ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes

Abstract

Type 2 diabetes mellitus (T2DM) significantly impacts on human health and patient numbers are predicted to rise. Discovering novel drugs and targets for treating T2DM is a research priority. In this study, we investigated targeting of the glycolysis enzyme, enolase, using the small molecule ENOblock, which binds enolase and modulates its non-glycolytic ‘moonlighting’ functions. In insulin-responsive cells ENOblock induced enolase nuclear translocation, where this enzyme acts as a transcriptional repressor. In a mammalian model of T2DM, ENOblock treatment reduced hyperglycemia and hyperlipidemia. Liver and kidney tissue of ENOblock-treated mice showed down-regulation of known enolase target genes and reduced enolase enzyme activity. Indicators of secondary diabetic complications, such as tissue apoptosis, inflammatory markers and fibrosis were inhibited by ENOblock treatment. Compared to the well-characterized anti-diabetes drug, rosiglitazone, ENOblock produced greater beneficial effects on lipid homeostasis, fibrosis, inflammatory markers, nephrotoxicity and cardiac hypertrophy. ENOblock treatment was associated with the down-regulation of phosphoenolpyruvate carboxykinase and sterol regulatory element-binding protein-1, which are known to produce anti-diabetic effects. In summary, these findings indicate that ENOblock has potential for therapeutic development to treat T2DM. Previously considered as a ‘boring’ housekeeping gene, these results also implicate enolase as a novel drug target for T2DM.

Alpha-enolase in viral target cells suppresses the human immunodeficiency virus type 1 integration.

“…Since the expression of about 48 kDa HA-tagged TgENO1 has been con rmed by western immunoblotting [31], it is expected that its N-terminal long form has migrated into the nucleus and has the capacity for binding to putative gene promoters to control gene expression during the intracellular proliferation of T. gondii [31]. Furthermore, Cho et al showed that ENOblock, a chemical probe for elucidating the moonlighting functions of ENO1, induces the nuclear localization of the long form of 48 kDa ENO1 [32]. It is generally considered that proteins with a molecular weight of about 40 kDa or larger cannot pass through the nuclear pore for their shuttling from the cytoplasm into the nucleoplasm.…”

Dietary fish oil supplement induces age-specific contractile and proteomic responses in muscles of male rats

“…Interestingly, beta enolase, also a glycolytic protein, exhibited a greater decrease in adult vs. aged muscles with DFO. However, non-glycolytic functions of enolase related to repression of transcription have recently been identified [ 70 ]. Since enolase is not believed to play a major regulatory role (i.e., a rate-limiting step) in glycolysis [ 71 ], the changes observed here may be more related to these non-glycolytic functions.…”

“…Since enolase is not believed to play a major regulatory role (i.e., a rate-limiting step) in glycolysis [ 71 ], the changes observed here may be more related to these non-glycolytic functions. Future work could examine changes in beta enolase localization, which has been linked to glycolytic vs. non-glycolytic function [ 70 ].…”

Screening ginseng saponins in progenitor cells identifies 20(R)-ginsenoside Rh2 as an enhancer of skeletal and cardiac muscle regeneration

“…1 d after freezing, cryosections were taken at a 7 µm thickness (Leica CM1850). Masson's trichrome staining was performed using the previously published protocol 71 . Microscopic images were obtained at 25× magnification and the thickness of the left ventricle was measured using Image J 1.48 v software (National Institutes of Health).…”