• Anand Kumar Bachhawat

      Articles written in Journal of Biosciences

    • 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

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      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.

    • Yeast glutaredoxin, GRX4, functions as a glutathione S-transferase required for red ade pigment formation in Saccharomyces cerevisiae

      ASHWIN KUMAR JAINARAYANAN SHAMBHU YADAV ANAND KUMAR BACHHAWAT

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      The adenine biosynthetic mutants ade1 and ade2 of Saccharomyces cerevisiae accumulate a characteristic redpigment in their vacuoles under adenine limiting conditions. This red pigmentation phenotype, widely used in avariety of genetic screens and assays, is the end product of a glutathione-mediated detoxification pathway,where the glutathione conjugates are transported into the vacuole. The glutathione conjugation step, however,has still remained unsolved. We show here, following a detailed analysis of all the members of the thioredoxinfoldsuperfamily, the involvement of the monothiol glutaredoxin GRX4 as essential for pigmentation. GRX4plays multiple roles in the cell, and we show that the role in ade pigmentation does not derive from itsregulatory role of the iron transcription factor, Aft1p, but a newly identified GST activity of the protein that wecould demonstrate using purified Grx4p. Further, we demonstrate that the GRX domain of GRX4 and its activesite cysteine C171 is critical for this activity. The findings thus solve a decades old enigma on a critical step inthe formation of this red pigmentation.

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