4LV4: A noncompetitive inhibitor for M. tuberculosis's class IIa fructose 1,6-bisphosphate aldolase

Class II fructose 1,6-bisphosphate aldolase (FBA) is an enzyme critical for bacterial, fungal, and protozoan glycolysis/gluconeogenesis. Importantly, humans lack this type of aldolase, having instead a class I FBA that is structurally and mechanistically distinct from class II FBAs. As such, class II FBA is considered a putative pharmacological target for the development of novel antibiotics against pathogenic bacteria such as Mycobacterium tuberculosis, the causative agent for tuberculosis (TB). To date, several competitive class II FBA substrate mimic-styled inhibitors have been developed; however, they lack either specificity, potency, or properties that limit their potential as possible therapeutics. Recently, through the use of enzymatic and structure-based assisted screening, we identified 8-hydroxyquinoline carboxylic acid (HCA) that has an IC50 of 10 +/- 1 muM for the class II FBA present in M. tuberculosis (MtFBA). As opposed to previous inhibitors, HCA behaves in a noncompetitive manner, shows no inhibitory properties toward human and rabbit class I FBAs, and possesses anti-TB properties. Furthermore, we were able to determine the crystal structure of HCA bound to MtFBA to 2.1 A. HCA also demonstrates inhibitory effects for other class II FBAs, including pathogenic bacteria such as methicillin-resistant Staphylococcus aureus. With its broad-spectrum potential, unique inhibitory characteristics, and flexibility of functionalization, the HCA scaffold likely represents an important advancement in the development of class II FBA inhibitors that can serve as viable preclinical candidates.
PDB ID: 4LV4Download
MMDB ID: 116513
PDB Deposition Date: 2013/7/25
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.08  Å
Source Organism:
Similar Structures:
Biological Unit for 4LV4: tetrameric; determined by author and by software (PISA)
Molecular Components in 4LV4
Label Count Molecule
Proteins (4 molecules)
Fructose-bisphosphate Aldolase
Molecule annotation
Chemicals (24 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB