Deamidation is a naturally occurring chemical modification that affects proteins after they have been created within living organisms. This spontaneous process involves a change to specific amino acid building blocks that make up a protein. This common alteration can occur over time, influencing protein characteristics.
The Chemical Mechanism of Deamidation
Deamidation primarily affects two amino acids: asparagine (Asn) and glutamine (Gln). Asparagine is significantly more prone to this modification than glutamine. The core chemical reaction involves the conversion of the amide side chain of these amino acids into a carboxylic acid side chain. This transformation occurs through hydrolysis, a reaction with water.
For asparagine, deamidation proceeds through a cyclic intermediate called a succinimide. This intermediate can then hydrolyze to form either aspartic acid or isoaspartic acid, both of which contain a carboxylic acid group. This pathway is common and contributes to asparagine’s higher reactivity. Several factors can accelerate this spontaneous reaction, including higher temperatures.
Non-neutral pH conditions, whether acidic or basic, also promote the rate of deamidation. Neighboring amino acids in the protein sequence can also influence the reaction rate. Specific amino acids next to asparagine or glutamine can stabilize or destabilize the amide bond, affecting how quickly deamidation occurs.
Impact on Protein Structure and Function
Deamidation’s chemical change has direct physical consequences for proteins. Replacing a neutral amide group with a negatively charged carboxylic acid group significantly alters the protein’s overall charge. This charge change can disrupt internal electrostatic bonds that maintain the protein’s three-dimensional folded shape. Proteins rely on these specific shapes to perform their biological roles.
A change in shape, known as a conformational change, can reduce or eliminate the protein’s biological function. For example, an enzyme might lose its ability to recognize and bind to its specific target molecule, thereby becoming inactive. Improperly folded proteins can also become “sticky,” leading to aggregation. This process can further impair protein function and form insoluble protein deposits.
Role in Biological Aging and Disease
Deamidation acts as a form of cumulative molecular damage that can influence the lifespan of proteins within the body. As proteins deamidate over time, cellular machinery recognizes and targets them for degradation and replacement. This process is relevant in age-related conditions where protein integrity declines.
An example involves the deamidation of crystallin proteins in the eye’s lens. These proteins maintain lens transparency, and their deamidation contributes to cataracts, a clouding that impairs vision. Deamidation is also associated with neurodegenerative diseases. It can contribute to the aggregation of specific proteins implicated in conditions such as Alzheimer’s disease, where misfolded proteins form harmful deposits in the brain.
Implications for Protein-Based Therapeutics
Many modern medicines, known as biologics or biotherapeutics, are protein-based drugs, including monoclonal antibodies and hormones like insulin. For these products, deamidation presents a challenge as a primary degradation pathway. This chemical modification can reduce the drug’s effectiveness, also known as its potency.
Deamidation can also shorten the shelf-life of a protein-based therapeutic. This chemical instability is a quality attribute pharmaceutical companies must monitor and control throughout drug development. Managing deamidation during manufacturing and storage ensures patient safety and consistent drug efficacy.