PMID- 10584067
OWN - NLM
STAT- MEDLINE
DCOM- 19991229
LR  - 20191103
IS  - 0887-3585 (Print)
IS  - 0887-3585 (Linking)
VI  - 37
IP  - 2
DP  - 1999 Nov 1
TI  - Modelling the catalytic reaction in human aldose reductase.
PG  - 218-27
AB  - Aldose reductase (ALR2) has received considerable attention due to its possible 
      link to long-term diabetic complications. Although crystal structures and kinetic 
      data reveal important aspects of the reaction mechanism, details of the catalytic 
      step are still unclear. In this paper a computer simulation study is presented 
      that utilizes the hybrid quantum mechanical and molecular mechanical (QM-MM) 
      potential to elucidate the nature of the hydride and proton transfer steps in the 
      reduction of D-glyceraldehyde by ALR2. Several reaction pathways were 
      investigated in two models with either Tyr48 or protonated His110+ acting as the 
      potential proton donor in the active site. Calculations show that the substrate 
      binds to ALR2 through hydrogen bonds in an orientation that facilitates the 
      stereospecific catalytic step in both models. It is established that in the case 
      that His110 is present in the protonated form in the native complex, it is the 
      energetically favored proton donor compared with Tyr48 in the active pocket with 
      neutral His110. The reaction mechanisms in the different models are discussed 
      based on structural and energetic considerations.
FAU - Varnai, P
AU  - Varnai P
AD  - Physical and Theoretical Chemistry Laboratory, Oxford University, United Kingdom.
FAU - Richards, W G
AU  - Richards WG
FAU - Lyne, P D
AU  - Lyne PD
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proteins
JT  - Proteins
JID - 8700181
RN  - 367-47-5 (Glyceraldehyde)
RN  - EC 1.1.1.21 (Aldehyde Reductase)
SB  - IM
MH  - Aldehyde Reductase/*chemistry/metabolism
MH  - Catalysis
MH  - Catalytic Domain
MH  - Energy Metabolism
MH  - Glyceraldehyde/chemistry
MH  - Humans
MH  - Models, Molecular
MH  - Oxidation-Reduction
MH  - Static Electricity
MH  - Stereoisomerism
EDAT- 1999/12/03 09:00
MHDA- 2000/06/20 09:00
CRDT- 1999/12/03 09:00
PHST- 1999/12/03 09:00 [pubmed]
PHST- 2000/06/20 09:00 [medline]
PHST- 1999/12/03 09:00 [entrez]
AID - 10.1002/(SICI)1097-0134(1999)37:3+<218::AID-PROT28>3.0.CO;2-X [pii]
AID - 10.1002/(sici)1097-0134(19991101)37:2<218::aid-prot7>3.0.co;2-e [doi]
PST - ppublish
SO  - Proteins. 1999 Nov 1;37(2):218-27. doi: 
      10.1002/(sici)1097-0134(19991101)37:2<218::aid-prot7>3.0.co;2-e.