Tetrahydrobiopterin Salvage Pathway

The tetrahydrobiopterin (BH4) salvage pathway is a metabolic route that regenerates BH4, an essential cofactor for aromatic amino acid hydroxylases and nitric oxide synthases, from its oxidized forms. This pathway operates alongside the de novo biosynthetic pathway to maintain cellular BH4 levels, especially under conditions where oxidative stress leads to BH4 depletion. The salvage pathway primarily involves sepiapterin reductase (SR) and dihydrofolate reductase (DHFR). Defects or downregulation in components of the salvage pathway can impair endothelial function by reducing NO bioavailability. Restoration or enhancement of this pathway has therapeutic potential for cardiovascular diseases. Methotrexate inhibits DHFR activity, thus blocking the conversion steps within the salvage route.

Enhancement of BH4 synthesis via sepiapterin reductase and dihydrofolate reductase