Gabaculine is a potent inhibitor of the vitamin B6-dependent key enzyme in chlorophyll biosynthesis, glutamate-1-semialdehyde aminomutase (GSAM). The inhibition effect is caused by an enzymatic deprotonation of the neurotoxin and requires the aldimine (PLP) form of the cofactor at the active site. In this study, we show that a single-point mutation confers resistance to gabaculine. A combined functional and structural analysis of wild-type GSAM in complex with gabaculine and the GSAM M248I form allowed us to decipher in atomic detail the molecular basis of this unique resistance. Interestingly, the gabaculine tolerance is caused by the absence of an essential water molecule that has a dual functional role. It serves as a nucleophilic shuttle for the hydroxyl anion along the reaction pathway and holds active-site Lys273 in a catalytically competent conformation. The single-point mutant is not able to fix this catalytic water between the β-branched side chain of Ile248 and Lys273. As a consequence, the mutant enzyme is trapped in a gabaculine-insensitive but still enzymatically active amine (PMP) form.—Orriss, G. L., Patel, T. R., Sorensen, J., Stetefeld, J. Absence of a catalytic water confers resistance to the neurotoxin gabaculine.
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Absence of a catalytic water confers resistance to the neurotoxin gabaculine
Orriss, George L.; Patel, Trushar R.; Sorensen, John; Stetefeld, Jörg
Follow The FASEB Journal
, Volume 24 (2): 404
Fed of American Socs for Experimental Biology – Feb 1, 2010
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