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Structure-function relationships of mitochondrial monoamine oxidase A and B: chimaeric enzymes and site-directed mutagenesis studies

  • A. M. Cesura
  • J. Gottowik
  • G. Lang
  • P. Malherbe
  • M. Da Prada
Part of the Journal of Neural Transmission. Supplement book series (NEURAL SUPPL, volume 52)

Summary

To gain insight into the structure of monoamine oxidases (MAO) A and B, we investigated the properties of various chimaeric enzymes, engineered by moving progressively the junction between the NH2- and the COOH-termini of each MAO form. Whereas exchange of the ADP-binding sequence did not modify the catalytic properties of either MAO isoforms, chimaeras with increasing length of the NH2-terminus of MAO-A (up to position 256) showed a marked decrease in affinity towards substrates and inhibitors. Two sequences, spanning position 62 to 103 and 146 to 220, appeared of particular importance in putatively constituting the binding site of MAO-B. Conversely, the catalytic properties and specificity of MAO-A were insensitive to substitution of both the NH2- (up to position 112) and COOHtermini (from residue 395), but further modification of the central sequence of MAO-A was not compatible with activity. None of the engineered chimaeras showed a shift in substrate and inhibitor specificity. Investigation on MAO-B by site-directed mutagenesis revealed that His382 and Thr158 may represent residues relevant for MAO-B catalytic mechanism.

Keywords

Monoamine Oxidase Single Amino Acid Mutation Conserve Tyrosine Residue Mitochondrial Monoamine Oxidase Liver Monoamine Oxidase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Wien 1998

Authors and Affiliations

  • A. M. Cesura
    • 1
    • 2
  • J. Gottowik
    • 1
  • G. Lang
    • 1
  • P. Malherbe
    • 1
  • M. Da Prada
    • 1
  1. 1.Pharma Division, Preclinical Research, Nervous System DiseasesF. Hoffmann-La Roche LtdBaselSwitzerland
  2. 2.Pharma Division, Preclinical Research (PRPN, 70/304)F. Hoffmann-La Roche LtdBaselSwitzerland

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