Metabolic Regulation of Malic Enzymes in Cancer

Malic enzymes (MEs) occupy a central node in cancer metabolism by catalysing the conversion of malate to pyruvate while generating NAD(P)H to support biosynthesis and redox balance. Three isoforms—cytosolic ME1, mitochondrial NAD(P)+-dependent ME2 and mitochondrial NADP+-specific ME3—differ in cofactor preference and subcellular localization, yet collectively they shape tumour energetic and anabolic programmes. In many cancers, upregulation or post-translational modification of MEs facilitates the diversion of tricarboxylic acid cycle intermediates into glycolysis or lipid synthesis, sustains antioxidant defences through NADPH production and interfaces with parallel pathways such as the pentose phosphate pathway. Dynamic regulation of ME expression and activity enables malignant cells to adapt to fluctuating nutrient and oxygen availability, contributing to proliferation, survival under metabolic stress and therapy resistance. Consequently, malic enzymes are emerging as both biomarkers of aggressive phenotypes and candidates for targeted intervention in diverse tumour types.

Research from Nature Portfolio

Recent studies have unveiled a pivotal role for cytosolic ME2 in orchestrating the glycolytic switch in response to growth stimuli. Phosphorylation of a full-length ME2 isoform by a key kinase prevents its mitochondrial import and promotes assembly of a cytosolic scaffold that recruits core glycolytic enzymes, thereby enhancing lactate production and tumour cell growth. In parallel, exploration of basal-like breast carcinomas has revealed that focal amplification of the ME1 gene drives heightened glucose uptake, suppressed oxidative respiration and increased lactate secretion, correlating with larger tumour size, higher grade and poorer patient outcomes. Together, these findings emphasise how post-translational control and genomic amplification of distinct ME isoforms converge on enhanced glycolytic capacity to fuel aggressive malignancies.

Metabolic Regulation of Malic Enzymes in Cancer publication trend

The graph below shows the total number of articles in metabolic regulation of malic enzymes in cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Malic enzymes (MEs): NAD(P)-dependent enzymes converting malate to pyruvate, linking the tricarboxylic acid cycle to biosynthetic and redox pathways.

NADPH: Nicotinamide adenine dinucleotide phosphate in its reduced form; a critical cofactor for anabolic reactions and antioxidant defence.

Aerobic glycolysis: Metabolic phenotype in which cells preferentially convert glucose to lactate despite oxygen availability, also known as the Warburg effect.

Pentose phosphate pathway (PPP): Cytosolic route for glucose oxidation that generates ribose-5-phosphate for nucleotide synthesis and NADPH for reductive biosynthesis.

Post-translational modification: Covalent alteration of a protein after synthesis, such as phosphorylation, which can alter enzyme activity or localization.

References

1. AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis. Nature Communications (2024).
2. ME1 promotes basal-like breast cancer progression and associates with poor prognosis. Scientific Reports (2018).
3. NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Signal Transduction and Targeted Therapy (2020).
4. Evidence for a direct cross-talk between malic enzyme and the pentose phosphate pathway via structural interactions. Journal of Biological Chemistry (2017).
5. Inhibition of malic enzyme 1 disrupts cellular metabolism and leads to vulnerability in cancer cells in glucose-restricted conditions. Oncogenesis (2017).