Sepiapterin reductase (SPR)

Sepiapterin reductase is a cytosolic enzyme that catalyzes the terminal reduction steps required for synthesizing tetrahydrobiopterin (BH4), a critical cofactor necessary for aromatic amino acid hydroxylases involved in producing key neurotransmitters like dopamine, norepinephrine, epinephrine, and serotonin. It belongs structurally to the short-chain dehydrogenases/reductases family with conserved active site residues facilitating NADPH-dependent reduction reactions on pterins. Deficiency leads to severe neurological symptoms due to disrupted monoamine neurotransmitter biosynthesis but does not cause hyperphenylalaninemia unlike other BH4 pathway defects because phenylalanine metabolism remains intact. The enzyme has emerging significance as a therapeutic target—especially peripherally—for conditions such as chronic pain without central side effects seen with global inhibition; it is also implicated more broadly across cardiovascular diseases and cancer biology through its regulatory role over cellular redox state and NO signaling pathways.[1][2][3][4][6]

Other names

SPRSDR38C1Sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming)Short chain dehydrogenase/reductase family 38C, member 1[7]Dopa-responsive dystonia due to sepiapterin reductase deficiency (disease context)[3][9]SPR deficiency[3][9]

Drugs or inhibitors targeting sepiapterin reductase act by blocking the final step in tetrahydrobiopterin biosynthesis, thereby reducing BH4 levels. This can decrease excessive neurotransmitter synthesis or modulate immune responses depending on tissue distribution.[2][6] Inhibitors may also block both the enzyme's reductive activity on pterins and its isomerization function.[2]