Phosphorylation by Ca2+/calmodulin‐dependent protein kinase II and protein kinase C of sepiapterin reductase, the terminal enzyme in the biosynthetic pathway of tetrahydrobiopterin

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Abstract
Sepiapterin reductase, the terminal enzyme in the biosynthetic pathway of tetrahydrobiopterin, was stoichiometrically phosphorylated by Ca2+/calmodulin‐dependent protein kinase II and protein kinase C (Ca2+/phospholipid‐dependent protein kinase) in vitro. Maximal incorporation of phosphate into the enzyme subunit by these was 3.05 ± 0.05 (n = 4) and 0.74 ± 0.03 (n = 5) 32P mol per mol enzyme subunit, respectively. The enzyme was not phosphorylated by cyclic nucleotide‐dependent protein kinase of either the cAMP‐dependent or cGMP‐dependent type in this study. Dihydropteridine reductase, another enzyme working in direct supply of tetrahydrobiopterin, was also a good substrate for Ca2+/calmodulin‐dependent protein kinase II. Phosphorylation of sepiapterin reductase by these protein kinases modified the kinetic properties of the enzyme. It is likely that these multifunctional Ca2+‐activated protein kinases may play a role in the regulation of the physiological function of the BH4‐generating enzymes in vivo, as was previously found in the case of BH4‐requiring enzymes.