Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2009-7-20
pubmed:abstractText
Glucokinase (GK), a glucose sensor, maintains plasma glucose homeostasis via phosphorylation of glucose and is a potential therapeutic target for treating maturity-onset diabetes of the young (MODY) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). To characterize the catalytic mechanism of glucose phosphorylation by GK, we combined molecular modeling, molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) calculations, experimental mutagenesis and enzymatic kinetic analysis on both wild-type and mutated GK. Our three-dimensional (3D) model of the GK-Mg(2+)-ATP-glucose (GMAG) complex, is in agreement with a large number of mutagenesis data, and elucidates atomic information of the catalytic site in GK for glucose phosphorylation. A 10-ns MD simulation of the GMAG complex revealed that Lys169 plays a dominant role in glucose phosphorylation. This prediction was verified by experimental mutagenesis of GK (K169A) and enzymatic kinetic analyses of glucose phosphorylation. QM/MM calculations were further used to study the role of Lys169 in the catalytic mechanism of the glucose phosphorylation and we found that Lys169 enhances the binding of GK with both ATP and glucose by serving as a bridge between ATP and glucose. More importantly, Lys169 directly participates in the glucose phosphorylation as a general acid catalyst. Our findings provide mechanistic details of glucose phorphorylation catalyzed by GK, and are important for understanding the pathogenic mechanism of MODY.
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-10426385, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-10480597, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-10525657, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-10686099, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-11237213, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-11916951, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-12050210, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-12426581, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-12666168, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-12869762, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-1323828, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-14517946, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-14993457, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-15016359, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-15677479, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-1570017, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-15752705, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-16105828, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-16200636, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-16938872, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-18370929, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-18397317, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-2136935, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-2770867, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-3041592, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-5919684, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-7656036, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-7742312, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-7821739, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-8071309, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-8194664, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-8433729, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-8446612, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-8638934, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-9435328, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-9519733, http://linkedlifedata.com/resource/pubmed/commentcorrection/19617908-9735292
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1932-6203
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
4
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
e6304
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Lys169 of human glucokinase is a determinant for glucose phosphorylation: implication for the atomic mechanism of glucokinase catalysis.
pubmed:affiliation
Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Graduate School of Chinese Academy of Sciences, Shanghai, China.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Validation Studies