PMID- 23389436
OWN - NLM
STAT- MEDLINE
DCOM- 20130823
LR  - 20131121
IS  - 1463-9084 (Electronic)
IS  - 1463-9076 (Linking)
VI  - 15
IP  - 11
DP  - 2013 Mar 21
TI  - The catalytic mechanism of glyceraldehyde 3-phosphate dehydrogenase from 
      Trypanosoma cruzi elucidated via the QM/MM approach.
PG  - 3772-85
LID - 10.1039/c3cp43968b [doi]
AB  - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been identified as a key 
      enzyme involved in glycolysis processes for energy production in the Trypanosoma 
      cruzi parasite. This enzyme catalyses the oxidative phosphorylation of 
      glyceraldehyde 3-phosphate (G3P) in the presence of inorganic phosphate (Pi) and 
      nicotinamide adenosine dinucleotide (NAD+). The catalytic mechanism used by GAPDH 
      has been intensively investigated. However, the individual roles of Pi and the C3 
      phosphate of G3P (Ps) sites, as well as some residues such as His194 in the 
      catalytic mechanism, remain unclear. In this study, we have employed Molecular 
      Dynamics (MD) simulations within hybrid quantum mechanical/molecular mechanical 
      (QM/MM) potentials to obtain the Potential of Mean Force of the catalytic 
      oxidative phosphorylation mechanism of the G3P substrate used by GAPDH. According 
      to our results, the first stage of the reaction (oxidoreduction) takes place in 
      the Pi site (energetically more favourable), with the formation of oxyanion 
      thiohemiacetal and thioacylenzyme intermediates without acid-base assistance of 
      His194. Analysis of the interaction energy by residues shows that Arg249 has an 
      important role in the ability of the enzyme to bind the G3P substrate, which 
      interacts with NAD+ and other important residues, such as Cys166, Glu109, Thr167, 
      Ser247 and Thr226, in the GAPDH active site. Finally, the inhibition mechanism of 
      the GAPDH enzyme by the 3-(p-nitrophenoxycarboxyl)-3-ethylene propyl 
      dihydroxyphosphonate inhibitor was investigated in order to contribute to the 
      design of new inhibitors of GAPDH from Trypanosoma cruzi.
FAU - Reis, Mauro
AU  - Reis M
AD  - Laboratorio de Planejamento e Desenvolvimento de Farmacos, Instituto de Ciencias 
      Exatas e Naturais, Universidade Federal do Para, CP 11101, 66075-110, Belem, PA, 
      Brazil.
FAU - Alves, Claudio Nahum
AU  - Alves CN
FAU - Lameira, Jeronimo
AU  - Lameira J
FAU - Tunon, Inaki
AU  - Tunon I
FAU - Marti, Sergio
AU  - Marti S
FAU - Moliner, Vicent
AU  - Moliner V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Phys Chem Chem Phys
JT  - Physical chemistry chemical physics : PCCP
JID - 100888160
RN  - 0U46U6E8UK (NAD)
RN  - EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases)
SB  - IM
MH  - Biocatalysis
MH  - Glyceraldehyde-3-Phosphate Dehydrogenases/chemistry/*metabolism
MH  - *Molecular Dynamics Simulation
MH  - NAD/chemistry/metabolism
MH  - Oxidation-Reduction
MH  - Oxidative Phosphorylation
MH  - *Quantum Theory
MH  - Substrate Specificity
MH  - Trypanosoma cruzi/*enzymology
EDAT- 2013/02/08 06:00
MHDA- 2013/08/24 06:00
CRDT- 2013/02/08 06:00
PHST- 2013/02/08 06:00 [entrez]
PHST- 2013/02/08 06:00 [pubmed]
PHST- 2013/08/24 06:00 [medline]
AID - 10.1039/c3cp43968b [doi]
PST - ppublish
SO  - Phys Chem Chem Phys. 2013 Mar 21;15(11):3772-85. doi: 10.1039/c3cp43968b.