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Publication Abstract from PubMed

The search for anti-TB drugs active against persistent bacilli has led to our interest in metallo-dependent 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 M. tb on gluconeogenetic substrates and in glucose-containing medium. Surface labeling and enzymatic activity measurements revealed that this enzyme is exported to the cell surface of M. tb and is produced under various axenic growth conditions including oxygen depletion, and hence by non-replicating bacilli. Importantly, FBA-tb is also produced in vivo in the lungs of infected guinea pigs and mice. FBA-tb binds human plasmin(ogen) and protects FBA-tb-bound plasmin from regulation by alpha-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 angstroms 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 metallo-dependent 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.

Glycolytic and non-glycolytic functions of the fructose-1,6-bisphosphate aldolase of Mycobacterium tuberculosis, an essential enzyme produced by replicating and non-replicating bacilli.,Santangelo MD, Gest PM, Guerin ME, Coincon M, Pham H, Ryan G, Puckett SE, Spencer JS, Gonzalez-Juarrero M, Daher R, Lenaerts AJ, Schnappinger D, Therisod M, Ehrt S, Sygusch J, Jackson M J Biol Chem. 2011 Sep 23. PMID:21949126^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.