Sepiapterin reductase

Sepiapterin reductase (SPR) is a 28 kDa enzyme that catalyzes the final reduction steps in tetrahydrobiopterin (BH4) biosynthesis, producing 5,6,7,8-tetrahydrobiopterin (UniProt: P35270). BH4 is an essential cofactor for multiple biosynthetic and signaling pathways in the central nervous system. Mutations in SPR cause DOPA-responsive dystonia due to sepiapterin reductase deficiency (DRDSPRD), a neurological disorder characterized by dopamine and serotonin deficiencies, progressive motor dysfunction, and cognitive impairment (UniProt: P35270).

In Alzheimer's disease, SPR is significantly upregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2FC: 0.4247; Chaparral AD proteomics). This upregulation was observed across multiple subcellular fractions in a TMT-labeled tandem mass spectrometry analysis of four cellular compartments (P2, P3, S2, S3). The increased expression may reflect an attempt to boost BH4-dependent antioxidant or neurotransmitter synthesis pathways in response to AD-associated neurodegeneration and oxidative stress.