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Title 

A critical role for the histidine residues in the catalytic function of acyl-CoA:cholesterol acyltransferase catalysis: evidence for catalytic difference between ACAT1 and ACAT2

Authors 

So-Jin AnK H ChoWoo Song LeeJ O LeeY K PaikTae Sook Jeong

Publisher 

Elsevier

Issue Date 

2006

Citation 

FEBS Letters, vol. 580, no. 11, pp. 2741-2749

Keywords 

Acyl-CoA:cholesterol acyltransferase-1Acyl-CoA:cholesterol acyltransferase-2catalysisenzyme active sitehistidinepoint mutation25 hydroxycholesterolacyl coa:cholesterol acyltransferase 1acyl coa:cholesterol acyltransferase 2alanine

Abstract 

To investigate a role for histidine residues in the expression of normal acyl-CoA:cholesterol acyltransferase (ACAT) activity, the histidine residues located at five different positions in two isoenzymes were substituted by alanine, based on the sequence homology between ACAT1 and ACAT2. Among the 10 mutants generated by baculovirus expression technology, H386A-ACAT1, H460A-ACAT1, H360A-ACAT2, and H399A-ACAT2 lost their enzymatic activity completely. A reduction in catalytic activity is unlikely to result from structural changes in the substrate-binding pocket, because their substrate-binding affinities were normal. However, the enzymatic activity of H386A-ACAT1 was restored to <37% of the level of the wild-type activity when cholesterol was replaced by 25-hydroxycholesterol as substrate. H527A-ACAT1 and H501A-ACAT2, termed carboxyl end mutants, exhibit activities of ∼96% and ∼75% of that of the wild-type. Interestingly, H425A-ACAT1 showed 59% of the wild-type activity, in contrast to its equivalent mutant, H399A-ACAT2. These results demonstrate that the histidine residues located at the active site are very crucial both for the catalytic activity of the enzyme and for distinguishing ACAT1 from ACAT2 with respect to enzyme catalysis and substrate specificity.

ISSN 

0014-5793

Link 

http://dx.doi.org/10.1016/j.febslet.2006.04.035

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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