Uncovering malate dehydrogenase: structure, function and role in disease

Malate dehydrogenases (MDHs) have been extensively studied since the 1960s due to their key roles in carbon metabolism and pathways such as redox balance and lipid synthesis. Recently, there has been renewed interest in these enzymes with the discovery of their role in the metabolic changes that occur during cancer and a widespread community of undergraduate teaching laboratories addressing MDH research questions, the Malate Dehydrogenase CUREs Community (MCC). This special issue describes different facets of MDH, including its physiological role, its structure-function relationships, its regulation through post-translational modifications, and perspectives on its evolutionary history. There are two human isoforms: a cytoplasmic isoform that carries out formation of NAD+ for glycolysis, and a mitochondrial isoform that plays a major role in the citric acid cycle. Although the sequences of these two isoforms vary, the structures of the enzymes are similar, and studies suggest that each isoform may form complexes with other enzymes in common pathways. Experimental and theoretical advances have helped to characterize the post-translational modifications of MDH, allowing us to ask more complex questions involving the regulation of the enzyme and substrate promiscuity in the context of cancer. Additionally, there are many unresolved questions on the role of malate dehydrogenase in other organisms, especially in parasites. The review articles in this issue seek to shed light on the latest advances in our understanding of MDH and highlight areas for future studies.