Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By GenBank database searches and PCR, we have identified a novel human Bcl2-like gene, Bcl2-L-10, which contains conserved BH4, BH1 and BH2 domains but lacks BH3 domain. The Bcl2-L-10 gene has been assigned to chromosome 15q21.2. Transfection experiments demonstrated that Bcl2-L-10 can block apoptosis induced by interleukin-3 withdrawal and Bax expression, by prevention of cytochrome C release, caspase-3 activation and mitochondrial membrane potential collapse. Bcl2-L-10 cannot block TNFalpha-induced apoptosis. Furthermore, both the BH4 domain and the transmembrane domain of Bcl2-L-10 are necessary for its suppressive action on cell death. Our results demonstrated that Bcl2-L-10 is a newly detected anti-apoptotic member of the Bcl-2 family and that it blocks apoptosis in the mitochondrial death pathway but not in the death receptor pathway.
Hum Mol Genet 2001 Oct 01
PMID:Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway. 1168 80

The crystal structures of the catalytic domain (DeltaN1-102/DeltaC428-452) of human phenylalanine hydroxylase (hPheOH) in its catalytically competent Fe(II) form and binary complex with the reduced pterin cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) have been determined to 1.7 and 1.5 A, respectively. When compared with the structures reported for various catalytically inactive Fe(III) forms, several important differences have been observed, notably at the active site. Thus, the non-liganded hPheOH-Fe(II) structure revealed well defined electron density for only one of the three water molecules reported to be coordinated to the iron in the high-spin Fe(III) form, as well as poor electron density for parts of the coordinating side-chain of Glu330. The reduced cofactor (BH4), which adopts the expected half-semi chair conformation, is bound in the second coordination sphere of the catalytic iron with a C4a-iron distance of 5.9 A. BH4 binds at the same site as L-erythro-7,8-dihydrobiopterin (BH2) in the binary hPheOH-Fe(III)-BH2 complex forming an aromatic pi-stacking interaction with Phe254 and a network of hydrogen bonds. However, compared to that structure the pterin ring is displaced about 0.5 A and rotated about 10 degrees, and the torsion angle between the hydroxyl groups of the cofactor in the dihydroxypropyl side-chain has changed by approximately 120 degrees enabling O2' to make a strong hydrogen bond (2.4 A) with the side-chain oxygen of Ser251. Carbon atoms in the dihydroxypropyl side-chain make several hydrophobic contacts with the protein. The iron is six-coordinated in the binary complex, but the overall coordination geometry is slightly different from that of the Fe(III) form. Most important was the finding that the binding of BH4 causes the Glu330 ligand to change its coordination to the iron when comparing with non-liganded hPheOH-Fe(III) and the binary hPheOH-Fe(III)-BH2 complex.
J Mol Biol 2001 Nov 23
PMID:High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin. 1171 61

Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase as well as a cofactor of aromatic amino acid hydroxylases. However, its role in pregnancy is not yet understood. We evaluated the concentrations of BH4 throughout normal pregnancy and puerperium, and compared them with those of non-pregnant women by measuring its oxidation product biopterin. In addition, we also measured 6-pyruvoyl tetrahydropterin synthase (PTPS) activities, the rate-limiting enzyme in synthesizing BH4, in pregnant women at the 30th gestational week and non-pregnant women. Although the urinary biopterin levels did not remarkably change, plasma biopterin levels significantly decreased from the 10th gestational week to the 1st day of postpartum compared with those of non-pregnant women. There was no significant difference in PTPS activities between pregnant and non-pregnant women. However, the proportion of reticulocytes, which have been shown to possess high PTPS activity, is significantly higher in pregnant women than in non-pregnant women. Our results suggest that decreased plasma BH4 levels in pregnancy is caused by impaired PTPS activity.
Int J Mol Med 2002 Jan
PMID:Decreased plasma tetrahydrobiopterin in pregnant women is caused by impaired 6-pyruvoyl tetrahydropterin synthase activity. 1174 95

The activity and expression of nitric oxide synthase (NOS) isoforms and protein nitrotyrosine (NT) residues were investigated in whole encephalic mass (WEM) homogenates during the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. EAE stages (0-III) were daily defined by clinical evaluation, and in the end of each stage, WEMs were removed for analysis of NOS activity, protein NT residues and mRNA for the different NOS isoforms. In the presence of NADPH, WEMs from EAE-III rats showed lower Ca2+-dependent NOS activity than those from control group. These differences disappeared in the presence of exogenous calmodulin, flavin adenine dinucleotide (FAD), tetrahydrobiopterin (BH4) and NADPH. Of all the cofactors, just the omission of FAD caused comparable decrease of Ca2+-dependent NOS activity from both groups. Ca2+-independent NOS activity from EAE-III animals was insensitive to the omission of any of the cofactors, while in control animals this activity was significantly inhibited by the omission of either FAD or BH4. Increased levels of both iNOS mRNA and protein NT expression were observed in animals with EAE, which also showed lower levels of a thermolabile NOS inhibitor in WEM homogenates and sera than controls. In conclusion, during late EAE stages, constitutive Ca2+-dependent NOS activity decreases concomitantly with iNOS upregulation, which could be responsible for the high protein NT levels. The differential dependence of iNOS activity on cofactors and the absence of an endogenous thermolabile NOS inhibitor in animals with EAE could reflect additional control mechanisms of NOS activity in this model of multiple sclerosis.
Brain Res Mol Brain Res 2002 Feb 28
PMID:Expression and activity of nitric oxide synthase isoforms in rat brain during the development of experimental allergic encephalomyelitis. 1186 4

A 25-year-old woman with mild hyperphenylalaninemia developed disabling depression and panic attacks. The mutations on the phenylalanine hydroxylase gene indicated that she might be responsive to tetrahydrobiopterin therapy. Mutation analyses were performed by the John F. Kennedy Institute in Glostrup, Denmark. The response to tetrahydrobiopterin therapy was impressive at an oral dose of 50 mg twice a day. A 25-year-old woman with mild hyperphenylalaninemia due to a PAH mutation of IVS12nt1g-->a/E390G has been treated for 1 year with BH4 therapy. A maintenance dosage of only 100 mg/day has resulted in significant improvement of depression and panic attacks, with discontinuation of psychotropic medication.
Mol Genet Metab 2002 Mar
PMID:Mental illness in mild PKU responds to biopterin. 1191 42

Molecular cloning and nucleotide sequencing of cDNA encoding Bombyx mori nitric oxide synthase (BmNOS) was conducted to analyse its possible role in insect immunity. The amino acid sequence deduced from the BmNOS cDNA showed 84%, 54% and 53% identity with those of NOSs from Manduca sexta, Drosophila melanogaster and Rhodonius prolixus. Recombinant BmNOS produced in insect cells using baculovirus was found to require NADPH, Ca2+, calmodulin and tetrahydrobiopterin (BH4) for its activity. The BmNOS gene was constitutively expressed at a low level in the larval fat body, haemocyte, Malpighian tubule and midgut, and adult antenna, and induced strongly in the fat body by lipopolysaccharide (LPS), suggesting that the BmNOS gene plays different physiological roles in different tissues. Injection of NO donors that produce NO in vivo induced the gene expression of an antibacterial peptide, cecropin B, strongly suggesting that NO produced by BmNOS following LPS stimulation is involved in signal transduction as a signalling molecule for immune gene expression.
Insect Mol Biol 2002 Jun
PMID:cDNA cloning, characterization and gene expression of nitric oxide synthase from the silkworm, Bombyx mori. 1200 Jun 45

Hyperphenylalaninemia (HPA), due to a deficiency of phenylalanine hydroxylase (PAH) enzyme, is caused by mutations in the PAH gene. Molecular analysis in 23 Italian patients with PAH deficiency identified two novel (P281R, L287V) and 20 previously described genetic lesions in the PAH gene. The detection of the A403V amino acid substitution in combination with null mutations in patients with BH4-responsive PAH deficiency leads us to correlate it with BH4 responsiveness.
Mol Genet Metab 2002 Nov
PMID:Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in Italian patients with hyperphenylalaninemia. 1240 76

Since 1999 an increasing number of patients with phenylalanine hydroxylase (PAH) deficiency are reported to be able to decrease their plasma phenylalanine (Phe) concentrations after a 6R-tetrahydrobiopterin (BH(4)) challenge. The majority of these patients have mild PKU or MHP (mild hyperphenylalaninemia) and harbour at least one missense mutation in the PAH gene associated with this phenotype. The rate of decrease and the lowest achieved Phe level vary between patients with different genotypes but appears to be similar in patients with the same genotype. A number of the mutations associated with BH(4)-responsiveness have been studied in an 'in vitro' eukaryotic cell expression system leading to biosynthesis of a mutant PAH enzyme with some residual activity. Patients bearing mutations that cause severe structural distortion in the expressed protein (loss of function mutations), leading to undetectable PAH activity, are not responsive to BH(4). These observations suggest that residual PAH activity (in vitro) is a prerequisite for BH(4)-responsiveness. However, an in vitro residual PAH activity is not a guarantee for in vivo BH(4)-responsiveness. Mechanisms behind this responsiveness could be relieve of decreased binding affinity for BH(4), BH(4)-mediated increase of PAH gene expression or stabilization of the mutant enzyme protein by BH(4). BH(4)-responsive PAH-deficient patients have only been reported since 1999. For the western countries this is explained by the fact that the manufacturer changed the diastereoisomeric purity of the BH4 preparation from 69% of the natural 6R-BH4 (31% of 6S-BH4) to 99.5% 6R-BH4. The new findings on BH(4)-responsiveness may be of clinical relevance because these patients can be treated with BH(4) with concomitant relief or withdrawal of the burdensome PKU diet. These observations warrant further clinical studies to assess efficacy, optimal dosage, and safety of BH(4) treatment in this group. The data strongly emphasize the necessity of the BH(4) loading test in patients detected in the newborn PKU screening.
Mol Genet Metab 2003 Feb
PMID:Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, state of the art. 1261 80

The normal mode frequencies and corresponding vibrational assignments of of hafnium tetrahydroborate in T symmetry are examined theoretically using the Gaussian 98 set of quantum chemistry codes. All normal modes were successfully assigned to one of to one of six types of motion (B-H stretch, Hf-B stretch, B-Hf-B bend, H-B-H bend, BH4 wag, and BH4 twist) predicted by a group theoretical analysis. By comparing the vibrational frequencies with IR and Raman spectra available in the literature, a set of scaling factors is derived. Theoretical IR and Raman intensities are reported. Quantum chemical calculations predict that the molecule does not possess strict Td symmetry. The Td structure possesses one negative eigenvalue. The minimum energy structure possesses T symmetry.
Spectrochim Acta A Mol Biomol Spectrosc 2003 Jan 15
PMID:Vibrational frequencies and structural determination of hafnium tetrahydroborate. 1268 12

The normal mode frequencies and corresponding vibrational assignments of aluminum tetrahydroborate in D3 symmetry are examined theoretically using the 98 set of quantum chemistry codes. All normal modes were successfully assigned to one of seven types of motion (B-H stretch, Al-B stretch, B-Al-B bend, H-B-H bend, BH4 wag, BH4 rock, and BH4 twist) predicted by a group theoretical analysis. By comparing the vibrational frequencies with infrared and Raman spectra available in the literature, a set of scaling factors is derived. Theoretical infrared intensities and Raman activities are reported.
Spectrochim Acta A Mol Biomol Spectrosc 2003 May
PMID:Vibrational frequencies and structural determination of aluminum tetrahydroborate. 1271 80


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