Metronidazole Activation by a Deeply Entangled Dimeric Malic Enzyme in Entamoeba histolytica

Metronidazole is the preferred drug for treating amoebiasis caused by <i>Entamoeba histolytica</i>. Its antiamoebic activity is primarily attributed to activation by various reductases. This study reports an alternative activation pathway in <i>E. histolytica</i> mediated by the decarboxylating malic enzyme. Functional characterization of this NADPH-dependent enzyme reveals that it is secreted into the extracellular milieu and may play a role in <i>E. histolytica</i> adhesion to human enteric cells. Structural analysis of the <i>E. histolytica</i> malic enzyme (EhME) demonstrates that the protein forms a strict dimer, with the protomers interlocked by a unique knot structure formed by two polypeptide chains. This distinctive structural feature closely aligns EhME with its prokaryotic counterparts. In conclusion, our findings reveal that <i>E. histolytica</i> harbors a deeply entangled dimeric malic enzyme that contributes to metronidazole susceptibility, sharing structural similarities with bacterial malic enzymes.