23JV

Crystal structure of human cytosolic NADP(+)-dependent malic enzyme in complex with small molecules

Summary for 23JV

• Entry DOI: 10.2210/pdb23jv/pdb
• Descriptor: NADP-dependent malic enzyme, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, MANGANESE (II) ION, ... (5 entities in total)
• Functional Keywords: complex, metabolic role, inhibitor, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 260267.06

Authors

Huang, S.J.,Wen, W.Y. (deposition date: 2026-02-09, release date: 2026-09-23)

Primary citation

Cao, S.Y.,Hu, K.,Huang, S.,Guan, X.L.,Wang, J.,Shen, Y.,Ming, H.,Gu, A.,Wang, C.,Shen, X.,Wu, Q.,Chen, Z.,Yin, M.,Wen, W.,Lei, Q.Y.
Malic enzyme 1 senses L-lactate to determine tumor heterogeneity.
Signal Transduct Target Ther, 11:-, 2026

PubMed Abstract: L-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-α 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 epithelial‒mesenchymal 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 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.

PubMed: 42728262
DOI: 10.1038/s41392-026-02839-6

Experimental method

X-RAY DIFFRACTION (2.03 Å)