Fructose-1,6-bisphosphate aldolase

Fructose-1,6-bisphosphate aldolase (Aldolase; FBA) is a conserved metabolic enzyme that catalyzes the reversible cleavage of fructose-1,6-bisphosphate into dihydroxyacetone phosphate and glyceraldehyde-3-phosphate during glycolysis and gluconeogenesis, thereby establishing it as a central regulator of cellular energy metabolism. Vertebrates express three major isoenzymes—Aldolase A (muscle and erythrocytes; ALDOA), Aldolase B (liver, kidney, and intestine; ALDOB), and Aldolase C (brain; ALDOC)-which exhibit distinct tissue distribution patterns yet possess highly conserved catalytic structures. Aldolase also performs non-canonical "moonlighting" functions, such as signal transduction, transcription, cytoskeletal organization, pathogen virulence, host cell adhesion, and immunomodulation. In Francisella novicida, Aldolase directly regulates the transcription of katG and rpoA, thereby linking metabolic signals to host redox regulation and inflammatory responses. In the field of oncology, the dysregulation of ALDOA, ALDOB, and ALDOC contributes to metabolic reprogramming, tumor proliferation, metastasis, and therapeutic resistance.
In prostate cancer, the overexpression of ALDOA promotes proliferation and tumor growth; conversely, the Aldolase A inhibitor naphthol AS-E phosphate suppresses cancer cell growth in a dose-dependent manner, thereby supporting the rationale for metabolism-targeted therapeutic strategies. In oral squamous cell carcinoma, ALDOC inhibits cell migration, invasion, ATP production, and lactate generation through its catalytic residues, Arg42 and Lys146, highlighting its subtype-specific functional relevance. In the realm of infectious diseases, given that mammals primarily express Class I aldolases, microbial Class II aldolases have emerged as promising targets for antimicrobial therapy. Structure-guided design has facilitated the development of zinc-chelating hydroxamate inhibitors that exhibit nanomolar potency and high selectivity for microbial Class II aldolases, providing lead compounds for the development of novel therapeutics against tuberculosis and other bacterial infections. In Mycobacterium tuberculosis, the deletion of FBA leads to bacterial clearance during both acute and chronic infection, validating its essentiality in vivo.