Amino Acid Delivery

Amino acid delivery ensures the proper supply of the building blocks necessary for protein synthesis, which is central to all biological functions. This process involves the transport of amino acids across cell membranes, facilitated by a variety of transport systems that are specific to amino acid type, such as neutral, basic, and acidic transporters. These transport systems can be broadly classified into solute carrier (SLC) families and ATP-powered pumps, which function to maintain the intracellular amino acid pool according to cellular needs and environmental conditions. The regulation of amino acid delivery is tightly linked to nutrient availability and demand, and it plays a pivotal role in metabolic signaling pathways, notably the mTOR (mechanistic target of rapamycin) pathway, which is a key regulator of cell growth and proliferation. The mTOR complex senses amino acid levels and, in response, modulates protein synthesis by phosphorylating key components of the initiation machinery of translation. This ensures that protein synthesis is synchronized with amino acid availability, preventing the misfolding and aggregation of proteins that can occur under conditions of amino acid scarcity. Furthermore, amino acid delivery is essential for the maintenance of cellular homeostasis and the response to metabolic stress. Cells utilize amino acids not only for protein synthesis but also for the production of neurotransmitters, hormones, and other metabolites critical for cellular signaling and function.

Figure 1 The p53 pathway. (Wang, 2023)

Representative Targets in Amino Acid Delivery

PAD3

PAD3 (Peptidyl Arginine Deiminase, Type III) is one of the members of the peptidyl arginine deiminases (PADs) family, enzymes that catalyze the conversion of peptidyl arginine to citrulline in a process known as citrullination or deimination. This post-translational modification plays significant roles in the regulation of protein function and gene expression by altering the charge and conformation of proteins. PAD3, in particular, is primarily expressed in the epidermis and hair follicles, where it is believed to contribute to the structural integrity and function of keratin and keratin-associated proteins, essential components of the skin and hair. The specific functions and roles of PAD3 are less well-characterized compared to other PAD family members like PAD4, but emerging research suggests that it may be involved in the pathogenesis of certain diseases, particularly in dermatological conditions. For example, abnormalities in PAD3 activity have been linked to skin diseases such as psoriasis and other inflammatory conditions. In these contexts, PAD3-mediated citrullination could potentially alter the properties of structural proteins, thereby affecting the barrier function of the skin and immune responses. Moreover, the enzymatic activity of PAD3 and its potential implications in pathological processes makes it a candidate of interest in understanding disease mechanisms and exploring new therapeutic strategies. For instance, inhibitors targeting PAD3 could theoretically be beneficial in treating conditions where excessive or aberrant citrullination contributes to disease pathology.

ASPG

ASPG, also known as asparaginase, is an enzyme that plays a crucial role in amino acid metabolism by catalyzing the hydrolysis of asparagine to aspartic acid and ammonia. This reaction is particularly significant in the context of medical oncology, where asparaginase is utilized as a therapeutic agent primarily in the treatment of acute lymphoblastic leukemia (ALL) and other malignancies. The rationale behind its use in cancer therapy lies in the dependency of certain cancer cells, notably leukemic cells, on exogenous asparagine for survival and proliferation, as these cells often lack sufficient expression of asparagine synthetase to synthesize asparagine internally. By depleting the available asparagine in the bloodstream through its enzymatic activity, asparaginase starves the leukemic cells of an essential nutrient, leading to their apoptosis or programmed cell death. This selective toxicity makes asparaginase a critical component of chemotherapy regimens for ALL, particularly in pediatric cases, where it has significantly improved survival rates. However, the administration of asparaginase can be associated with various side effects, including allergic reactions, liver toxicity, coagulation abnormalities, and pancreatitis, necessitating careful management and monitoring during treatment.

PADI2

PADI2, or Peptidyl Arginine Deiminase Type II, is a member of the peptidyl arginine deiminases family that catalyzes the conversion of arginine residues in proteins to citrulline, a process known as citrullination or deimination. This enzymatic activity results in post-translational modifications that can significantly alter the structure and function of proteins, influencing a variety of cellular processes including gene regulation, differentiation, and the immune response. PADI2 is broadly expressed in various tissues, including the brain, skin, and immune cells, reflecting its diverse roles in different physiological contexts. In the central nervous system, PADI2-mediated citrullination has been implicated in the regulation of myelination and neural plasticity. For instance, abnormal levels of citrullinated proteins, potentially mediated by PADI2, have been observed in neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD). In these conditions, citrullination may affect the structure and function of neural proteins, contributing to disease pathology by disrupting normal cellular processes. In the immune system, PADI2 has been studied for its role in modulating the function of immune cells and the inflammatory response. Similar to PADI4, PADI2's activity in immune cells can lead to the production of citrullinated proteins that may become targets of the immune response in autoimmune diseases. However, the specific implications of PADI2 in conditions like rheumatoid arthritis are less defined compared to PADI4. The ability of PADI2 to regulate protein function and interactions through citrullination also underscores its potential as a therapeutic target.

Full List of Targets in Amino Acid Delivery

For research use only. Not intended for any clinical use.