Molecular and mechanistic properties of the membrane-bound mitochondrial monoamine oxidases.
The past decade has brought major advances in our knowledge of the structures and mechanisms of MAO A and MAO B, which are pharmacological targets for specific inhibitors. In both enzymes, crystallographic and biochemical data show their respective C-terminal transmembrane helices anchor the enzymes to the outer mitochondrial membrane. Pulsed EPR data show both enzymes are dimeric in their membrane-bound forms with agreement between distances measured in their crystalline forms. Distances measured between active site-directed spin-labels in membrane preparations show excellent agreement with those estimated from crystallographic data. Our knowledge of requirements for development of specific reversible MAO B inhibitors is in a fairly mature status. Less is known regarding the structural requirements for highly specific reversible MAO A inhibitors. In spite of their 70% level of sequence identity and similarities of C(alpha) folds, the two enzymes exhibit significant functional and structural differences that can be exploited in the ultimate goal of the development of highly specific inhibitors. This review summarizes the current structural and mechanistic information available that can be utilized in the development of future highly specific neuroprotectants and cardioprotectants.
Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA. deedmon@emory.edu
Dale E
DE
Edmondson
Claudia
C
Binda
Jin
J
Wang
Anup K
AK
Upadhyay
Andrea
A
Mattevi
D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D002082:Butylamines / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats
D000498:Allyl Compounds; D002082:Butylamines; C058000:mofegiline; D008995:Monoamine Oxidase