Sepiapterin acts through a dual mechanism to enhance the activity of phenylalanine hydroxylase (PAH), an enzyme critical for metabolizing the amino acid phenylalanine (Phe).
- Conversion to Tetrahydrobiopterin (BH4):
- Sepiapterin serves as a precursor to BH4, a vital cofactor for PAH. By increasing BH4 availability, sepiapterin stabilizes and enhances PAH function, facilitating the conversion of phenylalanine to tyrosine.
- BH4 also acts as a cofactor for nitric oxide synthase (NOS) and other enzymes involved in aromatic amino acid metabolism, further supporting metabolic homeostasis.
- Chaperone Effect:
- Sepiapterin exhibits an independent chaperone function, protecting PAH from misfolding and degradation. This molecular chaperone activity ensures proper PAH folding and enzymatic activity, even in conditions where PAH mutations or deficiencies impair its function.
- Impact on Neurotransmitter Synthesis:
- By promoting PAH activity, sepiapterin reduces blood phenylalanine levels, which is particularly beneficial in phenylketonuria (PKU), a genetic disorder characterized by toxic phenylalanine accumulation.
- Lowering phenylalanine levels mitigates neurological damage associated with PKU, including intellectual disability, seizures, and behavioral issues.
- Immunometabolic Regulation:
- Emerging research suggests sepiapterin-derived BH4 influences immune cell metabolism. For example, in HER2-positive breast cancer models, sepiapterin reprograms tumor-associated macrophages (TAMs) from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype, enhancing antitumor immunity.
Clinical Implications:
- PKU Treatment: Sepiapterin is under development (e.g., PTC Therapeutics’ NDA submission to the FDA) as a potential therapy for PKU, aiming to address unmet medical needs by targeting the root cause of phenylalanine toxicity.
- Cancer Prevention: Its role in modulating immunometabolic pathways offers therapeutic potential beyond PKU, particularly in cancers where metabolic reprogramming is a hallmark.
