Disease relevance of sepiapterin

• CONCLUSIONS: These data indicate that exogenous administration of sepiapterin or MH4 restores the response to endothelium-dependent vasodilators in pig coronary arterioles after ischemia/ reperfusion [1].
• The BH4 toxicity was initiated extracellularly, because elevation of intracellular BH4 by sepiapterin did not result in cell damage [2].
• A novel type of NADPH-dependent sepiapterin reductase, which catalysed uniquely the reduction of sepiapterin to l-threo-dihydrobiopterin, was purified 533-fold from the cytosolic fraction of Chlorobium tepidum, with an overall yield of 3% [3].
• Production of sepiapterin in Escherichia coli by coexpression of cyanobacterial GTP cyclohydrolase I and human 6-pyruvoyltetrahydropterin synthase [4].
• Oral dietary supplementation with sepiapterin had no effect on glucose, triglyceride, cholesterol levels and body weight [5].

High impact information on sepiapterin

• Genetic suppression was studied in the purple mutant of Drosophila melanogaster and in suppressed purple by measurement of sepiapterin synthase activity [6].
• We show here that sepiapterin synthase activity is 30 percent of normal in pr and prbw, two naturally occurring alleles of purple, and is restored to nearly normal levels by the suppressor su(s)2 [7].
• As after ischemia/reperfusion, incubation of control vessels with 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, decreased endothelium-dependent vasodilation, which was restored in the presence of sepiapterin or MH4 [1].
• In a Chinese hamster ovary cell mutant lacking dihydrofolate reductase (DUKX-B11), endogenous formation of BH4 proceeds normally but, unlike the parent cells, these cells or extracts of them do not convert sepiapterin or 7,8-dihydrobiopterin to BH4 [8].
• In supernatant fractions of bovine adrenal medulla, the conversion of sepiapterin to BH4 is completely inhibited by methotrexate [8].

Chemical compound and disease context of sepiapterin

• The E. coli transformant produced sepiapterin, which was identified by high-performance liquid chromatography and enzymatically converted to dihydrobiopterin by sepiapterin reductase [4].
• Escherichia coli 6-pyruvoyltetrahydropterin synthase ortholog encoded by ygcM has a new catalytic activity for conversion of sepiapterin to 7,8-dihydropterin [9].
• Our analysis of the pteridine content in the integument of this phenotype revealed a significant change in sepiapterin content per body weight with age [10].
• The deduced amino acid sequence had marked homologies to the Bacillus subtilis yueD protein (41% identity), the yeast open reading frame YIR036C protein (31%), and the mammalian sepiapterin reductases (28% to 30%), suggesting that benzil reductase is a novel short-chain de-hydrogenases/ reductase [11].
• Structural elucidation of an intensely blue fluorescent compound (A) formed from sepiapterin by Bacillus subtilis is described [12].

Biological context of sepiapterin

• Increasing the intracellular BH4 levels by sepiapterin supplementation restored the nNOS activity, inhibited superoxide formation, increased proteasome activity, decreased protein ubiquitination, and attenuated apoptosis in MPP+-treated cells [13].
• However, further cell cycle analysis shows that the inhibition of cell differentiation by 7,8-BH2 and sepiapterin may not be due to the reversal of cell proliferation [14].
• The N-terminal amino acid sequence was revealed as Met-Lys-His-Ile-Leu-Leu-Ile-Thr-Gly-Ala-Xaa-Lys - Lys - Ile - Xaa - Arg - Ala - Ile - Ala - Leu - Glu - Xaa - Ala - Arg - Xaa-Xaa-Xaa-His-His-His-, which shared relatively high sequence similarity with other sepiapterin reductases [3].
• These results indicate that sepiapterin improves endothelial dysfunction in SMA from db/db mice by reducing oxidative stress [5].
• Furthermore, the addition of BH(4) or sepiapterin to DAHP-pretreated V146 and V1-69 cells restored cell viability [15].

Anatomical context of sepiapterin

• Addition of sepiapterin or N-acetylserotonin had no consistent effect on total extractable tyrosine hydroxylase activity or on catecholamine content in the cultured chromaffin cells [16].
• Both spontaneous inhibition and IFN-gamma-induced inhibition of Plasmodium yoelii-infected murine hepatocytes were increased with the addition of the NO synthase cofactor tetrahydrobiopterin, or sepiapterin, which is converted to tetrahydrobiopterin [17].
• Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice [5].
• An exogenous supply of tetrahydrobiopterin through sepiapterin led to a further increase of nitric oxide production, even in fully activated macrophages [18].
• In both cases, the Michaelis constants for sepiapterin and NADPH were essentially equal; 20 microM and 6 microM respectively for stimulated mononuclear blood cells and 22 microM and 5 microM respectively for amniotic fibroblasts [19].

Associations of sepiapterin with other chemical compounds

• The amounts of sepiapterin and red pteridine eye pigments (drosopterins) in Drosophila melanogaster are known to be reduced in the purple mutant and restored to normal by a suppressor mutation [7].
• The swiveled sepiapterin binding results in the conversion of the side chain configuration, exposing the opposite face for hydride transfer from NADPH [20].
• Intraventricular injection of sepiapterin increased dihydro- and 5,6,7,8-tetrahydrobiopterin levels in rat brain by more than eightfold [21].
• NO synthesis was prevented by an inhibitor of GTPCH, 2,4-diamino-6-hydroxypyrimidine, and this inhibition was completely reversed by administration of sepiapterin, a substrate for BH4 synthesis via pterin salvage pathway [22].
• Dialytic perfusion of sepiapterin increased tissue levels of reduced biopterin (mainly 6R-BH4) but not the extracellular levels [23].

Gene context of sepiapterin

• Supplementing HMC with the BH4 donor sepiapterin potentiated IL-1beta/TNF-alpha-induced COX-2 expression by approximately 2-fold [24].
• In contrast, the NOS inhibitor L-NAME and the soluble guanylate cyclase inhibitor ODQ did not block sepiapterin amplification of COX-2 expression [24].
• Pretreatment of cells with sepiapterin to promote BH(4) biosynthesis or cell-permeable iron chelator and TfR antibody to prevent iron-catalyzed BH(4) decomposition inhibited MPP(+) cytotoxicity [25].
• Treatment with the GTPCH inhibitor 2,4-diamino-6-hydroxypyrimidine prevented IL-1 beta-induced NOS activity in untreated or FSH-stimulated cells, and this inhibition was completely reversed by sepiapterin, a substrate for BH4 biosynthesis, via an alternative pterin salvage pathway present in many cell types [26].
• We isolated the genes encoding yeast YIR036C protein and gerbil sepiapterin reductase, and both recombinant proteins also reduced benzil to (S)-benzoin in vitro [27].

Analytical, diagnostic and therapeutic context of sepiapterin

• Four kinds of pteridines in the integument including a yellow pigment (sepiapterin) were determined by HPLC [10].
• Additionally, using capillary electrophoresis, we provide evidence that sepiapterin is responsible for the yellow colour and blue-light induced fluorescence in zebrafish embryos [28].
• Sepiapterin did not influence vascular reactivity in the control groups [29].

References