Serine hydrolases represent a large and diverse group of enzymes performing a wide array of functions throughout living organisms. These proteins account for approximately 1% of the genes in the human body, numbering around 200 distinct enzymes. Their primary role involves breaking down molecules by using water to split chemical bonds, a process known as hydrolysis. This family of enzymes participates in many biological processes, ranging from digestion and metabolism to nervous system signaling and immune responses.
How Serine Hydrolases Work
Serine hydrolases operate through a precise chemical mechanism within their “active site.” A specific serine residue plays a central role in catalysis. This serine is activated by a “catalytic triad,” typically consisting of serine, histidine, and aspartate or glutamate.
The serine’s oxygen atom acts as a “nucleophile,” initiating the reaction by attacking a specific bond within the target molecule. This attack forms a “covalent acyl-enzyme intermediate,” where part of the original molecule links to the enzyme’s serine. The “oxyanion hole” in the active site helps stabilize this unstable intermediate by interacting with its negatively charged oxygen atom.
The catalytic process generally unfolds in two main steps. First, the serine attacks the substrate, forming the intermediate and releasing one part of the original molecule. In the second step, a water molecule enters the active site and attacks the intermediate, breaking the bond between the enzyme and the remaining part of the molecule. This final step regenerates the free enzyme, allowing it to repeat the process with another substrate molecule.
Key Biological Roles
Serine hydrolases are involved in a wide range of biological activities, maintaining the proper functioning of many bodily systems. In the digestive system, serine proteases like trypsin and chymotrypsin break down proteins into smaller peptides and amino acids, aiding nutrient absorption. Similarly, lipases, such as pancreatic and gastric lipases, hydrolyze dietary fats (triglycerides) into fatty acids and glycerol, which are then absorbed and utilized by the body.
Lipid metabolism relies on these enzymes. Intracellular lipases like adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL) regulate fat storage and release from cells. They break down complex lipids, making fatty acids available for energy production or as signaling molecules. Dysregulation of these enzymes can impact overall lipid balance.
The nervous system also depends on serine hydrolases for nerve cell communication. Acetylcholinesterase (AChE) rapidly breaks down acetylcholine, ending nerve signals at synapses and muscle junctions. Other enzymes, like fatty acid amide hydrolase (FAAH), degrade endocannabinoids such as anandamide, which influence mood, pain sensation, and appetite. These enzymes fine-tune the levels of lipid signaling molecules in the brain.
Serine hydrolases also play roles in inflammation and blood clotting. Phospholipases like PLA2G7 can generate pro-inflammatory molecules from oxidized lipids, contributing to inflammatory responses. In the coagulation cascade, serine proteases like thrombin and activated factor Xa form blood clots, preventing excessive bleeding. The precise regulation of these enzymes is important for maintaining both processes in balance.
Carboxylesterases (CES) detoxify various substances, including drugs and environmental toxins, by breaking them down. This broad activity highlights their importance in maintaining physiological balance across biological pathways. Their presence across systems underscores their adaptability and fundamental role.
Serine Hydrolases and Disease
Disruptions in the normal function of serine hydrolases can contribute to the development and progression of various health conditions. When these enzymes exhibit altered activity or genetic mutations, they can impact the delicate balance of biological processes. This makes them relevant in understanding and addressing numerous diseases.
In neurodegenerative disorders, imbalances in serine hydrolase activity are observed. For instance, reduced acetylcholinesterase activity is a characteristic feature in Alzheimer’s disease, leading to an accumulation of acetylcholine and contributing to cognitive decline. Altered activity of endocannabinoid hydrolases, such as diacylglycerol lipase alpha (DAGLĪ±) or palmitoyl-protein thioesterase 1 (PPT1), may also play a role in conditions like Niemann-Pick type C disease, affecting lipid metabolism in the brain.
Metabolic diseases are another area where serine hydrolase dysfunction is implicated. Dysregulation of lipases like adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), lipoprotein lipase (LPL), and endothelial lipase (EL) has been linked to conditions such as gestational diabetes, obesity, and hypertriglyceridemia. Additionally, a complete lack of lysosomal acid lipase (LAL) activity causes severe lipid accumulation in Wolman’s disease; partial deficiency leads to cholesteryl ester storage disease.
Serine hydrolases also have connections to cancer. Enzymes like monoacylglycerol lipase (MGLL) and fatty acid synthase (FASN) have altered activity in various cancers, promoting tumor growth and survival. The metabolic pathways involving serine synthesis, mediated by enzymes such as phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH), are often reprogrammed and overactive in cancer cells, supporting rapid proliferation, metastasis, and treatment resistance.
Due to their diverse roles and disease involvement, serine hydrolases are important drug targets. Several medications currently modulate these enzymes’ activity. Examples include acetylcholinesterase inhibitors for Alzheimer’s disease, drugs targeting dipeptidyl peptidase-4 (DPP-4) for type 2 diabetes, and anticoagulants inhibiting thrombin or activated factor Xa. Ongoing research aims to identify new therapeutic compounds to precisely control these enzymes for a wider range of conditions.