[Role of tetrahydrobiopterin in the regulation of activity of human placental nitric oxide synthase in normal and pre-eclamptic pregnancies].

The discovery of nitrogen monoxide (NO), the structurally simplest signal molecule has motivated intensive research work in medical biochemistry. Among the enzymes synthesizing NO, the type III isoform (or endothelial NO-synthase) is produced by the syncytiotrophoblasts of human placenta and the endothelial cells of placental and umbilical blood vessels. In this paper some of the characteristic molecular properties and certain evident or putative physiological roles of NO-synthase III (NOS III) as well as those experimental results of the author's group that demonstrate the concept of dual regulation of placental NOS III activity by Ca2+ and tetrahydrobiopterin (BH4) are reviewed. BH4 promotes the formation of the enzymatically active stable homodimeric structure of NOS III. In addition, BH4 remains bound to the enzyme during the catalytic cycle and takes part in the electron transfer necessary for NO synthesis. Work of the author's group and data from the literature indicate that BH4 is bound tightly to one of the subunits of the homodimeric enzyme, whereas the binding affinity to the second binding site (which is present on the second subunit) is markedly smaller. Tightly and loosely bound BH4 molecules are supposed to ensure the basal and the BH4-regulated enzyme activities, respectively. In first trimester placentae NOS III exhibits 42-81% of the BH4-dependent maximal activity, whereas in terminal placentae this value falls to 16-59%. BH4 concentrations of individual placentae are variable and as a rule, it decreases during pregnancy together with a decrease of enzyme concentration. Studies of the author's group indicate that in some of the preeclamptic pregnant women, activation of placental NOS III by physiological concentrations of BH4 is not detectable while the basal activity of the enzyme remains unchanged. Mechanisms that can explain how the malfunction of placental NOS III might be involved in the pathogenesis of preeclampsia are discussed.