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Journal of Biosciences

, Volume 35, Issue 1, pp 21–25 | Cite as

A futile cycle, formed between two ATP-dependant γ-glutamyl cycle enzymes, γ-glutamyl cysteine synthetase and 5-oxoprolinase: the cause of cellular ATP depletion in nephrotic cystinosis?

  • Akhilesh Kumar
  • Anand Kumar Bachhawat
Brief Communication

Abstract

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 γ-glutamyl cycle leads to ATP depletion. The enzyme γ-glutamyl cysteine synthetase (γ-GCS), in the absence of cysteine, forms 5-oxoproline (instead of the normal substrate, γ-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.

Keywords

ATP depletion cysteine synthetase cystinosis γ-glutamyl cycle γ-glutamyl glutathione 5-oxoproline 

Abbreviations used

ADP

adenosine diphosphate

ATP

adenosine triphosphate

CDME

cystine dimethyl ester

CTNS

cystine transporter

γ-GCS

γ-glutamyl cysteine synthetase

γ-GT

gamma-glutamyl transpeptidase

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Copyright information

© Indian Academy of Sciences 2010

Authors and Affiliations

  1. 1.Institute of Microbial TechnologyChandigarhIndia

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