Genomes and Genes
Summary: A natural product that has been considered as a growth factor for some insects.
- Trefz F, Burton B, Longo N, Casanova M, Gruskin D, Dorenbaum A, et al. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr. 2009;154:700-7 pubmed publisher..001). No severe or serious related adverse events were observed. Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU. ..
- Thida M, Earl J, Zhao Y, Wang H, Tse C, Vickers J, et al. Effects of sepiapterin supplementation and NOS inhibition on glucocorticoid-induced hypertension. Am J Hypertens. 2010;23:569-74 pubmed publisher..ACTH- (129 +/- 4 mm Hg, NS) or dexamethasone-induced hypertension (135 +/- 3 mm Hg, NS), although plasma total biopterin concentrations were increased. NOLA increased SBP in rats prior to dexamethasone or saline treatment...
- SILBERMAN G, Fan T, Liu H, Jiao Z, Xiao H, Lovelock J, et al. Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction. Circulation. 2010;121:519-28 pubmed publisher..Cardiac oxidation, independently of vascular changes, can lead to uncoupled cardiac NOS and diastolic dysfunction. BH(4) may represent a possible treatment for diastolic dysfunction. ..
- Kim H, Ha S, Han J. Potential therapeutic applications of tetrahydrobiopterin: from inherited hyperphenylalaninemia to mitochondrial diseases. Ann N Y Acad Sci. 2010;1201:177-82 pubmed publisher..BH(4) supplementation successfully prevents the development or progression of these diseases and thus has valuable clinical potential. ..
- Maglione M, Oberhuber R, Cardini B, Watschinger K, Hermann M, Obrist P, et al. Donor pretreatment with tetrahydrobiopterin saves pancreatic isografts from ischemia reperfusion injury in a mouse model. Am J Transplant. 2010;10:2231-40 pubmed publisher..002) and improved survival and endocrine function (p = 0.0002 each). H4B donor pretreatment abrogates ischemia-induced parenchymal damage and represents a promising strategy to prevent IRI following pancreas transplantation. ..
- Sugiyama T, Levy B, Michel T. Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. J Biol Chem. 2009;284:12691-700 pubmed publisher..an enzyme-recycling oxidized BH4 (7,8-dihydrobiopterin (BH2)), and studied the effects on eNOS regulation and biopterin metabolism in cultured aortic endothelial cells...
- Noguchi K, Hamadate N, Matsuzaki T, Sakanashi M, Nakasone J, Uchida T, et al. Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo. Am J Physiol Heart Circ Physiol. 2011;301:H721-9 pubmed publisher..These results indicate, for the first time, that increasing BH(2) causes eNOS dysfunction in vivo even in the absence of BH(4) deficiency, demonstrating a novel insight into the regulation of endothelial function. ..
- Schmidt K, Neubauer A, Kolesnik B, Stasch J, Werner E, Gorren A, et al. Tetrahydrobiopterin protects soluble guanylate cyclase against oxidative inactivation. Mol Pharmacol. 2012;82:420-7 pubmed publisher..Protection of sGC against oxidative inactivation may contribute to the known beneficial effects of BH4 in cardiovascular disorders associated with oxidative stress...
- Antoniades C, Bakogiannis C, Leeson P, Guzik T, Zhang M, Tousoulis D, et al. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation. 2011;124:335-45 pubmed publisher..These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103. ..
- Watschinger K, Fuchs J, Yarov Yarovoy V, Keller M, Golderer G, Hermetter A, et al. Catalytic residues and a predicted structure of tetrahydrobiopterin-dependent alkylglycerol mono-oxygenase. Biochem J. 2012;443:279-86 pubmed publisher..Prediction of a part of the structure using the Rosetta membrane ab initio method led to a plausible suggestion for a structure of the catalytic site of alkylglycerol mono-oxygenase. ..
- Tejero J, Stuehr D. Tetrahydrobiopterin in nitric oxide synthase. IUBMB Life. 2013;65:358-65 pubmed publisher..In this review, we summarize our current knowledge about the role of tetrahydrobiopterin in the structure, function, and catalytic mechanism of NOS enzymes. ..
- Abudukadier A, Fujita Y, Obara A, Ohashi A, Fukushima T, Sato Y, et al. Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase-dependent manner in diabetic mice. Diabetes. 2013;62:3033-43 pubmed publisher..Taken together, BH4 suppresses hepatic gluconeogenesis in an eNOS-dependent manner, and BH4 has a glucose-lowering effect as well as an insulin-sensitizing effect in diabetic mice. BH4 has potential in the treatment of type 2 diabetes. ..
- Du J, Wei N, Xu H, Ge Y, Vasquez Vivar J, Guan T, et al. Identification and functional characterization of phosphorylation sites on GTP cyclohydrolase I. Arterioscler Thromb Vasc Biol. 2009;29:2161-8 pubmed publisher..Such information might be useful in designing new therapies aiming at improving BH4 bioavailability. ..
- Matei V, Rodriguez Vilarrupla A, Deulofeu R, García Calderó H, Fernandez M, Bosch J, et al. Three-day tetrahydrobiopterin therapy increases in vivo hepatic NOS activity and reduces portal pressure in CCl4 cirrhotic rats. J Hepatol. 2008;49:192-7 pubmed publisher..These data support the concept that tetrahydrobiopterin supplementation may represent a new therapeutic strategy for portal hypertension. ..
- Gersting S, Kemter K, Staudigl M, Messing D, Danecka M, Lagler F, et al. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am J Hum Genet. 2008;83:5-17 pubmed publisher..Thus, PKU has evolved from a model of a genetic disease that leads to severe neurological impairment to a model of a treatable protein-folding disease with loss of function. ..
- Sugiyama T, Michel T. Thiol-metabolizing proteins and endothelial redox state: differential modulation of eNOS and biopterin pathways. Am J Physiol Heart Circ Physiol. 2010;298:H194-201 pubmed publisher..Greater understanding of the differential regulation of thiol-metabolizing proteins may lead to the development of new pharmacological targets for diseases associated with oxidative stress in the vascular wall. ..
- Shimazu T, Otani H, Yoshioka K, Fujita M, Okazaki T, Iwasaka T. Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction. Am J Physiol Heart Circ Physiol. 2011;301:H2061-72 pubmed publisher..These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH(4) synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS. ..
- Tatham A, Crabtree M, Warrick N, Cai S, Alp N, Channon K. GTP cyclohydrolase I expression, protein, and activity determine intracellular tetrahydrobiopterin levels, independent of GTP cyclohydrolase feedback regulatory protein expression. J Biol Chem. 2009;284:13660-8 pubmed publisher..We suggest that GTPCH expression is the primary regulator of BH4 levels, and changes in GTPCH or BH4 are not necessarily accompanied by changes in GFRP expression. ..
- Masano T, Kawashima S, Toh R, Satomi Kobayashi S, Shinohara M, Takaya T, et al. Beneficial effects of exogenous tetrahydrobiopterin on left ventricular remodeling after myocardial infarction in rats: the possible role of oxidative stress caused by uncoupled endothelial nitric oxide synthase. Circ J. 2008;72:1512-9 pubmed
- Blau N, Hennermann J, Langenbeck U, Lichter Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 2011;104 Suppl:S2-9 pubmed publisher..best sample for the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), and dihydropteridine reductase activity from a single specimen...
- Moens A, Kietadisorn R, Lin J, Kass D. Targeting endothelial and myocardial dysfunction with tetrahydrobiopterin. J Mol Cell Cardiol. 2011;51:559-63 pubmed publisher..This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.'' ..
- Utz J, Lorentz C, Markowitz D, Rudser K, Diethelm Okita B, Erickson D, et al. START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients. Mol Genet Metab. 2012;105:193-7 pubmed publisher..START results were evaluated for response-genotype correlates and trends in molecular characteristics...
- Förstermann U, Sessa W. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33:829-37, 837a-837d pubmed publisher..Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins. ..
- Kar S, Kavdia M. Modeling of biopterin-dependent pathways of eNOS for nitric oxide and superoxide production. Free Radic Biol Med. 2011;51:1411-27 pubmed publisher..The importance of the ratio of BH(4) to oxidized biopterins versus absolute levels of total biopterin in determining the extent of eNOS uncoupling remains to be determined...
- Moens A, Ketner E, Takimoto E, Schmidt T, O Neill C, Wolin M, et al. Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure. J Mol Cell Cardiol. 2011;51:564-9 pubmed publisher..This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.'' ..
- Katusic Z, d Uscio L, Nath K. Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects. Trends Pharmacol Sci. 2009;30:48-54 pubmed publisher..This review also addresses the emerging roles of BH4 in the regulation of endothelial function and their therapeutic implications. ..
- Jo H, Otani H, Jo F, Shimazu T, Okazaki T, Yoshioka K, et al. Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice. Clin Exp Pharmacol Physiol. 2011;38:485-93 pubmed publisher..5. These results suggest that sepiapterin inhibits uncoupling of NOS and improves LV function presumably by increasing iNOS-derived nitric oxide in the diabetic heart. ..
- Clot F, Grabli D, Cazeneuve C, Roze E, Castelnau P, Chabrol B, et al. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia. Brain. 2009;132:1753-63 pubmed publisher..Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later. ..
- Druhan L, Forbes S, POPE A, Chen C, Zweier J, Cardounel A. Regulation of eNOS-derived superoxide by endogenous methylarginines. Biochemistry. 2008;47:7256-63 pubmed publisher..These observations have important implications with regard to the therapeutic use of l-arginine and the methylarginine-NOS inhibitors in the treatment of disease. ..
- Vladic N, Ge Z, Leucker T, Brzezinska A, Du J, Shi Y, et al. Decreased tetrahydrobiopterin and disrupted association of Hsp90 with eNOS by hyperglycemia impair myocardial ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2011;301:H2130-9 pubmed publisher..The results suggest that eNOS dysregulation may be a central mechanism of impaired cardioprotection during hyperglycemia...
- Sucher R, Gehwolf P, Oberhuber R, Hermann M, Margreiter C, Werner E, et al. Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury. Kidney Int. 2010;77:681-9 pubmed publisher..We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans. ..
- Adlam D, Herring N, Douglas G, de Bono J, Li D, Danson E, et al. Regulation of Î²-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin. Cardiovasc Res. 2012;93:694-701 pubmed publisher..GCH1 expression and BH4 are novel determinants of cardiac autonomic regulation that may have important roles in cardiovascular pathophysiology. ..
- Sawabe K, Yamamoto K, Harada Y, Ohashi A, Sugawara Y, Matsuoka H, et al. Cellular uptake of sepiapterin and push-pull accumulation of tetrahydrobiopterin. Mol Genet Metab. 2008;94:410-6 pubmed publisher..Consequently, sepiapterin was enforcedly taken up by the cell where it accumulated tetrahydrobiopterin in the cytosol in continuous manner. ..
- Kwak S, Suk J, Choi J, Yang S, Kim J, Sohn S, et al. Autophagy induction by tetrahydrobiopterin deficiency. Autophagy. 2011;7:1323-34 pubmed publisher..In addition, this study first documents mTORC1 inactivation and autophagy induction in PKU patients with BH? deficiency. ..
- Okazaki T, Otani H, Shimazu T, Yoshioka K, Fujita M, Katano T, et al. Reversal of inducible nitric oxide synthase uncoupling unmasks tolerance to ischemia/reperfusion injury in the diabetic rat heart. J Mol Cell Cardiol. 2011;50:534-44 pubmed publisher..These results suggest that the inhibition of iNOS uncoupling unmasks tolerance to I/R injury through enhanced protein S-nitrosylation in the diabetic rat heart. ..
- Xia N, Daiber A, Habermeier A, Closs E, Thum T, Spanier G, et al. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J Pharmacol Exp Ther. 2010;335:149-54 pubmed publisher..This novel mechanism (reversal of eNOS uncoupling) might contribute to the protective effects of resveratrol. ..
- Crabtree M, Tatham A, Al Wakeel Y, Warrick N, Hale A, Cai S, et al. Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression. J Biol Chem. 2009;284:1136-44 pubmed publisher..Doxycycline abolished GTPCH mRNA expression and GTPCH protein, leading to markedly diminished total biopterin levels and a decreased ratio of BH4 to oxidized biopterins in cells expressing eNOS...
- Ge Z, Ionova I, Vladic N, Pravdic D, Hirata N, Vasquez Vivar J, et al. Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia. Cardiovasc Res. 2011;91:340-9 pubmed publisher..Increased BH(4) by cardiomyocyte-specific overexpression of GTPCH-1 preserves the ability of IPC to elicit myocardial and mitochondrial protection that is impaired by HG, and this action appears to be dependent on NO. ..
- Crabtree M, Tatham A, Hale A, Alp N, Channon K. Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways. J Biol Chem. 2009;284:28128-36 pubmed publisher..In contrast to the decreased BH4:BH2 ratio induced by DHFR knockdown, GTPCH knockdown greatly reduced total biopterin levels but with no change in BH4:BH2 ratio...
- Sanchez A, CONTRERAS C, Martínez M, Climent B, Benedito S, García Sacristán A, et al. Role of neural NO synthase (nNOS) uncoupling in the dysfunctional nitrergic vasorelaxation of penile arteries from insulin-resistant obese Zucker rats. PLoS ONE. 2012;7:e36027 pubmed publisher..The present study assessed the role of oxidative stress in the dysfunctional neural vasodilator responses of penile arteries in the obese Zucker rat (OZR), an experimental model of metabolic syndrome/prediabetes...
- Noguchi K, Hamadate N, Matsuzaki T, Sakanashi M, Nakasone J, Sakanashi M, et al. Improvement of impaired endothelial function by tetrahydrobiopterin in stroke-prone spontaneously hypertensive rats. Eur J Pharmacol. 2010;631:28-35 pubmed publisher..These results demonstrate that the impaired endothelial function in SHRSP cannot be explained simply by the decrease in absolute amount of BH4...
- Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010;459:923-39 pubmed publisher..Also, dietary polyphenolic antioxidants can reduce oxidative stress, whereas clinical trials with antioxidant vitamins C and E failed to show an improved cardiovascular outcome. ..
- Crabtree M, Channon K. Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide. 2011;25:81-8 pubmed publisher..These studies indicate that not only BH4 level, but the recycling pathways regulating BH4 bioavailability represent potential therapeutic targets and will be discussed in this review. ..
- ..the exception of sepiapterin reductase and the dominant form of GTP cyclohydrolase I deficiency that results in biopterin deficiency/insufficiency only in the brain...
- Antoniades C, Shirodaria C, Van Assche T, Cunnington C, Tegeder I, Lotsch J, et al. GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. J Am Coll Cardiol. 2008;52:158-65 pubmed publisher..We examined the associations between haplotypes of the GCH1 gene, GCH1 expression and biopterin levels, and the effects on endothelial function and vascular superoxide production...
- Ziesch B, Weigel J, Thiele A, Mütze U, Rohde C, Ceglarek U, et al. Tetrahydrobiopterin (BH4) in PKU: effect on dietary treatment, metabolic control, and quality of life. J Inherit Metab Dis. 2012;35:983-92 pubmed publisher..Tetrahydrobiopterin (BH(4))-sensitive phenylketonuria (PKU) can be treated with sapropterin dihydrochloride. We studied metabolic control and health-related quality of life (HRQoL) in PKU patients treated with BH(4)...
- Watschinger K, Keller M, Golderer G, Hermann M, Maglione M, Sarg B, et al. Identification of the gene encoding alkylglycerol monooxygenase defines a third class of tetrahydrobiopterin-dependent enzymes. Proc Natl Acad Sci U S A. 2010;107:13672-7 pubmed publisher..This sequence assignment suggests that alkylglycerol monooxygenase forms a distinct third group among tetrahydrobiopterin-dependent enzymes. ..