Document Detail

Comparison of dynamics of wildtype and V94M human UDP-galactose 4-epimerase-A computational perspective on severe epimerase-deficiency galactosemia.
MedLine Citation:
PMID:  23732289     Owner:  NLM     Status:  MEDLINE    
UDP-galactose 4'-epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose, an important step in galactose catabolism. Type III galactosemia, an inherited metabolic disease, is associated with mutations in human GALE. The V94M mutation has been associated with a very severe form of type III galactosemia. While a variety of structural and biochemical studies have been reported that elucidate differences between the wildtype and this mutant form of human GALE, little is known about the dynamics of the protein and how mutations influence structure and function. We performed molecular dynamics simulations on the wildtype and V94M enzyme in different states of substrate and cofactor binding. In the mutant, the average distance between the substrate and both a key catalytic residue (Tyr157) and the enzyme-bound NAD+ cofactor and the active site dynamics are altered making substrate binding slightly less stable. However, overall stability or dynamics of the protein is not altered. This is consistent with experimental findings that the impact is largely on the turnover number (kcat), with less substantial effects on Km. Active site fluctuations were found to be correlated in enzyme with substrate bound to just one of the subunits in the homodimer suggesting inter-subunit communication. Greater active site loop mobility in human GALE compared to the equivalent loop in Escherichia coli GALE explains why the former can catalyze the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine while the bacterial enzyme cannot. This work illuminates molecular mechanisms of disease and may inform the design of small molecule therapies for type III galactosemia.
David J Timson; Steffen Lindert
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-05-31
Journal Detail:
Title:  Gene     Volume:  526     ISSN:  1879-0038     ISO Abbreviation:  Gene     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-07-29     Completed Date:  2013-10-18     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  7706761     Medline TA:  Gene     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  318-24     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier B.V. All rights reserved.
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MeSH Terms
Escherichia coli / genetics,  metabolism
Galactosemias / genetics*
Molecular Dynamics Simulation*
Protein Binding
Protein Conformation
Protein Stability
Substrate Specificity
UDPglucose 4-Epimerase / chemistry*,  genetics*
Grant Support
R01 GM031749/GM/NIGMS NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
EC 4-Epimerase

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