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The histamine N-methyltransferase T105I polymorphism affects active site structure and dynamics
Karen Rutherford1, W W Parson, Valerie Daggett
1Department of Biochemistry, University of Washington, Box 355061, Seattle, Washington 98195-5061, USA.
Biochemistry
|December 25, 2007
Summary
The common T105I genetic variation in histamine N-methyltransferase (HNMT) alters enzyme structure and function. Molecular dynamics reveal this polymorphism impacts histamine breakdown in the brain.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Histamine N-methyltransferase (HNMT) is crucial for histamine inactivation in the brain.
- A common human genetic polymorphism (T105I) affects HNMT activity and protein levels.
- Previous structural studies did not fully explain the functional impact of the T105I variant.
Purpose of the Study:
- To investigate the structural and dynamic effects of the T105I polymorphism in HNMT using molecular dynamics simulations.
- To elucidate the molecular mechanisms by which the T105I variant leads to reduced enzyme activity.
Main Methods:
- Molecular dynamics simulations of both wild-type (105T) and variant (105I) HNMT at 37°C.
- Analysis of structural changes, intramolecular interactions, and active site dynamics.
Main Results:
- The T105I substitution results in increased burial of residue 105 and tighter packing within the protein.
- This altered packing affects the orientation of active site residues involved in cosubstrate binding.
- Simulations revealed large-scale motions in the histamine-binding domain, impacting catalytic residue accessibility and substrate-binding site hydrophobicity.
Conclusions:
- The T105I polymorphism in HNMT alters protein structure and dynamics, leading to reduced enzyme activity.
- These findings provide a molecular basis for the functional consequences of this common genetic variation on histamine metabolism.
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