PubMed · 16564744
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Birgit Högl. 2006-03-27. Circadian rhythms in RLS.. https://doi.org/10.1016/j.sleep.2006.01.002
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Crystal structures are reported for the endothelial nitric oxide synthase (eNOS)-arginine-CO ternary complex as well as the neuronal nitric oxide synthase (nNOS) heme domain complexed with L: -arginine and diatomic ligands, CO or NO, in the presence of the native cofactor, tetrahydrobiopterin, or its oxidized analogs, dihydrobiopterin and 4-aminobiopterin. The nature of the biopterin has no influence on the diatomic ligand binding. The binding geometries of diatomic ligands to nitric oxide synthase (NOS) follow the {MXY}(n) formalism developed from the inorganic diatomic-metal complexes. The structures reveal some subtle structural differences between eNOS and nNOS when CO is bound to the heme which correlate well with the differences in CO stretching frequencies observed by resonance Raman techniques. The detailed hydrogen-bonding geometries depicted in the active site of nNOS structures indicate that it is the ordered active-site water molecule rather than the substrate itself that would most likely serve as a direct proton donor to the diatomic ligands (CO, NO, as well as O(2)) bound to the heme. This has important implications for the oxygen activation mechanism critical to NOS catalysis.
(6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) is crucial in the hydroxylation of L-phenylalanine-, L-tyrosine-, and L-tryptophan-regulating catecholamine and serotonin synthesis as well as tyrosinase in melanogenesis. The rate-limiting step of 6BH4 de novo synthesis is controlled by guanosine triphosphate (GTP) cyclohydrolase I (GTPCHI) and its feedback regulatory protein (GFRP), where binding of L-phenylalanine to GFRP increases enzyme activities, while 6BH4 exerts the opposite effect. Earlier it was demonstrated that the human epidermis holds the full capacity for autocrine 6BH4 de novo synthesis and recycling. However, besides the expression of epidermal mRNA for GFRP, the presence of a functioning GFRP feedback has never been shown. Therefore, it was tempting to investigate whether this important mechanism is present in epidermal cells. Our results identified indeed a functioning GFRP/GTPCHI axis in epidermal keratinocytes and melanocytes in the cytosol, adding the missing link for 6BH4 de novo synthesis which in turn controls cofactor supply for catecholamine and serotonin biosynthesis as well as melanogenesis in the human epidermis. Moreover, GFRP expression and GTPCHI activities have been found in the nucleus of both cell types. The significance of this result warrants further investigation.
BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) has a circadian component with symptoms being prominent at night. The dopaminergic (DAergic) system, which plays a role in RLS, entails circadian changes that parallel RLS symptom changes. The aim of this study was to look for relative and diurnal differences in DAergic activity. PATIENTS AND METHODS: All RLS subjects were treated prior to their enrollment in the study but were all drug-free for at least 2 weeks prior to evaluation. Cerebrospinal fluid (CSF) collected at 10 p.m. was used to determine DA-related co-factors and metabolites. These were compared to CSF values collected in a previous study at 10 a.m. RESULTS: The only significant finding from the 10 p.m. samples (30 RLS; 22 control) was increased 3-ortho-methyldopa (3OMD) for RLS compared to controls. A comparison of the 10 p.m. to 10 a.m. values (16 RLS; 9 controls) showed small, non-significant diurnal changes for controls but large diurnal changes in tetrahydrobiopterin (BH4), HVA:5HIAA ratio and 3OMD for RLS, with the 10 a.m. sample showing increases in all three CSF factors compared to the 10 p.m. sample. CONCLUSIONS: The greater diurnal changes in RLS suggest greater fluctuations than normal in DAergic circadian dynamics. The increased 3OMD concentration in the absence of concurrent exogenous levodopa (l-dopa) suggests changes in synthesis or metabolism of l-dopa in RLS.