Control Mechanism of the Formation of Neurotransmitter Monoamines by Pteridine Cofactor.

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Tetrahydrobiopterin (BH_4) is an essential cofactor of aromatic amino acid hydroxylases such as tyrosine hydroxylase and tryptophan hydroxylase which are rate-limiting enzymes in the biosyntheses of catecholamine and indolamine. Thus the change in the concetration of BH_4 in the tissue effectively controls the formation of monoamines. (1)Some secretory functions of the rat salivary gland are regulated by the sympathetic nervous system. BH_4 in salivary glands of rate were meaured by HPLC method. An apparently constant biopterin concentration was observed in the gland, during the period after maturation in sympathetic innervation of the gland and the concentration of catecholamines behaved similarly. (2)Ret liver has quite high activity of sepiapterin reductase (SPR) which is an enzyme involved in the last step of the biosynthetic pathway of BH_4.SPR activity in rat liver was transiently stimulated by the injection of glucagon. This hormonal stimulation was quite similar, in time of maximal strimulation after injection, to that of hepatic phenylalanine hydroxylase which requires BH_4 as a confactor. (3)SPR acts as a NADPH-oxidoreductase against intermediates of keto-comound in BH_4 biosynthesis to form BH_4. Besides this activity, we found that SPR has an" isomerase activity" catalyzing the conversion of 6-lactoyl tetrahydropterin (Cl'-keto PH_4) into 6-1'-hydroxy-2'-oxopropyl tetrahydropterin (C2'-keto PH_4) which are both monoketo intermediates in the biosynthetic pathway of BH_4. It was also found that the new activity was stimulated by a small amount of NADP+ or NADPH. We postulated that reduction of pyruvoyl tetrahydropterin to BH_4 by SPR involves this isomerizing reaction in its sequential reaction; i.e., pyruvoyl tetrahydropterin ->[Cl'-keto PH_4 -> C2'-keto PH_4] -> BH_4. (4)Biosynthesis of BH_4 in animals or in reaction mechanism of its last step was summarized in our revies.