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J Biosci ; 35(1): 21-5, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20413906

RESUMO

Cystinosis, an inherited disease caused by a defect in the lysosomal cystine transporter (CTNS), is characterized by renal proximal tubular dysfunction. Adenosine triphosphate (ATP) depletion appears to be a key event in the pathophysiology of the disease, even though the manner in which ATP depletion occurs is still a puzzle. We present a model that explains how a futile cycle that is generated between two ATP-utilizing enzymes of the gamma-glutamyl cycle leads to ATP depletion. The enzyme gamma-glutamyl cysteine synthetase (gamma-GCS), in the absence of cysteine, forms 5-oxoproline (instead of the normal substrate, gamma-glutamyl cysteine) and the 5-oxoproline is converted into glutamate by the ATP-dependant enzyme, 5-oxoprolinase. Thus, in cysteine-limiting conditions, glutamate is cycled back into glutamate via 5-oxoproline at the cost of two ATP molecules without production of glutathione and is the cause of the decreased levels of glutathione synthesis, as well as the ATP depletion observed in these cells. The model is also compatible with the differences seen in the human patients and the mouse model of cystinosis, where renal failure is not observed.


Assuntos
Trifosfato de Adenosina/química , Sistemas de Transporte de Aminoácidos Neutros/química , Glutamato-Cisteína Ligase/fisiologia , Piroglutamato Hidrolase/fisiologia , Animais , Cisteína/química , Cistinose/metabolismo , Modelos Animais de Doenças , Glutamato-Cisteína Ligase/química , Ácido Glutâmico/química , Humanos , Camundongos , Modelos Biológicos , Piroglutamato Hidrolase/química , Ácido Pirrolidonocarboxílico/química
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