Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B.
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.
De Colibus
Luigi
L
Department of Genetics and Microbiology, University of Pavia, via Abbiategrasso 207, 27100 Pavia, Italy.
Li
Min
M
Binda
Claudia
C
Lustig
Ariel
A
Edmondson
Dale E
DE
Mattevi
Andrea
A
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D051381:Rats; D040681:Structural Homology, Protein
D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase