Deciphering the role of the two metal-binding sites of DapE enzyme via metal substitution

被引:0
作者
Paul, Atanuka [1 ]
Mishra, Sabyashachi [1 ]
机构
[1] Indian Inst Technol Kharagpur, Dept Chem, Kharagpur, India
关键词
DapE enzyme; Metalloenzyme; QM; MM calculations; Substrate binding; N-SUCCINYL-L; L-DIAMINOPIMELIC ACID DESUCCINYLASE; HAEMOPHILUS-INFLUENZAE; MOLECULAR-DYNAMICS; TRANSITION-METALS; LYSINE; DIAMINOPIMELATE; BIOSYNTHESIS; CATALYSIS; HYDROLYSIS; MECHANISM;
D O I
10.1016/j.compbiolchem.2023.107832
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
DapE is a microbial metalloenzyme that hosts two Zn ions in its active site, although it shows catalytic activity with varying efficiency when the Zn ions in one or both of its metal-binding sites (MBS) are replaced by other transition-metal ions. The metal-ion promiscuity of DapE is believed to be a microbial strategy to overcome the homeostatic regulation of Zn ions by the mammalian host. Here, a hybrid QM/MM study is performed on a series of mixed-metal DapEs, where the Zn ion in the first MBS (MBS-1) is substituted by Mn, Co, Ni, and Cu ions, while the MBS-2 is occupied by Zn(II). The substrate binding affinity and the mechanism of catalytic action are estimated by optimizing the intermediates and the transition states with hybrid QM/MM method. Comparison of the binding affinity of the MBS-1 and MBS-2 substituted DapEs reveals that the MBS-1 substitution does not affect the substrate binding affinity in the mixed-metal DapEs, while a strong metal specificity was observed in MBS-2 substituted DapEs. On the contrary, the activation energy barriers show a high metal specificity at MBS-1 compared to MBS-2. Taken together, the QM/MM studies indicate that MBS-2 leads the substrate binding process, while MBS-1 steers the catalytic activity of the DapE enzyme.
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页数:9
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共 49 条
  • [1] Metal ions in biological catalysis: from enzyme databases to general principles
    Andreini, Claudia
    Bertini, Ivano
    Cavallaro, Gabriele
    Holliday, Gemma L.
    Thornton, Janet M.
    [J]. JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY, 2008, 13 (08): : 1205 - 1218
  • [2] Substrate specificity, metal binding properties, and spectroscopic characterization of the DapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Haemophilus influenzae
    Bienvenue, DL
    Gilner, DM
    Davis, RS
    Bennett, B
    Holz, RC
    [J]. BIOCHEMISTRY, 2003, 42 (36) : 10756 - 10763
  • [3] Hydrolysis of N-succinyl-L,L-diaminopimelic acid by the Haemophilus influenzae dapE-encoded desuccinylase:: Metal activation, solvent isotope effects, and kinetic mechanism
    Born, TL
    Zheng, RJ
    Blanchard, JS
    [J]. BIOCHEMISTRY, 1998, 37 (29) : 10478 - 10487
  • [4] Structure/function studies on enzymes in the diaminopimelate pathway of bacterial cell wall biosynthesis
    Born, TL
    Blanchard, JS
    [J]. CURRENT OPINION IN CHEMICAL BIOLOGY, 1999, 3 (05) : 607 - 613
  • [5] CLONING, CHARACTERIZATION, AND EXPRESSION OF THE DAPE GENE OF ESCHERICHIA-COLI
    BOUVIER, J
    RICHAUD, C
    HIGGINS, W
    BOGLER, O
    STRAGIER, P
    [J]. JOURNAL OF BACTERIOLOGY, 1992, 174 (16) : 5265 - 5271
  • [6] Metalloprotein Crystallography: More than a Structure
    Bowman, Sarah E. J.
    Bridwell-Rabb, Jennifer
    Drennan, Catherine L.
    [J]. ACCOUNTS OF CHEMICAL RESEARCH, 2016, 49 (04) : 695 - 702
  • [7] Targeting Metalloenzymes for Therapeutic Intervention
    Chen, Allie Y.
    Adamek, Rebecca N.
    Dick, Benjamin L.
    Credille, Cy V.
    Morrison, Christine N.
    Cohen, Seth M.
    [J]. CHEMICAL REVIEWS, 2019, 119 (02) : 1323 - 1455
  • [8] The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from haemophilus influenzae is a dinuclear metallohydrolase
    Cosper, NJ
    Bienvenue, DL
    Shokes, JE
    Gilner, DM
    Tsukamoto, T
    Scott, RA
    Holz, RC
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2003, 125 (48) : 14654 - 14655
  • [9] Perspectives on Metals in Microbiology
    Djoko, Karrera
    Cavet, Jennifer
    [J]. MICROBIOLOGY-SGM, 2022, 168 (07):
  • [10] Active Site Dynamics in Substrate Hydrolysis Catalyzed by DapE Enzyme and Its Mutants from Hybrid QM/MM-Molecular Dynamics Simulation
    Dutta, Debodyuti
    Mishra, Sabyashachi
    [J]. JOURNAL OF PHYSICAL CHEMISTRY B, 2017, 121 (29) : 7075 - 7085