caa a22 4500 605488207 CHVBK 20210128100454.0 cr unu---uuuuu 210128e20150501xx s 000 0 eng 10.1007/s00214-015-1674-y doi (NATIONALLICENCE)springer-10.1007/s00214-015-1674-y Electronic effects on the reaction mechanism of the metalloenzyme peptide deformylase [Elektronische Daten] [Jason Fell, Darren Steele, Tommy Hatcher III, Benjamin Gherman] The metalloenzyme peptide deformylase (PDF) plays a crucial role in the biosynthesis of proteins by eubacteria, making the enzyme a promising target for antibacterial agents. In a reaction catalyzed by an Fe(II) coordination complex in the enzyme active site, PDF cleaves a formyl group from the N-terminus of nascent eubacterial proteins. Computational chemistry methods are combined with the use of in silico models of the enzyme chemistry to examine specific effects on the enzymatic catalysis. In particular, density functional theory calculations have been carried out on a biomimetic model system based on a heteroscorpionate N2Sthiolate biomimetic ligand system bearing a range of electron-donating and electron-withdrawing substituents. In this way, the effects of electronic changes to the metal coordination environment on the thermodynamics and kinetics of the deformylation reaction are determined. The reaction was found to be more thermodynamically favorable as the added substituents shifted from electron-withdrawing to electron-donating [or, equivalently, with decreasing Hammett parameters (σ p) for the substituents]. As the substituents change from electron-withdrawing to electron-donating, the hydroxide ligand responsible for initiating nucleophilic attack on the carbonyl group of the formyl-terminated peptide substrate is shown to become decreasingly strongly bound to the metal, making the reaction less endergonic. The rate of reaction was found to be fastest for substituents with σ p≈0, and progressively slower as the substituents became increasingly electron-donating or electron-withdrawing. At σ p≈0, a balance is found between the reactivity of the hydroxide ligand involved in the nucleophilic attack and activation of the carbonyl group by the iron center toward that nucleophilic attack. Springer-Verlag Berlin Heidelberg, 2015 Peptide deformylase nationallicence Substituent effects nationallicence Density functional calculations nationallicence Reaction thermodynamics and kinetics nationallicence Metalloenzymes nationallicence Fell Jason Department of Chemistry, California State University, Sacramento, 6000 J Street, 95819-6057, Sacramento, CA, USA aut Steele Darren Department of Chemistry, California State University, Sacramento, 6000 J Street, 95819-6057, Sacramento, CA, USA aut Hatcher III Tommy Department of Chemistry, California State University, Sacramento, 6000 J Street, 95819-6057, Sacramento, CA, USA aut Gherman Benjamin Department of Chemistry, California State University, Sacramento, 6000 J Street, 95819-6057, Sacramento, CA, USA aut Theoretical Chemistry Accounts Springer Berlin Heidelberg 134/5(2015-05-01), 1-7 1432-881X 134:5<1 2015 134 214 https://doi.org/10.1007/s00214-015-1674-y text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00214-015-1674-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fell Jason Department of Chemistry, California State University, Sacramento, 6000 J Street, 95819-6057, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Steele Darren Department of Chemistry, California State University, Sacramento, 6000 J Street, 95819-6057, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Hatcher III Tommy Department of Chemistry, California State University, Sacramento, 6000 J Street, 95819-6057, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Gherman Benjamin Department of Chemistry, California State University, Sacramento, 6000 J Street, 95819-6057, Sacramento, CA, USA aut NATIONALLICENCE 773 0- Theoretical Chemistry Accounts Springer Berlin Heidelberg 134/5(2015-05-01), 1-7 1432-881X 134:5<1 2015 134 214