Aspartyl proteases are enzymes that speed up chemical reactions in living organisms. As proteases, their function is to break down proteins. They achieve this by cleaving bonds between amino acids, the building blocks of proteins, thereby breaking large proteins into smaller peptides or individual amino acids. Aspartyl proteases play an important role in various biological processes across different forms of life.
How Aspartyl Proteases Work
Aspartyl proteases are characterized by a catalytic mechanism relying on two aspartic acid residues in their active site. This pair of aspartates is often referred to as a “catalytic dyad.” The enzyme’s structure features a bilobed shape, with the active site between these two lobes.
The mechanism activates a water molecule, coordinated between the two highly conserved aspartate residues. One aspartate removes a proton from the water, making it reactive to attack the carbon atom of the peptide bond. This forms a temporary, unstable tetrahedral oxyanion intermediate, stabilized by hydrogen bonds with the second aspartic acid residue. Unlike some other proteases, aspartyl proteases do not form a covalent bond with the protein they are cutting during this process; the cleavage occurs in a single step. The intermediate’s rearrangement protonates the amide group in the peptide bond, splitting the protein into two peptide fragments and regenerating the active site.
Diverse Roles in Biological Systems
Aspartyl proteases perform important functions within living organisms.
In the human digestive system, pepsin is an aspartyl protease produced in the stomach. Pepsin initiates the breakdown of dietary proteins into smaller peptides, aiding protein digestion at the acidic pH in the stomach. It exhibits broad cleavage specificity, preferring to cut bonds near hydrophobic or aromatic amino acids.
Renin is an aspartyl protease secreted by the kidneys. Renin functions as part of the renin-angiotensin-aldosterone system (RAAS), a hormonal system regulating the body’s water balance and blood pressure. Renin cleaves angiotensinogen to produce angiotensin I, which undergoes further processing to affect blood vessel constriction and fluid retention, influencing blood pressure.
Within cells, lysosomal cathepsins, such as cathepsin D, are aspartyl proteases in lysosomes, the cell’s recycling centers. These enzymes break down unwanted or damaged proteins or other macromolecules delivered to lysosomes through processes like autophagy (cellular self-eating) and endocytosis. This degradation recycles amino acids, maintaining cellular health.
Targeting Aspartyl Proteases in Medicine
Aspartyl proteases are also important targets for drug development due to their involvement in various diseases. A key example is the HIV-1 protease, produced by the human immunodeficiency virus. This viral enzyme is important for the virus to mature into an infectious form by cleaving large viral precursor proteins into smaller, functional components.
HIV-1 protease inhibitors block this enzyme’s activity, preventing the virus from replicating and maturing. These inhibitors bind to the HIV-1 protease’s active site, disabling it and reducing viral load in infected individuals. This therapeutic strategy has been successful in treating AIDS, often used in combination with other antiretroviral drugs as part of highly active antiretroviral therapy (HAART).
Renin, involved in blood pressure regulation, is another target for hypertension treatment. Direct renin inhibitors, such as aliskiren, block renin’s ability to convert angiotensinogen to angiotensin I, interrupting the RAAS cascade at its initial step. This reduces angiotensin II, a potent vasoconstrictor, and promotes sodium and water excretion, ultimately lowering blood pressure.
Aspartyl proteases are also investigated for roles in other conditions. Beta-secretase (BACE1) is implicated in Alzheimer’s disease. BACE1 is involved in producing amyloid-beta peptides that accumulate in the brain to form amyloid plaques, a hallmark of Alzheimer’s. Inhibitors of BACE1 have been developed to reduce amyloid-beta production, with some in clinical trials to assess their potential as treatments for Alzheimer’s disease. Additionally, aspartyl proteases in malaria parasites, such as plasmepsins, are explored as potential drug targets for new antimalarial therapies, as these enzymes are necessary for parasite survival within the host.