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NMR Spectroscopic Analysis of the First Two Steps of the Pentose-Phosphate Pathway Elucidates the Role of 6-Phosphogluconolactonase

Abstract : The pentose-phosphate pathway provides reductive power and nucleotide precursors to the cell through oxidative and nonoxidative branches, respectively. 6-Phosphogluconolactonase is the second enzyme of the oxidative branch and catalyzes the hydrolysis of 6-phosphogluconolactones, the products of glucose 6-phosphate oxidation by glucose-6-phosphate dehydrogenase. The role of 6-phosphogluconolactonase was still questionable, because 6-phosphogluconolactones were believed to undergo rapid spontaneous hydrolysis. In this work, nuclear magnetic resonance spectroscopy was used to characterize the chemical scheme and kinetic features of the oxidative branch. We show that 6-phosphogluconolactones have in fact a nonnegligible lifetime and are highly electrophilic compounds. The d form (1-5) of the lactone is the only product of glucose 6-phosphate oxidation. Subsequently, it leads to the ? form (1-4) by intramolecular rearrangement. However, only the d form undergoes spontaneous hydrolysis, the ? form being a "dead end" of this branch. The d form is the only substrate for 6-phosphogluconolactonase. Therefore, 6-phosphogluconolactonase activity accelerates hydrolysis of the d form, thus preventing its conversion into the ? form. Furthermore, 6-phosphogluconolactonase guards against the accumulation of d-6-phosphogluconolactone, which may be toxic through its reaction with endogenous cellular nucleophiles. Finally, the difference between activity of human, Trypanosoma brucei, and Plasmodium falciparum 6-phosphogluconolactonases is reported and discussed.
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Contributor : Denis Roura Connect in order to contact the contributor
Submitted on : Wednesday, March 12, 2014 - 9:46:43 PM
Last modification on : Tuesday, October 18, 2022 - 4:17:03 AM

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Emeric Miclet, Véronique Stoven, Paul A. M. Michels, Fred Opperdoes, Jean-Yves Lallemand, et al.. NMR Spectroscopic Analysis of the First Two Steps of the Pentose-Phosphate Pathway Elucidates the Role of 6-Phosphogluconolactonase. Journal of Biological Chemistry, 2001, 276 (37), pp.34840-34846. ⟨10.1074/jbc.m105174200⟩. ⟨hal-00954878⟩



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