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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
PubMed
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.

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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.