PMID:21949126

Citation	de la Paz Santangelo, M, Gest, PM, Guerin, ME, Coinçon, M, Pham, H, Ryan, G, Puckett, SE, Spencer, JS, Gonzalez-Juarrero, M, Daher, R, Lenaerts, AJ, Schnappinger, D, Therisod, M, Ehrt, S, Sygusch, J and Jackson, M (2011) Glycolytic and non-glycolytic functions of Mycobacterium tuberculosis fructose-1,6-bisphosphate aldolase, an essential enzyme produced by replicating and non-replicating bacilli. J. Biol. Chem. 286:40219-31
Abstract	The search for antituberculosis drugs active against persistent bacilli has led to our interest in metallodependent class II fructose-1,6-bisphosphate aldolase (FBA-tb), a key enzyme of gluconeogenesis absent from mammalian cells. Knock-out experiments at the fba-tb locus indicated that this gene is required for the growth of Mycobacterium tuberculosis on gluconeogenetic substrates and in glucose-containing medium. Surface labeling and enzymatic activity measurements revealed that this enzyme was exported to the cell surface of M. tuberculosis and produced under various axenic growth conditions including oxygen depletion and hence by non-replicating bacilli. Importantly, FBA-tb was also produced in vivo in the lungs of infected guinea pigs and mice. FBA-tb bound human plasmin(ogen) and protected FBA-tb-bound plasmin from regulation by α(2)-antiplasmin, suggestive of an involvement of this enzyme in host/pathogen interactions. The crystal structures of FBA-tb in the native form and in complex with a hydroxamate substrate analog were determined to 2.35- and 1.9-Å resolution, respectively. Whereas inhibitor attachment had no effect on the plasminogen binding activity of FBA-tb, it competed with the natural substrate of the enzyme, fructose 1,6-bisphosphate, and substantiated a previously unknown reaction mechanism associated with metallodependent aldolases involving recruitment of the catalytic zinc ion by the substrate upon active site binding. Altogether, our results highlight the potential of FBA-tb as a novel therapeutic target against both replicating and non-replicating bacilli.
Links	PubMed PMC3220552 Online version:10.1074/jbc.M111.259440
Keywords	Animals; Bacterial Proteins/chemistry; Bacterial Proteins/genetics; Bacterial Proteins/metabolism; Crystallography, X-Ray; Fibrinolysin/genetics; Fibrinolysin/metabolism; Fructose-Bisphosphate Aldolase/chemistry; Fructose-Bisphosphate Aldolase/genetics; Fructose-Bisphosphate Aldolase/metabolism; Fructosediphosphates/chemistry; Fructosediphosphates/genetics; Fructosediphosphates/metabolism; Gene Knockdown Techniques; Gluconeogenesis; Guinea Pigs; Host-Pathogen Interactions/genetics; Humans; Mice; Mycobacterium tuberculosis/enzymology; Mycobacterium tuberculosis/genetics; Mycobacterium tuberculosis/pathogenicity; Protein Binding; Tuberculosis, Pulmonary/enzymology; Tuberculosis, Pulmonary/genetics; alpha-2-Antiplasmin/genetics; alpha-2-Antiplasmin/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MYCTU:ALF		GO:0006096: glycolysis	ECO:0000314:		P		Immunohistochemistry detected FBA-tb using polyclonal anti-FBA-tb antibodies and tyramide amplification signal in figure 3.	complete CACAO 5200
MYCTU:ALF		GO:0045820: negative regulation of glycolysis	ECO:0000314:		P		See supplemental Fig. S4.	complete CACAO 5311

References

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