TY - JOUR
T1 - Mechanistic insight on the inhibition of D, D-carboxypeptidase from Mycobacterium tuberculosis by β-lactam antibiotics
T2 - an ONIOM acylation study
AU - Ntombela, Thandokuhle
AU - Seupersad, Anya
AU - Maseko, Sibusiso
AU - Ibeji, Collins U.
AU - Tolufashe, Gideon
AU - Maphumulo, Siyabonga Innocent
AU - Naicker, Tricia
AU - Baijnath, Sooraj
AU - Maguire, Glenn E.M.
AU - Govender, Thavendran
AU - Lamichhane, Gyanu
AU - Honarparvar, Bahareh
AU - Kruger, Hendrik G.
N1 - Funding Information:
We thank the College of Health Sciences (CHS), MRC, and NRF for financial support. We are also grateful to the CHPC ( http://www.chpc.ac.za ) and UKZN cluster for computational resources. G Lamichhane was supported by award 1R21AI137720 from the National Institutes of Health (NIH), USA.
Publisher Copyright:
© 2021 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2022
Y1 - 2022
N2 - Mycobacterium tuberculosis cell wall is intricate and impermeable to many agents. A D, D-carboxypeptidase (DacB1) is one of the enzymes involved in the biosynthesis of cell wall peptidoglycan and catalyzes the terminal D-alanine cleavage from pentapeptide precursors. Catalytic activity and mechanism by which DacB1 functions is poorly understood. Herein, we investigated the acylation mechanism of DacB1 by β-lactams using a 6-membered ring transition state model that involves a catalytic water molecule in the reaction pathway. The full transition states (TS) optimization plus frequency were achieved using the ONIOM (B3LYP/6-31 + G(d): AMBER) method. Subsequently, the activation free energies were computed via single-point calculations on fully optimized structures using B3LYP/6-311++(d,p): AMBER and M06-2X/6-311++(d,p): AMBER with an electronic embedding scheme. The 6-membered ring transition state is an effective model to examine the inactivation of DacB1 via acylation by β-lactams antibiotics (imipenem, meropenem, and faropenem) in the presence of the catalytic water. The ΔG# values obtained suggest that the nucleophilic attack on the carbonyl carbon is the rate-limiting step with 13.62, 19.60 and 30.29kcal mol−1 for Imi–DacB1, Mero–DacB1 and Faro–DacB1, respectively. The electrostatic potential (ESP) and natural bond orbital (NBO) analysis provided significant electronic details of the electron-rich region and charge delocalization, respectively, based on the concerted 6-membered ring transition state. The stabilization energies of charge transfer within the catalytic reaction pathway concurred with the obtained activation free energies. The outcomes of this study provide important molecular insight into the inactivation of D, D-carboxypeptidase by β-lactams. Communicated by Ramaswamy H. Sarma.
AB - Mycobacterium tuberculosis cell wall is intricate and impermeable to many agents. A D, D-carboxypeptidase (DacB1) is one of the enzymes involved in the biosynthesis of cell wall peptidoglycan and catalyzes the terminal D-alanine cleavage from pentapeptide precursors. Catalytic activity and mechanism by which DacB1 functions is poorly understood. Herein, we investigated the acylation mechanism of DacB1 by β-lactams using a 6-membered ring transition state model that involves a catalytic water molecule in the reaction pathway. The full transition states (TS) optimization plus frequency were achieved using the ONIOM (B3LYP/6-31 + G(d): AMBER) method. Subsequently, the activation free energies were computed via single-point calculations on fully optimized structures using B3LYP/6-311++(d,p): AMBER and M06-2X/6-311++(d,p): AMBER with an electronic embedding scheme. The 6-membered ring transition state is an effective model to examine the inactivation of DacB1 via acylation by β-lactams antibiotics (imipenem, meropenem, and faropenem) in the presence of the catalytic water. The ΔG# values obtained suggest that the nucleophilic attack on the carbonyl carbon is the rate-limiting step with 13.62, 19.60 and 30.29kcal mol−1 for Imi–DacB1, Mero–DacB1 and Faro–DacB1, respectively. The electrostatic potential (ESP) and natural bond orbital (NBO) analysis provided significant electronic details of the electron-rich region and charge delocalization, respectively, based on the concerted 6-membered ring transition state. The stabilization energies of charge transfer within the catalytic reaction pathway concurred with the obtained activation free energies. The outcomes of this study provide important molecular insight into the inactivation of D, D-carboxypeptidase by β-lactams. Communicated by Ramaswamy H. Sarma.
KW - D
KW - D-carboxypeptidase (DacB1)
KW - a two-layered our Own N-layer integrated molecular mechanics (ONIOM)
KW - electrostatic potential (ESP)
KW - natural bond orbital (NBO)
KW - transition state (TS)
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U2 - 10.1080/07391102.2021.1899052
DO - 10.1080/07391102.2021.1899052
M3 - Article
C2 - 33719919
AN - SCOPUS:85102680916
SN - 0739-1102
VL - 40
SP - 7645
EP - 7655
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 17
ER -