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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., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

In this review, we examine the protein-protein interactions of cytosolic malate dehydrogenase (MDH), an under-studied area in cellular metabolism. We provide a comprehensive overview of MDH involvement in metabolism, especially its interactions with metabolic partners and dynamics of changing metabolism. We present an analysis of the biophysical nature of these interactions and the current methods used to study them. Our review includes an assessment of computational docking studies, which offer initial hypotheses about potential MDH interaction partners. Furthermore, we provide a summary of the sparse yet insightful experimental evidence available, establishing a foundation for future research. By integrating biophysical analysis and methodological advancements, this paper aims to illuminate the intricate network of interactions involving cytosolic MDH and their metabolic implications. This work not only contributes to our understanding of MDH's role in metabolism but also highlights the potential impact of these interactions in metabolic disorders., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Malate dehydrogenase (MDH) is a key enzyme in mammalian metabolic pathways in cytosolic and mitochondrial compartments. Regulation of MDH through phosphorylation remains an underexplored area. In this review we consolidate evidence supporting the potential role of phosphorylation in modulating the function of mammalian MDH. Parallels are drawn with the phosphorylation of lactate dehydrogenase, a homologous enzyme, to reveal its regulatory significance and to suggest a similar regulatory strategy for MDH. Comprehensive mining of phosphorylation databases, provides substantial experimental (primarily mass spectrometry) evidence of MDH phosphorylation in mammalian cells. Experimentally identified phosphorylation sites are overlaid with MDH's functional domains, offering perspective on how these modifications could influence enzyme activity. Preliminary results are presented from phosphomimetic mutations (serine/threonine residues changed to aspartate) generated in recombinant MDH proteins serving as a proof of concept for the regulatory impact of phosphorylation. We also examine and highlight several approaches to probe the structural and cellular impact of phosphorylation. This review highlights the need to explore the dynamic nature of MDH phosphorylation and calls for identifying the responsible kinases and the physiological conditions underpinning this modification. The synthesis of current evidence and experimental data aims to provide insights for future research on understanding MDH regulation, offering new avenues for therapeutic interventions in metabolic disorders and cancer., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Malate dehydrogenase (MDH) is pivotal in mammalian tissue metabolism, participating in various pathways beyond its classical roles and highlighting its adaptability to cellular demands. This enzyme is involved in maintaining redox balance, lipid synthesis, and glutamine metabolism and supports rapidly proliferating cells' energetic and biosynthetic needs. The involvement of MDH in glutamine metabolism underlines its significance in cell physiology. In contrast, its contribution to lipid metabolism highlights its role in essential biosynthetic processes necessary for cell maintenance and proliferation. The enzyme's regulatory mechanisms, such as post-translational modifications, underscore its complexity and importance in metabolic regulation, positioning MDH as a potential target in metabolic dysregulation. Furthermore, the association of MDH with various pathologies, including cancer and neurological disorders, suggests its involvement in disease progression. The overexpression of MDH isoforms MDH1 and MDH2 in cancers like breast, prostate, and pancreatic ductal adenocarcinoma, alongside structural modifications, implies their critical role in the metabolic adaptation of tumor cells. Additionally, mutations in MDH2 linked to pheochromocytomas, paragangliomas, and other metabolic diseases emphasize MDH's role in metabolic homeostasis. This review spotlights MDH's potential as a biomarker and therapeutic target, advocating for further research into its multifunctional roles and regulatory mechanisms in health and disease., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)