Research Article: Structures of the Mycobacterium tuberculosis GlpX protein (class II fructose-1,6-bisphosphatase): implications for the active oligomeric state, catalytic mechanism and citrate inhibition

Date Published: April 01, 2018

Publisher: International Union of Crystallography

Author(s): Nina M. Wolf, Hiten J. Gutka, Farahnaz Movahedzadeh, Celerino Abad-Zapatero.


Structures of native and variants (T84S and T84A) of M. tuberculosis class II fructose-1,6-bisphosphatase are presented and compared with those of other homologs. The structure is a 222-symmetric homotetramer. Citrate was bound at a dimer interface and was found to be an inhibitor.

Partial Text

Tuberculosis (TB) affects two billion individuals, with ten million new cases and 1.5 million deaths reported each year (Quan et al., 2017 ▸). Multidrug-resistant, extensively drug-resistant and totally drug-resistant strains of tuberculosis complicate the already tedious treatment protocol (Balganesh et al., 2008 ▸). The World Health Organization has the goal of eliminating the disease by 2050 (Koul et al., 2011 ▸). To accomplish this feat, drugs with new modes of action need to be explored.

The structure of the MtFBPaseII protein encoded by the glpX gene of Mtb presented in this work is very similar to that of the corresponding EcFBPaseII, confirming the GlpX-like phosphatase fold of this carbohydrate-phosphatase superfamily. The noncrystallographic dimer found in the structures of the Mtb enzyme (apo and T84A and T84S mutants) differs from the elongated dimer described for the E. coli enzyme. This observation, combined with the crystallographic symmetry in the two different lattices, supports the conclusion that FBPaseII is a 222 tetramer in solution. This inference is also consistent with the initial biochemical characterization of MtFBPaseII (Gutka, Rukseree et al., 2011 ▸), in which an oligomer (most likely a tetramer) was proposed based on molecular-weight estimation using SEC (127 kDa). The structures of the two other class II FBPases discussed (FBP/SBPases from Synechocystis and T. elongatus), which are closer homologs than EcFBPaseII, are also tetramers. The Synechocystis enzyme structure has a tetramer in the asymmetric unit (space group P65). A 222 homotetrameric structure is proposed as the functional unit for this enzyme class.




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