23jw | pdb_000023jw
Crystal structure of human cytosolic NADP(+)-dependent malic enzyme in a ternary complex with NADP+ and Mn2+
Structural highlights
FunctionPublication Abstract from PubMedL-lactate is generally elevated in tumors and acts as a signaling molecule that promotes tumor progression. Here, we reveal that malic enzyme 1 (ME1) functions as a previously unrecognized sensor of L-lactate through direct binding at arginine 155 (R155), thereby potentiating malignancy. Mechanistically, L-lactate binding promotes the nuclear translocation of ME1, a process involving reduced acetylation at lysine 362 (K362) and facilitated by nuclear import of karyopherin-alpha 4 (KPNA4). Nuclear accumulation of ME1 enhances metastatic potential, which is correlated with increased interaction with hepatoma-derived growth factor (HDGF) and acquisition of an epithelialâmesenchymal transition (EMT)-related phenotype. Under nutrient-deficient conditions, L-lactate promotes the assembly of a ME1-lactate dehydrogenase B (LDHB) complex, which enhances oxidative phosphorylation (OXPHOS) and increases ATP production, suggesting a metabolic adaptive mechanism that supports tumor cell survival. Notably, the ME1(R155A) mutation, which disrupts L-lactate binding, abolishes the protumorigenic effect of the L-lactate-ME1 axis on tumor progression in vivo. In conclusion, our findings identify ME1 as a direct sensor of L-lactate and support a model in which lactate-mediated signaling and metabolic adaptation converge on ME1 to regulate tumor cell plasticity in a context-dependent manner under heterogeneous metabolic conditions. These insights advance our understanding of the spatiotemporal control of metabolic adaptation in cancer and reveal a potential therapeutic target. Malic enzyme 1 senses L-lactate to determine tumor heterogeneity.,Cao SY, Hu K, Huang S, Guan XL, Wang J, Shen Y, Ming H, Gu A, Wang C, Shen X, Wu Q, Chen Z, Yin M, Wen W, Lei QY Signal Transduct Target Ther. 2026 Sep 11;11(1):386. doi: , 10.1038/s41392-026-02839-6. PMID:42728262[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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