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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Anthrax Edema Factor: An Ion-Adaptive Mechanism of Catalysis with Increased Transition-State Conformational Flexibility

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Jara, Gabriel E. ; Martinez, Leandro
Total Authors: 2
Document type: Journal article
Source: Journal of Physical Chemistry B; v. 120, n. 27, p. 6504-6514, JUL 14 2016.
Web of Science Citations: 1

Edema Factor (EF) is one of three major toxins of anthrax. EF is an adenylyl cyclase that disrupts cell signaling by accelerating the conversion of ATP into cyclic-AMP. EF has a much higher catalytic rate than that of mammalian adenylyl cyclases (mACs). Crystal structures were obtained for mACs and EF, but the molecular basis for different catalytic activities remained poorly understood. In particular, the arrangement of the active site in EF is unclear in what concerns the number of ions present and the conformation of the substrate. Here, we use quantum mechanics-molecular mechanics simulations to estimate the free-energy profiles for the reaction catalyzed by EF and a mAC. We found that EF catalysis is possible, and faster than that of mACs, in both one and two Mg2+-ion-binding modes, providing adaptive plasticity to host-cell environments. In both enzymes, the reaction mechanisms are highly associative. However, mechanistic differences exist. In the mAC, the nucleophile oxygen (ATP-O3') is consistently coordinated to one of the Mg2+ ions, increasing its acidity. In EF, on the other hand, this coordination is eventual and not essential for the reaction to proceed. The persistent coordination of O3' to the ion is favored in mACs by a greater ion partial charge. In EF, the reduced acidity of the O3' oxygen is compensated by the presence of the His351 residue for proton abstraction. As proton transfer in EF does not require persistent attachment of the substrate to an ion, the substrate (ATP) and transition state display greater conformational flexibilities. These greater flexibilities allow the sampling of lower energy conformations and might represent an entropic advantage for catalytic efficiency. (AU)

FAPESP's process: 13/22360-9 - Computational Study of the mechanism of conversion of ATP to cyclic-AMP catalyzed by the Edema Factor of Anthrax
Grantee:Gabriel Ernesto Jara
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 10/16947-9 - Correlations between dynamics, structure and function in protein: computer simulations and algorithms
Grantee:Leandro Martinez
Support type: Regular Research Grants
FAPESP's process: 13/08293-7 - CCES - Center for Computational Engineering and Sciences
Grantee:Munir Salomao Skaf
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 13/05475-7 - Computational methods in optimization
Grantee:Sandra Augusta Santos
Support type: Research Projects - Thematic Grants