Peptidylarginine Deiminase Type II, or PAD2, is an enzyme found throughout the human body. PAD2 plays a part in various biological processes, and its widespread presence and activity make it a subject of ongoing scientific inquiry.
How PAD2 Works
PAD2 functions by catalyzing a chemical reaction known as deimination, also referred to as citrullination. This process involves the conversion of the amino acid arginine, a building block of proteins, into another amino acid called citrulline. This transformation is calcium-dependent, requiring calcium ions to occur. During deimination, the positively charged guanidinium group of arginine is replaced by a neutral urea group, which changes the overall charge and structure of the protein. This chemical change can alter a protein’s shape, stability, and its ability to interact with other molecules, thereby affecting its function.
The mechanism by which PAD2 carries out this conversion involves a “substrate-assisted mechanism.” This means the arginine molecule itself helps to activate the enzyme’s active site, specifically Cys647, to initiate the reaction. These precise changes to proteins can influence various cellular processes.
PAD2’s Everyday Roles
PAD2 is a widely distributed enzyme, found in numerous tissues and organs, including the brain, spinal cord, spleen, pancreas, skeletal muscles, secretory glands, and various immune cells. PAD2 contributes to several physiological processes. Its activity can influence cell differentiation, the process by which cells become specialized.
PAD2 also plays a role in regulating gene expression, influencing which genes are turned on or off in cells. For instance, it can modify histone proteins, which are involved in packaging DNA, thereby affecting how genes are accessed and transcribed. PAD2 is also involved in immune responses, particularly within macrophages, a type of immune cell. It can affect macrophage differentiation and their ability to clear pathogens through processes like phagocytosis and pyroptosis, a form of inflammatory cell death.
PAD2 and Health Conditions
Dysregulation or abnormal activity of PAD2 has been linked to several health conditions, including autoimmune diseases and certain types of cancer. In autoimmune diseases like rheumatoid arthritis (RA), elevated levels of PAD2-citrullinated proteins are found in the synovial fluid of affected joints. These modified proteins can become targets for the immune system, leading to the production of anti-citrullinated protein antibodies (ACPAs), a hallmark of RA in about 70% of patients. This abnormal citrullination by PAD2 can intensify the inflammatory response seen in RA.
PAD2 is also implicated in multiple sclerosis (MS), a neurodegenerative disorder affecting the central nervous system. In MS, increased PAD2 expression and activity can lead to hypercitrullination and destabilization of myelin basic protein (MBP), a component of the myelin sheath that protects nerve fibers. This can disrupt nerve impulse transmission and potentially expose new MBP epitopes to the immune system, contributing to the disease’s progression.
In addition to autoimmune conditions, altered PAD2 activity is observed in certain cancers, including breast cancer and hepatocellular carcinoma (HCC). In breast cancer, PAD2 expression correlates with the presence of estrogen receptor (ER) and HER2, suggesting it could be a target for therapy. PAD2 may influence tumor cell proliferation by regulating cell cycle genes through epigenetic modifications. In HCC, higher PAD2 expression has been associated with a lower recurrence rate following surgical removal of the tumor, indicating a potential prognostic role.
Unlocking PAD2’s Secrets
Ongoing research into PAD2 continues to deepen our understanding of its complex roles in human biology and disease. By investigating the specific mechanisms by which PAD2 modifies proteins and influences cellular processes, scientists are uncovering new insights into the origins and progression of various conditions. This includes exploring how PAD2 interacts with other enzymes and signaling pathways within cells.
The knowledge gained from these studies holds promise for the development of new diagnostic tools and therapeutic strategies. For example, identifying specific citrullinated proteins or measuring PAD2 activity could serve as biomarkers for early disease detection or to monitor treatment effectiveness. Designing molecules that can selectively inhibit or modulate PAD2’s activity without affecting its beneficial functions could lead to novel treatments for autoimmune diseases, neurodegenerative disorders, and certain cancers.