9QM6
Crystal structure of highly stable methionine gamma-lyase from Thermobrachium celere in complex with PLP and norleucine
Summary for 9QM6
| Entry DOI | 10.2210/pdb9qm6/pdb |
| Descriptor | L-methionine gamma-lyase, NORLEUCINE, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | enzyme, methionine gamma-lyase, complex, plp, inhibitor, lyase |
| Biological source | Thermobrachium celere |
| Total number of polymer chains | 4 |
| Total formula weight | 184344.06 |
| Authors | |
| Primary citation | Ferchaud, N.,Kopecny, D.,Perina, M.,Boyer, A.,Hentati, S.,Pontoizeau, C.,Desterke, C.,Krystof, V.,Machover, D.,Briozzo, P. The methioninase from the alkalithermophile Thermobrachium celere possesses suitable properties for treatment of cancer. Int.J.Biol.Macromol., 330:147876-147876, 2025 Cited by PubMed Abstract: L-Methionine deprivation for cancer treatment requires pyridoxal 5'-phosphate (PLP)-dependent L-methionine γ-lyases (MGL) with sustained activity in plasma. We investigated the MGL from the alkaliphilic thermophile Thermobrachium celere (TcMGL), which was compared to that from Pseudomonas putida (PpMGL) as a reference. Catalysis was limited to L-methionine, L-homocysteine, and L-cysteine, with highest catalytic efficiency towards L-methionine. Binding of apo-TcMGL to PLP results from an endothermic entropy-driven process, contrasting with apo-PpMGL that binds to cofactor following an exothermic enthalpy-driven reaction, as demonstrated with isothermal titration calorimetry. The tetrameric crystal structure of TcMGL revealed a mobile domain adopting open and closed conformations, regulating access of substrate and PLP to the active site. TcMGL exhibited great stability in human plasma in vitro. Half-life of the active enzyme increased from 9.2 h to 66.7 h with increasing PLP concentration, in much greater magnitude than that of PpMGL. Two-way ANOVA demonstrated a highly significant effect on half-lives of enzyme type and PLP concentration. The enzyme eliminated L-methionine from human plasma and exerted potent cytotoxicity against human carcinoma cells in vitro. TcMGL favourable characteristics make it a suitable candidate for treatment of cancer. PubMed: 41005402DOI: 10.1016/j.ijbiomac.2025.147876 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.607 Å) |
Structure validation
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