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Chemical Compound Review

boranuide     boron(-1) tetrahydride anion

Synonyms: CHEBI:30157, BH4(-), AC1L1EO1, [BH4](-), tetrahydroborate(1-), ...
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Disease relevance of boranuide

  • These findings indicate that BH4 is an important mediator of eNOS regulation in diabetes and is a rational therapeutic target to restore NO-mediated endothelial function in diabetes and other vascular disease states [1].
  • Cotreatment with BH4 prevented NOS3 uncoupling and inhibited ROS, resulting in concentric nondilated hypertrophy [2].
  • We therefore conclude that ischemia/reperfusion alters the availability or production of BH4, which contributes to blunted endothelial nitroxidergic vasodilation [3].
  • All three mutations, R25Q, R16C, and K120-->Stop, affect evolutionarily conserved residues in PTPS, result in reduced enzymatic activity when reconstituted in E. coli, and are thus believed to be the molecular cause for the BH4 deficiency [4].
  • It was also shown that the BH4 domain, fused to the protein transduction domain of HIV TAT protein (TAT-BH4), efficiently prevented apoptotic cell death [5].

Psychiatry related information on boranuide


High impact information on boranuide

  • Here we report that Bcl-2 forms a tight complex with calcineurin, resulting in the targeting of calcineurin to Bcl-2 sites on cytoplasmic membranes, and show that this interaction is dependent on the BH4 domain of Bcl-2 [10].
  • The mechanism of inhibition of apoptosis by Nr13 is likely to involve a critical BH4 domain and interaction with death agonist Bax [11].
  • Tetrahydrobiopterin (BH4) is a required cofactor for eNOS activity; pharmacologic studies suggest that BH4 may mediate some of the adverse effects of diabetes on eNOS function [1].
  • We have now investigated the importance and mechanisms of BH4 availability in vivo using a novel transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, guanosine triphosphate-cyclohydrolase I (GTPCH) [1].
  • In diabetic GCH-Tg mice, superoxide production from the endothelium was markedly reduced compared with that of WT mice, endothelial BH4 levels were maintained despite some oxidative loss of BH4, and NO-mediated vasodilatation was preserved [1].

Chemical compound and disease context of boranuide

  • Basal levels of tetrahydrobiopterin and guanosine triphosphate (GTP)-cyclohydrolase (BH4 rate-limiting enzyme) expression and activity were determined in liver homogenates of control and rats with CCl4 cirrhosis [12].
  • Livers with cirrhosis showed reduced BH4 levels and decreased GTP-cyclohydrolase activity and expression, which were associated with impaired vasorelaxation to acetylcholine [12].
  • These results indicate that insulin resistance rather than hyperinsulinemia itself may be a pathogenic factor for decreased vascular relaxation through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O2- (NO/O2- imbalance), which are caused by relative deficiency of BH4 in vascular endothelial cells [13].
  • METHODS: Sapropterin hydrochloride, an active analogue of BH4 (2 mg/kg body weight), was administered orally to healthy male smokers and age-matched nonsmokers [14].
  • Implications of BH4 depletion in dopaminergic cells and sepiapterin supplementation to augment the striatal nNOS activity in the pathogenesis mechanism and treatment of Parkinson disease are discussed [15].

Biological context of boranuide


Anatomical context of boranuide

  • We found there are two BH4 pools in hepatocytes, one that is metabolically available (free BH4) and one that is not (bound BH4) [20].
  • Furthermore, BH4 oligopeptides of Bcl-2 and Bcl-x(L), but not mutant peptides, were able to inhibit both VDAC activity on liposomes even in the presence of Bax and apoptotic Deltapsi loss in isolated mitochondria [5].
  • Here we investigated the biochemical role of the conserved N-terminal homology domain (BH4) of Bcl-x(L), which has been shown to be essential for inhibition of apoptosis, with respect to the regulation of mitochondrial membrane permeability and found that BH4 was required for Bcl-x(L) to prevent cytochrome c release and Deltapsi loss [5].
  • In contrast to cells transduced with only TH, doubly transduced fibroblasts spontaneously produced both BH4 and 3, 4-dihydroxy-L-phenylalanine [21].
  • Thus, glucocorticoids regulate NOx production following cytokine exposure in cardiac microvascular endothelial cells primarily by limiting BH4 and L-arginine availability [22].

Associations of boranuide with other chemical compounds

  • Interconversion of activated and unactivated PAH and bound and free BH4 is driven by phenylalanine; and free BH4 concentration is determined by the state of activation and activity of PAH [20].
  • The most frequent form of this cofactor deficiency is due to lack of 6-pyruvoyl-tetrahydropterin synthase (PTPS) activity, the second enzyme in the biosynthetic pathway for BH4 [4].
  • The data show low brain levels of BH4, catecholamines, serotonin, and their metabolites together with low levels of tyrosine hydroxylase protein within the striatum [23].
  • Reconstitution with the exogenous BH4 substrate, sepiapterin, restored NO formation and inhibited exocytosis [24].
  • It is also the first enzyme of the biopterin (BH4) pathway in Homo sapiens, where it is encoded by a homologous folE gene [25].

Gene context of boranuide

  • Boo also has an N-terminal region with strong homology to the BH4 domain found to be important for the function of some anti-apoptotic Bcl-2 homologues [26].
  • A study using VDAC liposomes revealed that Bcl-x(L), but not Bcl-x(L) lacking the BH4 domain, inhibited VDAC activity [5].
  • BH4 exerted dose-dependent inhibition of the O-2 signals generated by eNOS [27].
  • Replacement of the BCL-2 BH4 domain with the related BCL-XL BH4 sequence resulted in a switch of FDCP-Mix BCL-2 cells to erythroid fate accompanied by persistence of Raf-1 protein expression [28].
  • This structural model provides a frame for understanding the specific interactions of TPH with L-tryptophan and substrate analogues, BH4 and cofactor analogues, L-DOPA and catecholamines [29].

Analytical, diagnostic and therapeutic context of boranuide

  • Antibody epitope mapping revealed that cleavage occurred at one or two target sites for caspases within the amino acid region YEWD31 (downward arrow) AGD34 (downward arrow) A, removing the N-terminal BH4 region known to be essential for the death-protective activity of Bcl-2 [30].
  • Because endothelial NO synthesis depends on the cofactor tetra-hydrobiopterin (BH4), we hypothesized that depletion of this cofactor underlies the reduction of endothelium-dependent dilation in reperfusion injury [3].
  • To determine the role of BH4 in gene therapy, fibroblast cells transduced with the gene for TH were additionally modified with the gene for GTP cyclohydrolase l; an enzyme critical for BH4 synthesis [21].
  • Microdialysis experiments indicated that only those lesioned animals that received the mixture of MD-TH and MD-GTPCHI vector displayed BH4 independent in vivo L-DOPA production (mean approximately 4-7 ng/ml) [31].
  • Analysis of macrophage cell extracts, using high performance liquid chromatography with electrochemical detection, showed that BH4 was present at 17 pmol/10(6) cells or 2.1 microM in macrophage supernatant [32].


  1. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. Alp, N.J., Mussa, S., Khoo, J., Cai, S., Guzik, T., Jefferson, A., Goh, N., Rockett, K.A., Channon, K.M. J. Clin. Invest. (2003) [Pubmed]
  2. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. Takimoto, E., Champion, H.C., Li, M., Ren, S., Rodriguez, E.R., Tavazzi, B., Lazzarino, G., Paolocci, N., Gabrielson, K.L., Wang, Y., Kass, D.A. J. Clin. Invest. (2005) [Pubmed]
  3. Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin. Tiefenbacher, C.P., Chilian, W.M., Mitchell, M., DeFily, D.V. Circulation (1996) [Pubmed]
  4. Hyperphenylalaninemia due to defects in tetrahydrobiopterin metabolism: molecular characterization of mutations in 6-pyruvoyl-tetrahydropterin synthase. Thöny, B., Leimbacher, W., Blau, N., Harvie, A., Heizmann, C.W. Am. J. Hum. Genet. (1994) [Pubmed]
  5. BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Shimizu, S., Konishi, A., Kodama, T., Tsujimoto, Y. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Effects of electroconvulsive shock on tetrahydrobiopterin and GTP-cyclohydrolase activity in the brain and adrenal gland of the rat. Hossain, M.A., Masserano, J.M., Weiner, N. J. Neurochem. (1992) [Pubmed]
  7. Tetrahydrobiopterin, a cofactor for NOS, improves endothelial dysfunction during chronic alcohol consumption. Sun, H., Patel, K.P., Mayhan, W.G. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  8. CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome. Earley, C.J., Hyland, K., Allen, R.P. Mov. Disord. (2001) [Pubmed]
  9. Evaluation of tetrahydrobiopterin (BH4) as a potential therapeutic agent to treat erectile dysfunction. Sommer, F., Klotz, T., Steinritz, D., Bloch, W. Asian J. Androl. (2006) [Pubmed]
  10. Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. Shibasaki, F., Kondo, E., Akagi, T., McKeon, F. Nature (1997) [Pubmed]
  11. Role of Nr13 in regulation of programmed cell death in the bursa of Fabricius. Lee, R.M., Gillet, G., Burnside, J., Thomas, S.J., Neiman, P. Genes Dev. (1999) [Pubmed]
  12. The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis. Matei, V., Rodríguez-Vilarrupla, A., Deulofeu, R., Colomer, D., Fernández, M., Bosch, J., Garcia-Pagán, J.C. Hepatology (2006) [Pubmed]
  13. Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2- imbalance in insulin-resistant rat aorta. Shinozaki, K., Kashiwagi, A., Nishio, Y., Okamura, T., Yoshida, Y., Masada, M., Toda, N., Kikkawa, R. Diabetes (1999) [Pubmed]
  14. Tetrahydrobiopterin restores endothelial function in long-term smokers. Ueda, S., Matsuoka, H., Miyazaki, H., Usui, M., Okuda, S., Imaizumi, T. J. Am. Coll. Cardiol. (2000) [Pubmed]
  15. Sepiapterin attenuates 1-methyl-4-phenylpyridinium-induced apoptosis in neuroblastoma cells transfected with neuronal NOS: role of tetrahydrobiopterin, nitric oxide, and proteasome activation. Shang, T., Kotamraju, S., Zhao, H., Kalivendi, S.V., Hillard, C.J., Kalyanaraman, B. Free Radic. Biol. Med. (2005) [Pubmed]
  16. The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4. Huang, D.C., Adams, J.M., Cory, S. EMBO J. (1998) [Pubmed]
  17. Bcl-2 Phosphorylation by p38 MAPK: identification of target sites and biologic consequences. De Chiara, G., Marcocci, M.E., Torcia, M., Lucibello, M., Rosini, P., Bonini, P., Higashimoto, Y., Damonte, G., Armirotti, A., Amodei, S., Palamara, A.T., Russo, T., Garaci, E., Cozzolino, F. J. Biol. Chem. (2006) [Pubmed]
  18. The hydroxylation of phenylalanine and tyrosine by tyrosine hydroxylase from cultured pheochromocytoma cells. Ribeiro, P., Pigeon, D., Kaufman, S. J. Biol. Chem. (1991) [Pubmed]
  19. Subunit interactions of endothelial nitric-oxide synthase. Comparisons to the neuronal and inducible nitric-oxide synthase isoforms. Venema, R.C., Ju, H., Zou, R., Ryan, J.W., Venema, V.J. J. Biol. Chem. (1997) [Pubmed]
  20. Coordinate regulation of tetrahydrobiopterin turnover and phenylalanine hydroxylase activity in rat liver cells. Mitnaul, L.J., Shiman, R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  21. Double transduction with GTP cyclohydrolase I and tyrosine hydroxylase is necessary for spontaneous synthesis of L-DOPA by primary fibroblasts. Bencsics, C., Wachtel, S.R., Milstien, S., Hatakeyama, K., Becker, J.B., Kang, U.J. J. Neurosci. (1996) [Pubmed]
  22. Glucocorticoids regulate inducible nitric oxide synthase by inhibiting tetrahydrobiopterin synthesis and L-arginine transport. Simmons, W.W., Ungureanu-Longrois, D., Smith, G.K., Smith, T.W., Kelly, R.A. J. Biol. Chem. (1996) [Pubmed]
  23. The hph-1 mouse: a model for dominantly inherited GTP-cyclohydrolase deficiency. Hyland, K., Gunasekara, R.S., Munk-Martin, T.L., Arnold, L.A., Engle, T. Ann. Neurol. (2003) [Pubmed]
  24. Tetrahydrobiopterin, a critical factor in the production and role of nitric oxide in mast cells. Gilchrist, M., Hesslinger, C., Befus, A.D. J. Biol. Chem. (2003) [Pubmed]
  25. Discovery of a new prokaryotic type I GTP cyclohydrolase family. El Yacoubi, B., Bonnett, S., Anderson, J.N., Swairjo, M.A., Iwata-Reuyl, D., de Cr??cy-Lagard, V. J. Biol. Chem. (2006) [Pubmed]
  26. Boo, a novel negative regulator of cell death, interacts with Apaf-1. Song, Q., Kuang, Y., Dixit, V.M., Vincenz, C. EMBO J. (1999) [Pubmed]
  27. Superoxide generation from endothelial nitric-oxide synthase. A Ca2+/calmodulin-dependent and tetrahydrobiopterin regulatory process. Xia, Y., Tsai, A.L., Berka, V., Zweier, J.L. J. Biol. Chem. (1998) [Pubmed]
  28. BCL-2 and BCL-XL restrict lineage choice during hematopoietic differentiation. Haughn, L., Hawley, R.G., Morrison, D.K., von Boehmer, H., Hockenbery, D.M. J. Biol. Chem. (2003) [Pubmed]
  29. A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis. Martínez, A., Knappskog, P.M., Haavik, J. Current medicinal chemistry. (2001) [Pubmed]
  30. Alphaviruses induce apoptosis in Bcl-2-overexpressing cells: evidence for a caspase-mediated, proteolytic inactivation of Bcl-2. Grandgirard, D., Studer, E., Monney, L., Belser, T., Fellay, I., Borner, C., Michel, M.R. EMBO J. (1998) [Pubmed]
  31. Characterization of intrastriatal recombinant adeno-associated virus-mediated gene transfer of human tyrosine hydroxylase and human GTP-cyclohydrolase I in a rat model of Parkinson's disease. Mandel, R.J., Rendahl, K.G., Spratt, S.K., Snyder, R.O., Cohen, L.K., Leff, S.E. J. Neurosci. (1998) [Pubmed]
  32. Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. Tayeh, M.A., Marletta, M.A. J. Biol. Chem. (1989) [Pubmed]
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