the alpha-ketoglutarate dehydrogenase complex and that mitochondrial malate dehydrogenase can associate with this binary complex to form a ternary complex. Formation of this ternary complex enables low levels of the alpha-ketoglutarate dehydrogenase complex, in the presence of the aminotransferase, to reverse inhibition of malate oxidation by glutamate. Thus, glutamate can react with the aminotransferase in this complex without glutamate inhibiting production of oxaloacetate by the malate dehydrogenase in the complex. The conversion of glutamate to alpha-ketoglutarate could also be facilitated because in the trienzyme complex, oxaloacetate might be directly transferred from malate dehydrogenase to the aminotransferase. In addition, association of malate dehydrogenase with these other two enzymes enhances malate dehydrogenase activity due to a marked decrease in the Km of malate. The potential ability of the aminotransferase to transfer directly alpha-ketoglutarate to the alpha-ketoglutarate dehydrogenase complex in this multienzyme system plus the ability of succinyl-CoA, a product of this transfer, to inhibit citrate synthase could play a role in preventing alpha-ketoglutarate and citrate from accumulating in high levels. This would maintain the catalytic activity of the multienzyme system because alpha-ketoglutarate and citrate allosterically inhibit malate dehydrogenase and dissociate this enzyme from the multienzyme system. Clinical Significance Mutations in the MDH2 gene have been associated with several cancers, including uterine cancer, prostate cancer, pheochromocytoma and other paragangliomas. In particular, MDH2 has been found to be overexpressed in doxorubicin-resistant uterine cancer cells and may contribute to drug resistance. Since MDH2 plays a major role in malate-aspartate shuttling in ATP production, its overexpression likely supplies additional energy for P-glycoprotein to pump chemotherapeutic drugs out of the cells. Likewise, MDH2 contributes to docetaxel resistance in prostate cancer cells via the JNK pathway, and its knockdown reduced ATP levels as well as increased drug sensitivity. Thus, MDH2 may be an effective therapeutic target to enhance drug treatments for cancer. Interactive pathway map See also Malate dehydrogenase References Mitochondrial proteins