What is the Origin of the Regioselective C3‐Hydroxylation of L‐Arg by the Nonheme Iron Enzyme Capreomycin C?

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(66)

Published: Aug. 27, 2024

Abstract The nonheme iron dioxygenase capreomycin C (CmnC) hydroxylates a free L‐arginine amino acid regio‐ and stereospecifically at the 3 ‐position as part of antibiotics biosynthesis. Little is known on its structure, catalytic cycle substrate specificity and, therefore, comprehensive computational study was performed. A large QM cluster model CmnC created 297 atoms mechanisms for −H, 4 −H 5 hydroxylation −C desaturation were investigated. All low‐energy pathways correspond to radical reaction with an initial hydrogen atom abstraction followed by OH rebound form alcohol product complexes. work compared alternative L‐Arg hydroxylating dioxygenases differences in active site polarity are compared. We show that tight bonding network binding pocket positions ideal orientation activation, whereby polar groups induce electric field effect guides selectivity.

Language: Английский

---

Origins of Catalysis in Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 2, 2024

Abstract Histone lysine demethylase 4 A (KDM4A), a non‐heme Fe(II)/2‐oxoglutarate (2OG) dependent oxygenase that catalyzes the demethylation of tri‐methylated residues at 9, 27, and 36 positions histone H3 (H3 K9me3, K27me3, K36me3). These methylated show contrasting transcriptional roles; therefore, understanding KDM4A's catalytic mechanisms with these substrates is essential to explain factors control different sequence‐dependent demethylations. In this study, we use molecular dynamics (MD)‐based combined quantum mechanics/molecular mechanics (QM/MM) methods investigate determinants KDM4A catalysis K27me3 K36me3 substrates. KDM4A‐H3 (5–14) K9me3 (23–32) ferryl complexes, O−H distance positively correlates activation barrier rate‐limiting step, however in (32–41) K36me3, no direct one‐to‐one relationship was found implying synergistic effects between geometric parameters, second sphere interactions intrinsic electric field contribute for effective substrate. The along Fe−O bond changes three complexes shows positive correlation HAT barrier, suggesting modulating can be used fine engineering KDM specific results reveal how uses combination strategies enable near equally efficient H3Kme3 residues.

Language: Английский

---

Mechanism of Substrate Activation by Tryptophan Hydroxylase: A Computational Study

ChemistryEurope, Journal Year: 2024, Volume and Issue: 3(1)

Published: Nov. 7, 2024

Abstract Serotonin is a hormone that responsible for mood regultion in the brain; however, details on its biosynthetic mechanism remain controversial. Tryptophan hydroxylase catalyzes first step serotonin biosynthesis human body, where it regio‐ and stereoselectively hydroxylates free tryptophan (Trp) amino acid at C 5 ‐position. In this work, we present computational study ranging from molecular dynamics (MD) to quantum mechanics (QM) methods, focused of hydroxylase. An MD simulation an enzyme structure with substrate, co‐substrate dioxygen bound reveals tightly conformation substrate co‐substrate, while protein's three‐dimensional stays virtually intact during simulation. Subsequently, large active‐site cluster models containing more than 200 atoms were created, oxygen atom transfer reactions studied. The calculations predict co‐factor tetrahydrobiopterin binds covalently iron center react molecule form iron(IV)‐oxo species pterin‐4a‐carbinolamine stepwise manner small energy barriers (<5 kcal mol −1 ) along exergonic pathway. However, rate‐determining step, Trp activation through C−O transition state, followed by rapid proton relay produce 5‐hydroxy‐L‐Trp.

Language: Английский

---