Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B

Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12684-9. doi: 10.1073/pnas.0505975102. Epub 2005 Aug 29.

Abstract

The three-dimensional structure of recombinant human monoamine oxidase A (hMAO A) as its clorgyline-inhibited adduct is described. Although the chain-fold of hMAO A is similar to that of rat MAO A and human MAO B (hMAO B), hMAO A is unique in that it crystallizes as a monomer and exhibits the solution hydrodynamic behavior of a monomeric form rather than the dimeric form of hMAO B and rat MAO A. hMAO A's active site consists of a single hydrophobic cavity of approximately 550 A3, which is smaller than that determined from the structure of deprenyl-inhibited hMAO B (approximately 700 A3) but larger than that of rat MAO A (approximately 450 A3). An important component of the active site structure of hMAO A is the loop conformation of residues 210-216, which differs from that of hMAO B and rat MAO A. The origin of this structural alteration is suggested to result from long-range interactions in the monomeric form of the enzyme. In addition to serving as a basis for the development of hMAO A specific inhibitors, these data support the proposal that hMAO A involves a change from the dimeric to the monomeric form through a Glu-151 --> Lys mutation that is specific of hMAO A [Andrès, A. M., Soldevila, M., Navarro, A., Kidd, K. K., Oliva, B. & Bertranpetit, J. (2004) Hum. Genet. 115, 377-386]. These considerations put into question the use of MAO A from nonhuman sources in drug development for use in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Monoamine Oxidase / chemistry*
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / chemistry
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Rats
  • Structural Homology, Protein

Substances

  • Monoamine Oxidase Inhibitors
  • Monoamine Oxidase

Associated data

  • PDB/2BXR
  • PDB/2BXS
  • PDB/2BYB