New aspects in biopterin biosynthesis in man

Abstract

Tetrahydrobiopterin is synthesized from guanosine triphosphate (GTP)in several enzymatic steps [1,2]. Details of the pathway of the biopterin biosynthesis in mammals are still unresolved [3]. In rat and human brain the rate-limiting enzyme was GTP cyclohydrolase [2], followed by D-erythro-7,8-dihydroneopterin triphosphate synthetase. D-Erythro-7,8-dihydroneopterin triphosphate was directly converted to 'quinonoid' dihydrobiopterin by an enzyme not requiring pyridine nucleotides or other cofactors for catalytic activity [2]. This is in contrast to other results [1] demonstrating that the conversion of D-erythro-7,8- dihydroneopterin triphosphate to L-erythro-dihydrobiopterin required 3 distinct protein fractions. A Mg2+ -dependent enzyme (A2) catalyzed the conversion of D-erythro-7,8-dihydroneopterin triphosphate to an intermediateX of unknown structure proposed to be 6(1 ',2'-dioxopropyl)-7,8-dihydropterin which could be degraded to pterin and pyruvic acid [1]. A heat labile and NADPH-dependent enzyme (A1) converted X to sepiapterin. We reported in [4] that 3'-hydroxysepiapterin is excreted in small amounts in the urine of healthy individuals but it is markedly increased in patients with dihydrobiopterin-deficiency. In connection with our studies of atypical phenylketonuria, it was of interest to investigate the biopterin biosynthesis in man. These data indicate that, indeed, also in human kidney and liver, biopterin synthesis might proceed via compound X and sepiapterin.