Delivery of exogenous tetrahydrobiopterin (BH4) to cells of target organs: Role of salvage pathway and uptake of its precursor in effective elevation of tissue BH4

Hasegawa, Hiroyuki; Sawabe, Keiko; Nakanishi, Nobuo; Wakasugi, Osuke K.

doi:10.1016/j.ymgme.2005.09.002

Cited by 67 publications

(56 citation statements)

References 24 publications

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“…Interestingly, the recovering enzyme dihydrofolate reductase (DHFR) was up-rather than downregulated in STZ diabetes (Fig. 4), but was apparently unable to prevent a depletion of BH 4. This result is in line with previous observations showing that DHFR, representing part of the so-called "salvage pathway" of BH 4 , is not sufficient to counteract depletion of BH 4 [37,38]. Bearing in mind that the BH 2 levels were increased along with decreased BH 4 , the compensatory activation of the salvage pathway points towards an oxidation of tetrahydrobiopterin in STZ, most likely due to increased vascular NADPH oxidase activity as evidenced by our results (Figs.…”

Section: Vascular Dysfunction Oxidative Stress and Diabetes Mellitussupporting

confidence: 93%

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

et al. 2008

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Objective-HMG-CoA reductase inhibitors have been shown to upregulate GTP cyclohydrolase I (GTPCH-I), the key enzyme for tetrahydrobiopterin de novo synthesis and to normalize tetrahydrobiopterin levels in hyperglycemic endothelial cells. We sought to determine whether in vivo treatment with the HMG-CoA reductase inhibitor atorvastatin is able to upregulate the GTPCH-I, to recouple eNOS and to normalize endothelial dysfunction in an experimental model of diabetes mellitus.Methods and results-In male Wistar rats, diabetes was induced by streptozotocin (STZ, 60 mg/ kg). In STZ rats, atorvastatin feeding (20 mg/kg/d, 7 weeks), normalized vascular dysfunction as analyzed by isometric tension studies, levels of circulating endothelial progenitor cells (FACSanalysis), superoxide formation (assessed by lucigenin-enhanced chemiluminescence and dihydroethidium staining), vascular levels of the phosphorylated vasodilator-stimulated phosphoprotein (P-VASP), tyrosine nitration of the prostacyclin synthase, expression of GTPCH-I, dihydrofolate reductase and eNOS, translocation of regulatory NADPH oxidase subunits rac1, p47phox and p67phox (assessed by Western blot) and vascular tetrahydrobiopterin levels as measured by HPLC. Dihydroethidine staining revealed that the reduction of vascular superoxide was at least in part due to eNOS recoupling.Conclusion-HMG-CoA reductase inhibition normalizes endothelial function and reduces oxidative stress in diabetes by inhibiting activation of the vascular NADPH oxidase and by preventing

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Section: Vascular Dysfunction Oxidative Stress and Diabetes Mellitussupporting

confidence: 93%

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

et al. 2008

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“…In addition, oral BH 4 may be oxidized and must be re-reduced, so this biochemistry becomes very important for the net result. It has been demonstrated that BH 2 can be more efficiently transported into cells over BH 4 , but must then be recycled back to BH 4 (51). Recently, Suckling et al (129) revealed that a novel BH 4 analog ADDP can diffuse from the plasma across cell membranes and cause vasodilatation by stimulating eNOS activity.…”

Section: The Role Of Nos Cofactor Bhmentioning

confidence: 99%

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Zhang¹,

Janssens

Wingler

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Zhang Y, Janssens SP, Wingler K, Schmidt HH, Moens AL. Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy. Am J Physiol Heart Circ Physiol 301: H634 -H646, 2011. First published May 27, 2011 doi:10.1152/ajpheart.01315.2010.-The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.endothelial nitric oxide synthase uncoupling; modulators; superoxide; tetrahydrobiopterin; enhancers; nitric oxide donors THE REVALENCE AND SEVERITY of incipient or overt cardiovascular diseases associated with reduced nitric oxide (NO) bioavailability has resulted in efforts to restore and conserve adequate NO signaling in the heart and blood vessels through therapeutic interventions. In the cardiovascular system, the signaling molecule NO, which is produced by the enzyme endothelial NO synthase (eNOS, NOS3), has a crucial role in maintaining normal vascular function, mediated by its vasodilating capacity and through a variety of antiatherogenic effects. eNOS is not only expressed in endothelial cells of the heart and blood vessels, in both atrial and ventricular myocytes, but also in specialized pacemaker tissue.Uncoupling of bioactive, i.e., dimeric eNOS to an inactive monomeric form (73) is caused by oxidative stress, which reduces the bioavailability of tetrahydrobiopterin (BH 4 ), an essential cofactor of eNOS. In this uncoupled state, NADPH consumption and oxygen reduction are uncoupled from L-arginine oxidation and NO formation with a subsequently decreased NO production and increased superoxide generation (157). eNOS generated superoxide, further oxidizes BH 4 , and hence enhances the uncoupling of eNOS. However, it is unclear which source of superoxide initiates eNOS uncoupling.Uncoupling of eNOS has been described in 1) situations associated with endothelial dysfunction such as atherosclerosis (3, 70), diabetes mellitus (135), ischemia-reperfusion (I/R) injury (35,138), hypertension (68), and chronic flow overload (78); 2) cardiac hypertrophy with ventricular remodeling (133); and 3) diastolic heart failure (149). eNOS also uncouples physiologically. For example, eNOS may uncouple postnatal in the lung, possibly leading to a developmental adaptation of the pulmonary vascular system to produce reactive oxygen species (ROS) (81). In addition, it ...

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“…Interestingly, studies show that exogenously administered BH4 is primarily oxidized to BH2 in the body through an ill-defined mechanism before being taken up by tissue and reduced back to BH4 (38), underlining the importance of DHFR in limiting the accumulation of oxidized biopterin.…”

Section: Tgt Inactivation Does Not Affect Pah Expression or Activity mentioning

confidence: 99%

Queuosine Deficiency in Eukaryotes Compromises Tyrosine Production through Increased Tetrahydrobiopterin Oxidation

Rakovich

Boland

Bernstein

et al. 2011

Journal of Biological Chemistry

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Queuosine is a modified pyrrolopyrimidine nucleoside found in the anticodon loop of transfer RNA acceptors for the amino acids tyrosine, asparagine, aspartic acid, and histidine. Because it is exclusively synthesized by bacteria, higher eukaryotes must salvage queuosine or its nucleobase queuine from food and the gut microflora. Previously, animals made deficient in queuine died within 18 days of withdrawing tyrosine, a nonessential amino acid, from the diet (Marks, T., and Farkas, W. R. (1997) Biochem. Biophys. Res. Commun. 230, 233-237). Here, we show that human HepG2 cells deficient in queuine and mice made deficient in queuosine-modified transfer RNA, by disruption of the tRNA guanine transglycosylase enzyme, are compromised in their ability to produce tyrosine from phenylalanine. This has similarities to the disease phenylketonuria, which arises from mutation in the enzyme phenylalanine hydroxylase or from a decrease in the supply of its cofactor tetrahydrobiopterin (BH4). Immunoblot and kinetic analysis of liver from tRNA guanine transglycosylase-deficient animals indicates normal expression and activity of phenylalanine hydroxylase. By contrast, BH4 levels are significantly decreased in the plasma, and both plasma and urine show a clear elevation in dihydrobiopterin, an oxidation product of BH4, despite normal activity of the salvage enzyme dihydrofolate reductase. Our data suggest that queuosine modification limits BH4 oxidation in vivo and thereby potentially impacts on numerous physiological processes in eukaryotes.Bacteria and humans have co-evolved for millennia, and many examples exist of how various symbiotic and commensal partnerships contribute to human health and nutrition ranging from the metabolism of complex carbohydrates to the provision of vital micronutrients (1). Queuosine is an example of a micronutrient, synthesized exclusively by bacteria but which, for poorly defined reasons, is utilized by almost all eukaryotic species with the exception of the baker's yeast, Saccharomyces cerevisiae (2).Bacterial queuosine biosynthesis occurs in two stages. First, a series of five enzymatic steps convert guanosine triphosphate nucleoside (GTP) to the soluble 7-aminomethyl-7-deazaguanine molecule. Subsequently, 7-aminomethyl-7-deazaguanine is inserted into the wobble position of tRNA containing a GUN consensus sequence (Tyr, Asp, Asn, and His) by means of the single enzyme species, tRNA guanine transglycosylase (TGT), and is further remodeled in situ to queuosine (3). Eukaryotes must acquire queuosine or its free nucleobase, queuine, from food and the gut microflora. Curiously, both cytosolic and mitochondrial tRNA species are modified by queuosine (2). The eukaryotic enzyme that performs this reaction, queuine tRNA ribosyltransferase, has recently been identified as a heterodimeric complex, consisting of the eukaryotic homologue of the catalytic TGT subunit and a related protein called queuine tRNA ribosyltransferase domain containing 1 (QTRTD1), both of which localize to the mitochondria (4, 5).Stu...

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Delivery of exogenous tetrahydrobiopterin (BH4) to cells of target organs: Role of salvage pathway and uptake of its precursor in effective elevation of tissue BH4

Cited by 67 publications

References 24 publications

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

Queuosine Deficiency in Eukaryotes Compromises Tyrosine Production through Increased Tetrahydrobiopterin Oxidation

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