4LV4

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

Summary for 4LV4

• Entry DOI: 10.2210/pdb4lv4/pdb
• Related: 3EKL 3EKZ 3ELF 4A21 4A22 4DEF 4DEL
• Descriptor: Fructose-bisphosphate aldolase, ZINC ION, 8-hydroxyquinoline-2-carboxylic acid, ... (6 entities in total)
• Functional Keywords: class ii fructose-1, 6-bisphosphate aldolase, zinc enzyme, mycobacterium tuberculosis, dihydroxyacetone, glyceraldehyde-3-phosphate, aldol condensation, glycolysis, lyase, metal-binding, 8-hydroxyquinoline-2-carboxylic acid, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 37952.46

Authors

Capodagli, G.C.,Pegan, S.D. (deposition date: 2013-07-25, release date: 2014-01-08, Last modification date: 2023-09-20)

Primary citation

Capodagli, G.C.,Sedhom, W.G.,Jackson, M.,Ahrendt, K.A.,Pegan, S.D.
A Noncompetitive Inhibitor for Mycobacterium tuberculosis's Class IIa Fructose 1,6-Bisphosphate Aldolase.
Biochemistry, 53:202-213, 2014

PubMed Abstract: 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 μM 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 Å. 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.

PubMed: 24325645
DOI: 10.1021/bi401022b

Experimental method

X-RAY DIFFRACTION (2.08 Å)