolism, transport, and the potential impact of polyamines on health and disease. In addition, a brief summary of the effects of oncogenes and signaling pathways on tumor polyamine metabolism is provided.

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“…A common PRMT dysregulation, specifically of PRMT5, has been correlated with the loss of MTAP (5-methylthioadenosine phosphorylase) expression in lung cancer, resulting in the accumulation of methylthioadenosine (MTA), which significantly inhibits PRMT5 activity [89,90]. The loss of MTAP expression, as a result of deletion, stands out as a significant area of interest due to its prevalence in over 10% of diverse human malignancies, including in NSCLC [91]. To comprehend the full impact of MTAP loss, it is crucial to examine its occurrence and distribution within specific types of NSCLC.…”

Section: Prmt Inhibitors and Mtap Deletion In Lung Cancermentioning

confidence: 99%

Exploring Therapeutic Avenues in Lung Cancer: The Epigenetic Perspective

Munteanu,

Tomuleasa,

Iuga

et al. 2023

Cancers

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Lung cancer, primarily non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), is distinguished by its high prevalence and marked mortality rates. Traditional therapeutic approaches, encompassing chemotherapy, radiation, and targeted therapies, frequently show limited efficacy due to acquired resistance and notable side effects. The objective of this review is to introduce a fresh perspective on the therapeutic strategies for lung cancer, emphasizing interventions targeting the epigenetic alterations often seen in this malignancy. This review presents the most recent advancements in the field, focusing on both past and current clinical trials related to the modulation of methylation patterns using diverse molecular agents. Furthermore, an in-depth analysis of the challenges and advantages of these methylation-modifying drugs will be provided, assessing their efficacy as individual treatments and their potential for synergy when integrated with prevailing therapeutic regimens.

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Extracellular 5′-methylthioadenosine inhibits intracellular symmetric dimethylarginine protein methylation of FUSE-binding proteins

Cited by 4 publications

References 35 publications

Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor

Polyamines: their significance for maintaining health and contributing to diseases

Exploring Therapeutic Avenues in Lung Cancer: The Epigenetic Perspective

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