glycolyseinhibitor

A glycolysis inhibitor is a molecule that reduces the rate of glycolysis, the cytosolic breakdown of glucose to pyruvate with generation of ATP and NADH. By targeting key steps in the glycolytic pathway, these compounds can lower ATP production in cells that rely heavily on glycolysis, such as rapidly proliferating cells or cells in hypoxic regions of tissues.

Most glycolysis inhibitors act by blocking specific enzymes within the pathway. Common targets include hexokinase, which catalyzes the first step of glucose phosphorylation; phosphofructokinase-1, a rate-limiting control point; glyceraldehyde-3-phosphate dehydrogenase; and pyruvate kinase or lactate dehydrogenase, which are involved in downstream steps. Some inhibitors are competitive or allosteric, while others are prodrugs activated in particular cellular environments. In addition, certain compounds used in research can disrupt mitochondrial metabolism, indirectly affecting glycolytic flux.

Notable examples include 2-deoxy-D-glucose, which inhibits hexokinase and interferes with glucose utilization; lonidamine, which targets hexokinase II and can affect mitochondrial function; and 3-bromopyruvate, a broad-spectrum blocker of several glycolytic enzymes such as hexokinase and GAPDH. Oxamate inhibits lactate dehydrogenase, reducing lactate production. Dichloroacetate influences metabolism by activating pyruvate dehydrogenase, thereby shifting cells away from glycolysis toward oxidative phosphorylation, though it is not a classic glycolysis inhibitor.

Applications of glycolysis inhibitors are primarily in research and experimental therapy, particularly in cancer metabolism, where they are explored to sensitize tumor cells to chemotherapy or radiotherapy and to exploit the Warburg effect. Challenges include toxicity to normal tissues, metabolic plasticity, and limited efficacy as standalone treatments, necessitating combination strategies and careful patient selection.