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1.
World J Biol Psychiatry ; 10(4 Pt 3): 893-9, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18979283

RESUMO

Bipolar affective disorder is a chronic, severe, debilitating illness affecting 1-2% of the population. Valproate, along with lithium and carbamazepine, are the only drugs for which long-term efficacy has been established. However, these drugs are ineffective for, and not well tolerated by, a large number of patients and are also associated with teratogenicity and reproductive defects. Therefore, there is a substantial need to develop more effective anti-bipolar drugs. We have previously shown that valproate, like lithium, decreases intracellular inositol, which supports the inositol depletion hypothesis. We employed inositol depletion in yeast as a screening tool to identify potential new anti-bipolar medications. We show here that hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, ethylhexanoate, and methyloctanoate decrease intracellular inositol levels and increase the expression of INO1, the gene encoding myo-inositol-3-phosphate synthase (MIPS). Similar to valproate, these inositol-depleting carboxylic acids inhibited MIPS indirectly. A correlation was shown between cell growth inhibition and the increase in INO1 expression by the carboxylic acids, factors that were reversed in the presence of inositol. Inositol depletion in yeast may be exploited as an easy and inexpensive screening test for potential new inositol depleting anti-bipolar drugs.


Assuntos
Anticonvulsivantes/efeitos adversos , Antimaníacos/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ácidos Carboxílicos/efeitos adversos , Inositol/deficiência , Inositol/metabolismo , Carbonato de Lítio/efeitos adversos , Ácido Valproico/efeitos adversos , Leveduras/fisiologia , Bioensaio , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Mio-Inositol-1-Fosfato Sintase/efeitos dos fármacos , Mio-Inositol-1-Fosfato Sintase/genética , Proteínas de Saccharomyces cerevisiae/efeitos dos fármacos , Proteínas de Saccharomyces cerevisiae/genética
2.
Eur J Biochem ; 271(20): 4014-25, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15479230

RESUMO

We reported previously that the major cysteine protease in embryos and larvae of the brine shrimp, Artemia franciscana, is a heterodimeric protein consisting of a catalytic subunit (28.5 kDa) with a high degree of homology with cathepsin L, and a noncatalytic subunit (31.5 kDa) of unknown function. In the study reported here the noncatalytic subunit, or cathepsin L-associated protein (CLAP), was separated from cathepsin L by chromatography on Mono S and found to contain multiple isoforms with pIs ranging from 5.9 to 6.1. Heterodimeric and monomeric cathepsin L showed similar activity between pH 5 and 6.5, while the heterodimer was about twice as active as monomeric cathepsin L below pH 5. The heterodimer was more stable than the monomer between pH 6 and 7.4 and at 30-50 degrees C. Artemia CLAP and cathepsin L are present in nearly equimolar amounts at all stages in the life cycle and most abundant in encysted eggs and embyros. Moreover, CLAP, either free or as a complex with cathepsin L, was resistant to hydrolysis by cathepsin L. Two clones coding for CLAP were isolated from an Artemia embryo cDNA library and sequenced. Both clones have nearly identical open reading frames, but show differences at the 5'- and 3'-termini. Each cDNA clone has an extensive 3'-untranslated region containing 70-72% A+T. The deduced amino acid sequence of CLAP cDNA revealed two domains which were very similar to domains in fasciclin I and other cell adhesion proteins. The nucleotide sequences of clones 1 and 2 have been entered into the NCBI database (AY307377 and AY462276). This study supports the view that the noncatalytic subunit of the heterodimeric cysteine protease in Artemia stabilizes cathepsin L at various pH and temperatures normally inconsistent with cathepsin L from other organisms, and that CLAP serves as a docking mechanism for cathepsin L at nonlysosomal sites in Artemia embryos.


Assuntos
Artemia/enzimologia , Catepsinas/genética , Catepsinas/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Sequência de Aminoácidos , Animais , Artemia/embriologia , Artemia/crescimento & desenvolvimento , Sequência de Bases , Domínio Catalítico , Catepsina L , Catepsinas/química , Catepsinas/isolamento & purificação , Moléculas de Adesão Celular Neuronais/química , Sequência Conservada/genética , Cisteína Endopeptidases/química , Cisteína Endopeptidases/isolamento & purificação , DNA Complementar/genética , Dimerização , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Eletroforese em Gel de Poliacrilamida , Embrião não Mamífero/enzimologia , Concentração de Íons de Hidrogênio , Focalização Isoelétrica , Isoenzimas , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Subunidades Proteicas , Temperatura
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