Thiomethyl Substituted Dicopper Complexes: Attempts to Reproduce the Asymmetry of the Active Site from Type 3 Copper Enzymes

2013 ◽  
Vol 639 (8-9) ◽  
pp. 1477-1482 ◽  
Author(s):  
Wassim Rammal ◽  
Katalin Selmeczi ◽  
Christian Philouze ◽  
Eric Saint-Aman ◽  
Jean-Louis Pierre ◽  
...  
Keyword(s):  
Active Site ◽  
Copper Enzymes ◽  
The Asymmetry ◽  
Type 3 ◽  
Dicopper Complexes

Dicopper complexes of a macrocyclic ligand as models for type 3 copper proteins

1983 ◽  
Vol 105 (17) ◽  
pp. 5693-5695 ◽  
Author(s):  
S. Martin Nelson ◽  
Ferida Esho ◽  
Aidan Lavery ◽  
Michael G. B. Drew
Keyword(s):  
Macrocyclic Ligand ◽  
Copper Proteins ◽  
Type 3 ◽  
Dicopper Complexes

scholarly journals Evaluating the Performance of a Non-Bonded Cu2+ Model Including Jahn−Teller Effect into the Binding of Tyrosinase Inhibitors

2020 ◽  
Vol 21 (13) ◽  
pp. 4783
Author(s):  
Lucas Sousa Martins ◽  
Jerônimo Lameira ◽  
Hendrik G. Kruger ◽  
Cláudio Nahum Alves ◽  
José Rogério A. Silva
Keyword(s):  
Active Site ◽  
Binding Free Energy ◽  
Classical Model ◽  
Md Simulations ◽  
Teller Effect ◽  
Binding Affinities ◽  
Linear Interaction ◽  
Jahn Teller ◽  
Jahn Teller Effect ◽  
Type 3

Tyrosinase (TYR) is a metalloenzyme classified as a type-3 copper protein, which is involved in the synthesis of melanin through a catalytic process beginning with the conversion of the amino acid l-Tyrosine (l-Tyr) to l-3,4-dihydroxyphenylalanine (l-DOPA). It plays an important role in the mechanism of melanogenesis in various organisms including mammals, plants, and fungi. Herein, we used a combination of computational molecular modeling techniques including molecular dynamic (MD) simulations and the linear interaction energy (LIE) model to evaluate the binding free energy of a set of analogs of kojic acid (KA) in complex with TYR. For the MD simulations, we used a dummy model including the description of the Jahn–Teller effect for Cu2+ ions in the active site of this enzyme. Our results show that the LIE model predicts the TYR binding affinities of the inhibitor in close agreement to experimental results. Overall, we demonstrate that the classical model provides a suitable description of the main interactions between analogs of KA and Cu2+ ions in the active site of TYR.

Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3

2019 ◽  
Vol 476 (21) ◽  
pp. 3369-3383 ◽  
Author(s):  
Amadeus Huang ◽  
Julia Burke ◽  
Richard D. Bunker ◽  
Yee-Foong Mok ◽  
Michael D. Griffin ◽  
...  
Keyword(s):  
Active Site ◽  
Metabolic Flux ◽  
Primary Hyperoxaluria ◽  
Inhibition Constant ◽  
Decarboxylase Activity ◽  
Loss Of Function ◽  
Primary Hyperoxaluria Type ◽  
Primary Hyperoxaluria Type 3 ◽  
Type 3 ◽  
Hyperoxaluria Type

4-hydroxy-2-oxoglutarate aldolase (HOGA1) is a mitochondrial enzyme that plays a gatekeeper role in hydroxyproline metabolism. Its loss of function in humans causes primary hyperoxaluria type 3 (PH3), a rare condition characterised by excessive production of oxalate. In this study, we investigated the significance of the associated oxaloacetate decarboxylase activity which is also catalysed by HOGA1. Kinetic studies using the recombinant human enzyme (hHOGA1) and active site mutants showed both these dual activities utilise the same catalytic machinery with micromolar substrate affinities suggesting that both are operative in vivo. Biophysical and structural studies showed that pyruvate was a competitive inhibitor with an inhibition constant in the micromolar range. By comparison α-ketoglutarate was a weak inhibitor with an inhibition constant in the millimolar range and could only be isolated as an adduct with the active site Lys196 in the presence of sodium borohydride. These studies suggest that pyruvate inhibits HOGA1 activity during gluconeogenesis. We also propose that loss of HOGA1 function could increase oxalate production in PH3 by decreasing pyruvate availability and metabolic flux through the Krebs cycle.

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