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Expression, Purification, Crystallization, and Enzyme Assays of Fumarylacetoacetate Hydrolase Domain-Containing Proteins
Published on: June 20, 2019
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Structural Features and Domain Movements Controlling Substrate Binding and Cofactor Specificity in Class II HMG-CoA
1Department of Chemistry, Bryn Mawr College , 101 North Merion Avenue, Bryn Mawr, Pennsylvania 19010, United States.
Biochemistry
|December 12, 2017
Summary
This study reveals the structural basis for cofactor specificity in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR). Insights into enzyme mechanism and domain movements were uncovered using crystal structures and kinetic data.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) is crucial for producing essential metabolites.
- While statin inhibition is known, HMGR's catalytic mechanism and cofactor specificity remain unclear.
Purpose of the Study:
- To elucidate the structural basis of cofactor specificity in HMGR.
- To understand the catalytic mechanism of HMGR, particularly domain movements and cofactor exchange.
Main Methods:
- X-ray crystallography of Streptococcus pneumoniae HMGR (SpHMGR).
- Kinetic analysis of enzyme cofactor preferences.
- Structural determination of SpHMGR bound to NADPH and HMG-CoA.
Main Results:
- Crystal structures of SpHMGR reveal NADPH-specific binding mechanisms.
- Observed large conformational domain movements in HMG-CoA-bound SpHMGR.
- Data suggests cofactor exchange occurs without intermediate release.
Conclusions:
- Provides critical insights into the HMGR reaction mechanism.
- Explains the structural basis for varying cofactor specificities across different HMGR enzymes.
- Advances understanding of natural product biosynthesis and enzyme catalysis.
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