Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study numerous amino acid analyses were performed in a family with increased incidence of tumors of the sympathetic nervous system. Since in 9 respectively 10 of a total of 13 surveyed persons an elevated urinary excretion of cystathionine was demonstrated with thin layer and column chromatographic methods, this constitutes the first report on cystathioninuria in familial neuroblastoma. Two family members also presented a homocystinuria in the spontaneously voided 24-hours urine. The only person whose plasma amino acids were analysed showed nearly normal levels. After oral loading with L-methionine the urinary excretion of cystathionine raised considerably. The different reaction of the two vitamin B6-dependent enzymes, cystathionine-synthetase and cystathionase, points at a different methionine induced sensitivity. The determination of pyridoxal phosphate and pyridoxal kinase detected a vitamin B6-deficiency, which corresponded well with an increased excretion of oxalic acid and a low normal urinary taurin excretion. Therefore these alterations of the amino acids are explained and thus urinary excretion of cystathionine can be interpreted as secondary cystathioninuria. Furthermore it was possible to provoke corresponding biochemical changes by oral administration of vitamin B6 such as reduction of the cystathioninuria and disappearance of the homocystinuria. In an infant the cystathioninuria could be observed over a period for 5 months, by which a transitory deficiency of the apoenzyme appears to be unlikely. The analysis of 24 hours urine samples of a gravida showed the persistance of cystathioninuria also during pregnancy. After radiation of a 5 year old girl with ganglioneuroblastoma an increase of the urinary cystathionine excretion and a first occurrence of homocystinuria was noted. These observations give rise to various considerations. The vitamin-B6-deficiency in familial neuroblastoma supports the assumption, that also the cystathioninuria in nonhereditary cases may be caused by vitamin-B6-deficiency. Since in this family the excretion of catecholamines was examined in a prior investigation a comparison of these two studies does not support the suggestion of a direct connection between the excretion of catecholamines and cystathioninuria, as it has been assumed to occur in sporadic neuroblastoma. The vitamin-B6-deficiency as seen in this family can also be considered in relation to tumor development. In the discussion about this possibility also the appearance of cystathioninuria in other tumors of early childhood is mentioned. Furthermore the relation of vitamin B6 to teratogenesis is commented on.
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PMID:[Secondary cystathioninuria due to vitamin B 6 deficiency in familial neuroblastoma]. 96 8

The primary structure of sheep brain pyridoxal kinase has been determined by direct chemical and physical methods. The enzyme contains 312 amino acid residues with an acetylated methionine at the N-terminus, yielding a molecular mass of 34,861 Da. The functional role played by the two tryptophanyl residues in positions 52 and 244 of the polypeptide chain has been investigated by fluorescence spectroscopy. The tryptophanyl residues are not completely exposed to the rapidly relaxing solvent and they are poorly accessible to collisional quenchers. Chemical modification with NBS abolishes the catalytic activity of the kinase. The amino acid sequence of the sheep brain enzyme shows high similarity (86.2% identity) with the human pyridoxal kinase recently reported [Hanna, Turner, and Kirkness, (1997), J. Biol. Chem. 272, 10756-10760]. Comparison of the mammalian proteins with bacterial and yeast putative pyridoxal kinases retrieved from the Swiss-Prot data bank shows a low degree of overall similarity. In particular, the putative ATP-binding domain is conserved, whereas the region that appears to be crucial in the binding of the pyridoxal substrate is not. Thus, the assignment of the bacterial and yeast cDNA-deduced proteins as pyridoxal kinases should be taken with caution.
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PMID:Structure of pyridoxal kinase from sheep brain and role of the tryptophanyl residues. 1039 44

Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine (R)-roscovitine (CYC202/Seliciclib). We here report the characterization of N-&-N1, a bioisoster of roscovitine displaying improved antitumoral properties. N-&-N1 shows exquisite selectivity for CDKs, with 2- to 3-fold enhanced potency compared with (R)-roscovitine. Inhibition of retinoblastoma protein phosphorylation and RNA polymerase II Ser2 phosphorylation in neuroblastoma SH-SY5Y cells exposed to N-&-N1 indicates that N-&-N1 is able to inhibit CDKs in a cellular context. N-&-N1 also down-regulates the expression of RNA polymerase. Cocrystal structures of N-&-N1 and (R)-roscovitine in complex with CDK2/cyclin A reveal that both inhibitors adopt similar binding modes. A competitive assay shows that, compared with (R)-roscovitine, N-&-N1 has reduced affinity for Erk2 and pyridoxal kinase. N-&-N1 triggers cell death in a panel of diverse cell lines. Cell death is accompanied by events characteristic of apoptosis: cytochrome c release, activation of effector caspases, and poly(ADP-ribose) polymerase cleavage. Induction of p53 and p21CIP1 and down-regulation of the Mcl-1 antiapoptotic factor were also observed. Studies in mice show that N-&-N1 has pharmacokinetics properties similar to those of (R)-roscovitine. Altogether, these results show that analogues of (R)-roscovitine can be designed with improved antitumor potential.
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PMID:N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine. 1879 Jul 52