Protein arginine methyltransferases (PRMTs) are a family of enzymes that chemically modify proteins through arginine methylation. This modification involves adding a methyl group to the amino acid arginine. PRMT activity acts as a regulatory switch, influencing how target proteins interact with each other and with DNA. PRMTs thus regulate essential cellular processes that dictate the life and death of a cell.
Defining the PRMT Enzyme Family
The PRMT family comprises nine distinct enzymes in humans, labeled PRMT1 through PRMT9. These enzymes share a conserved catalytic core known as the Rossmann fold. This region is responsible for binding the methyl-donating cofactor necessary for the chemical reaction.
PRMT enzymes are classified into three functional types based on the specific end product they generate. Type I PRMTs (PRMT1, 2, 3, 4, 6, 8) produce asymmetric dimethylarginine (ADMA). Type II PRMTs (PRMT5 and 9) catalyze the formation of symmetric dimethylarginine (SDMA). Type III is represented solely by PRMT7, which catalyzes only the initial monomethylation step. PRMT1 is the most abundant member, responsible for approximately 85% of total Type I activity. Unique domains outside the core help determine each enzyme’s specific substrate recognition and cellular location.
The Process of Arginine Methylation
Arginine methylation is a post-translational modification that begins with the transfer of a methyl group to a nitrogen atom within the guanidino side chain of an arginine residue. The methyl group is sourced from S-adenosylmethionine (SAM), which acts as the universal methyl donor in this enzymatic reaction. All PRMT types must first perform this single modification, resulting in monomethylarginine (MMA).
The key functional difference between enzyme types lies in how they proceed after the initial monomethylation step. Type I PRMTs add a second methyl group to the same terminal nitrogen atom on the arginine side chain. This creates an asymmetric dimethylarginine (ADMA) product, where the two methyl groups are clustered on one side of the guanidino group.
Conversely, Type II PRMTs catalyze the addition of the second methyl group to the other terminal nitrogen atom of the arginine side chain. This results in a symmetric dimethylarginine (SDMA) product. This subtle difference in methyl group placement dictates the functional outcome, as ADMA and SDMA marks create distinct biological signals.
The specific methylarginine product formed determines the shape and charge of the modified protein, influencing its ability to interact with other cellular components. The type of methylation acts as a precise code that directs the downstream biological response, recognized by specialized reader proteins.
Critical Functions in Cellular Biology
PRMT-mediated arginine methylation serves as a regulatory mechanism that maintains cellular homeostasis. A primary function involves epigenetic regulation through the modification of histone proteins that package DNA into chromatin. PRMT1, for instance, frequently methylates histone H4 at arginine 3 (H4R3), leading to an asymmetric mark (H4R3me2a) associated with the activation of gene transcription.
In contrast, the Type II enzyme PRMT5 often methylates histone H3 at arginine 8 (H3R8). This symmetric mark (H3R8me2s) is typically linked to the repression of gene expression. These opposing transcriptional outcomes illustrate how the precise location and nature of the methyl mark determine whether a gene is turned on or off. This control is fundamental to processes like cell differentiation and development.
Beyond histones, PRMTs modify a wide range of non-histone proteins, extending their regulatory reach into the cytoplasm and nucleus. These substrates include transcription factors, which control gene activity, and splicing factors, necessary for processing messenger RNA. For example, PRMT5 methylates proteins involved in RNA splicing, such as small nuclear ribonucleoproteins (snRNPs). PRMT activity is also involved in the cell’s response to DNA damage. PRMTs regulate the recruitment of repair proteins to the site of damage, ensuring the cell can maintain genomic integrity.
PRMTs as Therapeutic Targets in Disease
The precise regulatory role of PRMTs means that their dysfunction can directly contribute to the development and progression of human diseases. Aberrant expression or activity of specific PRMT enzymes is frequently observed in various cancers, positioning them as attractive targets for new therapies. In many tumor types, PRMT1 and PRMT5 are often overexpressed, promoting uncontrolled cell growth and survival.
PRMT5, in particular, is frequently implicated in solid and hematological malignancies, including glioblastoma. Its overexpression supports cancer cell proliferation by modulating tumor-suppressing genes and enhancing RNA processing necessary for rapid cell division. This makes PRMT5 an oncogenic driver whose inhibition is a focus of drug development efforts.
Dysregulation of PRMTs is also linked to a range of neurological disorders, including neurodegenerative and neurodevelopmental conditions. Specific PRMT mutations can disrupt the methylation patterns required for proper neural stem cell function and neuron development. Targeting PRMT activity offers a potential strategy for intervention by correcting these imbalanced methylation signals.
Researchers are actively developing small-molecule inhibitors designed to selectively block the activity of individual PRMT enzymes. Several PRMT inhibitors, particularly those targeting PRMT1 and PRMT5, have advanced into clinical trials for cancer treatment. A key challenge lies in achieving high specificity for one PRMT type while avoiding off-target effects, given the broad and interconnected functions of these enzymes throughout the cell.