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Open AccessArticle

Closure of the Human TKFC Active Site: Comparison of the Apoenzyme and the Complexes Formed with Either Triokinase or FMN Cyclase Substrates

1
Laboratório Associado LSRE-LCM, Escola Superior de Tecnologia e Gestão, Instituto Politécnico de Leiria, P-2411-901 Leiria, Portugal
2
Grupo de Enzimología, Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Medicina, Universidad de Extremadura, E-06006 Badajoz, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(5), 1099; https://doi.org/10.3390/ijms20051099
Received: 18 January 2019 / Revised: 20 February 2019 / Accepted: 27 February 2019 / Published: 4 March 2019
(This article belongs to the Special Issue Molecular Dynamics Simulations)
Human triokinase/flavin mononucleotide (FMN) cyclase (hTKFC) catalyzes the adenosine triphosphate (ATP)-dependent phosphorylation of D-glyceraldehyde and dihydroxyacetone (DHA), and the cyclizing splitting of flavin adenine dinucleotide (FAD). hTKFC structural models are dimers of identical subunits, each with two domains, K and L, with an L2-K1-K2-L1 arrangement. Two active sites lie between L2-K1 and K2-L1, where triose binds K and ATP binds L, although the resulting ATP-to-triose distance is too large (≈14 Å) for phosphoryl transfer. A 75-ns trajectory of molecular dynamics shows considerable, but transient, ATP-to-DHA approximations in the L2-K1 site (4.83 Å or 4.16 Å). To confirm the trend towards site closure, and its relationship to kinase activity, apo-hTKFC, hTKFC:2DHA:2ATP and hTKFC:2FAD models were submitted to normal mode analysis. The trajectory of hTKFC:2DHA:2ATP was extended up to 160 ns, and 120-ns trajectories of apo-hTKFC and hTKFC:2FAD were simulated. The three systems were comparatively analyzed for equal lengths (120 ns) following the principles of essential dynamics, and by estimating site closure by distance measurements. The full trajectory of hTKFC:2DHA:2ATP was searched for in-line orientations and short distances of DHA hydroxymethyl oxygens to ATP γ-phosphorus. Full site closure was reached only in hTKFC:2DHA:2ATP, where conformations compatible with an associative phosphoryl transfer occurred in L2-K1 for significant trajectory time fractions. View Full-Text
Keywords: triokinase; dihydroxyacetone kinase; FMN cyclase; phosphoryl transfer mechanism; protein domain mobility; active-site closure; normal mode analysis; molecular dynamics simulation; essential dynamics triokinase; dihydroxyacetone kinase; FMN cyclase; phosphoryl transfer mechanism; protein domain mobility; active-site closure; normal mode analysis; molecular dynamics simulation; essential dynamics
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Rodrigues, J.R.; Cameselle, J.C.; Cabezas, A.; Ribeiro, J.M. Closure of the Human TKFC Active Site: Comparison of the Apoenzyme and the Complexes Formed with Either Triokinase or FMN Cyclase Substrates. Int. J. Mol. Sci. 2019, 20, 1099.

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