Protein arginine methyltransferases, or PRMTs, are a family of enzymes found within cells that perform a specialized chemical modification. These enzymes play a broad role in regulating various cellular activities, influencing how cells grow, communicate, and respond to their environment. Understanding these enzymes helps illuminate fundamental biological processes.
The Function of Protein Arginine Methylation
PRMTs modify proteins after they have been synthesized, a process known as post-translational modification. This modification involves the transfer of a methyl group from S-adenosylmethionine (SAM) to specific arginine amino acids within a target protein.
The addition of this methyl group can subtly change the protein’s characteristics. This alteration might affect its three-dimensional shape, influencing how it folds or where it resides within the cell. The modification can also alter how the protein interacts with other molecules, effectively changing its function or signaling capabilities.
Classification of PRMTs
PRMTs are categorized into distinct types based on the specific chemical outcome of the methylation they perform on arginine residues. This classification reflects how many methyl groups are added and their placement on the arginine molecule.
Type I PRMTs, including enzymes like PRMT1 and PRMT4 (CARM1), generate asymmetric dimethylarginine (ADMA). Two methyl groups are added to one nitrogen atom of the arginine side chain. PRMT1 is particularly active, accounting for a large portion of cellular PRMT activity.
Type II PRMTs, exemplified by PRMT5, produce symmetric dimethylarginine (SDMA). One methyl group is added to each of the two terminal nitrogen atoms of the arginine side chain. PRMT5 activity often requires protein cofactors like MEP50.
A third category, Type III PRMTs, which includes PRMT7, performs monomethylation, adding a single methyl group to the arginine residue (MMA).
Key Cellular Processes Regulated by PRMTs
Protein arginine methylation plays a role in numerous fundamental cellular functions. PRMTs influence gene transcription, the process by which genetic information from DNA is used to create RNA. They can methylate histone proteins, which are structural components around which DNA is wrapped.
Methylation of histones, such as histone H4 and H3, can either promote or suppress gene expression. For example, PRMT4 (CARM1) enhances transcriptional activation by modifying histones, affecting chromatin structure and gene activation.
PRMTs also participate in RNA processing, particularly in messenger RNA (mRNA) splicing. Splicing involves editing the initial genetic message to remove non-coding regions and assemble the final mRNA molecule. PRMTs modify proteins that are components of the spliceosome, the complex machinery responsible for this editing.
These enzymes contribute to the cell’s DNA damage response system. When DNA strands are broken or damaged, PRMTs can methylate various DNA repair proteins, signaling them to the site of damage or altering their activity. This helps coordinate DNA repair, maintaining genetic material integrity.
Connection to Human Disease
When PRMT function is disrupted, it can contribute to the development and progression of various human diseases. Cancer is a prominent area where PRMT dysregulation is frequently observed. Over-activity of specific PRMTs, such as PRMT1 and PRMT5, has been linked to tumor growth and survival in many cancer types.
For instance, PRMT1 is often overexpressed in acute myeloid leukemia, while PRMT5 overexpression is common in lymphomas, leukemias, and various solid tumors. This increased activity can alter methylation patterns of proteins involved in cell proliferation, cell cycle control, and DNA repair, promoting the uncontrolled growth characteristic of cancer cells.
Beyond cancer, PRMT dysregulation has also been associated with cardiovascular diseases. Elevated levels of asymmetric dimethylarginine (ADMA) are recognized as a risk factor for cardiovascular conditions and increased mortality. Increased ADMA can inhibit nitric oxide production, important for healthy blood vessel function, potentially leading to endothelial dysfunction.
PRMTs are also implicated in neurological disorders. They are highly expressed in the central nervous system and contribute to neuronal maturation and differentiation. Aberrant PRMT function or expression has been linked to neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease.
Therapeutic Targeting of PRMTs
Given their involvement in disease, PRMTs have emerged as promising therapeutic targets. PRMT inhibitors are drugs designed to block the activity of certain PRMT enzymes. This approach aims to counteract the detrimental effects of overactive PRMTs observed in various pathologies.
In cancer treatment, PRMT inhibitors represent a novel strategy, particularly for tumors where specific PRMTs are overexpressed and drive disease progression. By inhibiting these enzymes, researchers aim to halt tumor growth or make cancer cells more susceptible to existing treatments. Several PRMT inhibitors are currently undergoing evaluation in clinical trials.
Examples include inhibitors targeting PRMT5, such as GSK3326595, JNJ-64619178, PRT543, AMG 193, and MRTX1719, which are being tested in various solid tumors and hematologic malignancies. Some of these inhibitors are designed to specifically affect tumor cells with certain genetic alterations, like MTAP deficiency, heralding a new frontier in precision medicine.