Mechanisms and Inhibitors of Histone Arginine Methylation

Fulton, Melody D.; Brown, Tyler; Zheng, Yu

doi:10.1002/tcr.201800082

Cited by 58 publications

(40 citation statements)

References 155 publications

(354 reference statements)

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“…Whether this is due to the lack of external factors such as binding partners or if this feature of PRMT7 activity is physiologically relevant remains to be seen. Additionally, given this enzyme's medical relevance in cancer regulation and genetic syndromes, there is an apparent absence for chemical probes and small molecule inhibitors specific to PRMT7, while many have been described for enzymes such as PRMT1 and PRMT5 [97]. However, the recent description of a potent (nM IC50 values) and relatively specific PRMT7 inhibitor SGC8158 and its cell-permeable pro-inhibitor SGC3027 may mark a new effective approach [36].…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

PRMT7 as a unique member of the protein arginine methyltransferase family: A review

Jain¹,

Clarke²

2019

Archives of Biochemistry and Biophysics

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Protein arginine methyltransferases (PRMTs) are found in a wide variety of eukaryotic organisms and can regulate gene expression, DNA repair, RNA splicing, and stem cell biology. In mammalian cells, nine genes encode a family of sequence-related enzymes; six of these PRMTs catalyze the formation of ω-asymmetric dimethyl derivatives, two catalyze ω-symmetric dimethyl derivatives, and only one (PRMT7) solely catalyzes ω-monomethylarginine formation. Purified recombinant PRMT7 displays a number of unique enzymatic properties including a substrate preference for arginine residues in R-X-R motifs with additional flanking basic amino acid residues and a temperature optimum well below 37 °C. Evidence has been presented for crosstalk between PRMT7 and PRMT5, where methylation of a histone H4 peptide at R17, a PRMT7 substrate, may activate PRMT5 for methylation of R3. Defects in muscle stem cells (satellite cells) and immune cells are found in mouse Prmt7 homozygous knockouts, while humans lacking PRMT7 are characterized by significant intellectual developmental delays, hypotonia, and facial dysmorphisms. The overexpression of the PRMT7 gene has been correlated with cancer metastasis in humans. Current research challenges include identifying cellular factors that control PRMT7 expression and activity, identifying the physiological substrates of PRMT7, and determining the effect of methylation on these substrates.

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Section: Perspectives and Conclusionmentioning

confidence: 99%

PRMT7 as a unique member of the protein arginine methyltransferase family: A review

Jain¹,

Clarke²

2019

Archives of Biochemistry and Biophysics

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“…Mammalian cells have nine PRMTs [17], and all have a highly conserved catalytic core composed of a Rossmann-like fold domain that binds SAM and a β-barrel that supports substrate binding (Figure 2) [18]. Upon the initial binding of SAM and substrate, PRMTs transfer the electrophilic methyl group from SAM to a terminal nitrogen on the guanidinium moiety of arginine residues to produce the monomethylarginine residue, Rme1 [3,6,7,8]. All PRMTs will catalyze this initial methyl transfer.…”

Section: Prmtsmentioning

confidence: 99%

“…Thus, metformin does not seem to act through PRMT inhibition. So far, a plethora of PRMT inhibitors have been reported [8,109,110,111]. We anticipate that potent PRMT1 inhibitors will be studied for their potential therapeutic value in counteracting hypertension and endothelial dysfunction.…”

Section: Adma—the Small Molecule Metabolite Product Of Arginine Mementioning

confidence: 99%

“…Arginine residues can be methylated on the guanidinium nitrogen atoms in three different states— N G -monomethylarginine (Rme1), asymmetric N G , N G -dimethylarginine (Rme2a), and symmetric N G , N’ G -dimethylarginine (Rme2s) (Figure 1) [3,6,7,8]. Reported results on the stoichiometric abundance of different methylation states, although varying at different degrees, generally support that monomethylated arginine is more abundant than dimethylated arginine sites in proteins.…”

Section: Introductionmentioning

confidence: 99%

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The Biological Axis of Protein Arginine Methylation and Asymmetric Dimethylarginine

Fulton

Brown

Zheng

2019

IJMS

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Protein post-translational modifications (PTMs) in eukaryotic cells play important roles in the regulation of functionalities of the proteome and in the tempo-spatial control of cellular processes. Most PTMs enact their regulatory functions by affecting the biochemical properties of substrate proteins such as altering structural conformation, protein–protein interaction, and protein–nucleic acid interaction. Amid various PTMs, arginine methylation is widespread in all eukaryotic organisms, from yeasts to humans. Arginine methylation in many situations can drastically or subtly affect the interactions of substrate proteins with their partnering proteins or nucleic acids, thus impacting major cellular programs. Recently, arginine methylation has become an important regulator of the formation of membrane-less organelles inside cells, a phenomenon of liquid–liquid phase separation (LLPS), through altering π-cation interactions. Another unique feature of arginine methylation lies in its impact on cellular physiology through its downstream amino acid product, asymmetric dimethylarginine (ADMA). Accumulation of ADMA in cells and in the circulating bloodstream is connected with endothelial dysfunction and a variety of syndromes of cardiovascular diseases. Herein, we review the current knowledge and understanding of protein arginine methylation in regards to its canonical function in direct protein regulation, as well as the biological axis of protein arginine methylation and ADMA biology.

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“…A similar approach could be considered for selective NfPRMT inhibitor development (33,34). There is still a need to improve both the affinity and selectivity of these micromolar, sub-micromolar potent PRMT inhibitors as well as to better understand the enzyme's biological and disease processes in greater scope (35). Recently, evidence of their propensity for adding new sequences or domains during ARS evolution hints at broader functions and complexity outside of translation (42).…”

Section: One Third Of Targets Attempted Produced Soluble Proteinmentioning

confidence: 99%

Naegleria fowleri: protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba

Barrett

Tillery

Goldstein

et al. 2020

Preprint

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Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain's frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogen's high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. N. fowleri genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen.

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Mechanisms and Inhibitors of Histone Arginine Methylation

Cited by 58 publications

References 155 publications

PRMT7 as a unique member of the protein arginine methyltransferase family: A review

PRMT7 as a unique member of the protein arginine methyltransferase family: A review

The Biological Axis of Protein Arginine Methylation and Asymmetric Dimethylarginine

Naegleria fowleri: protein structures to facilitate drug discovery for the deadly, pathogenic free-living amoeba

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