Relative conformations of the isoalloxazine rings of the 8α-S-cysteinylFAD coenzymes in human MAO B and MAO A (top). For comparison, the ring conformation of the FAD cofactor of Rhodotorula gracilus D-amino acid oxidase is also shown (below). These structures are taken from coordinates deposited in the PDB with codes: 1OJA, 2Z5X, and 1C0K, respectively.

Active site cavity and inhibitor binding in MAO A and MAO B. The protein molecule is rotated approximately 180° with respect to the orientation of Figure 1 (i.e. with the C-terminal α-helix pointing upwards). In the top panel, among the known structures of human MAO B in complex with various inhibitors (Figure 5), that with isatin (27) has been chosen to be compared with binding of harmine to human MAO A because they are both non-covalent inhibitors of similar size and binding affinity (MAO B-isatin K_i = 3 µM, MAO A-harmine K_i = 0.6 µM). In the bottom panel the structures of human and rat MAO A in complex with clorgyline are compared. The flavin and inhibitor molecules are in yellow and black ball-and-stick representation, respectively. The Tyr side chains beside the flavin (Tyr407 and Tyr444 in MAO A, Tyr398 and Tyr435 in MAO B) form the conserved “aromatic sandwich” (41). Among the other active site residues, Phe208 (Ile199 in MAO B) and Ile335 (Tyr326 in MAO B) are drawn to highlight their role in determining substrate/inhibitor specificity between MAO A and MAO B (see text). The PDB codes for each structure are in parentheses. The cavity-shaping loop (residue 210–216 in MAO A) is colored in cyan as in Figure 1. The cavities were calculated with VOIDOO (28) and the pictures were produced with Bobscript (42) and Raster3D (43).

Location of three bound Xe atoms in the entrance cavity and substrate cavity of human MAO B (only one monomeric unit is shown). Xenon is denoted as dark yellow spheres. FAD is in yellow. The substrate binding domain is in red, FAD binding domain in blue, and the membrane binding domain in green. The substrate and entrance cavities of MAO B are in cyan. Unpublished data from this laboratory.

Structures of MAO B-Specific Inhibitors.

General Mechanisms for C-H Bond Cleavage Reactions in Flavoenzymes.

Proposed Polar Nucleophilic Mechanism for the Reductive Half Reaction of MAO Catalysis.

Ribbon diagram showing the three-dimensional structures of human MAO A (24), human MAO B (25) and rat MAO A (26). All structures are oriented with the C-terminal trans-membrane helices pointing downwards. The FAD cofactor is in yellow ball-and-stick representation. Active site cavity in each enzyme molecule is drawn as a gray surface. The cavity-shaping loop (residues 210–216 in human and rat MAO A and the corresponding residues 201–207 in human MAO B) is highlighted in cyan. The loop lining the entrance cavity space in human MAO B (residues 99–110) (27) is featured in blue. The corresponding residues in rat and human MAO A adopt the same conformation. The cavities were calculated with VOIDOO (28) and the structural representations produced with Pymol (www.pymol.org).

Distances calculated from X-ray structures and determined from analysis of DEER dipolar couplings between the flavin cofactors (orange) and between the pargyline analogue spin labels (green). The positions of the pargyline spin labels in each active site are based on super-positions with the known structures of pargyline covalent adducts (blue).

Comparison of active site cavity structures of human MAO B in different enzyme-inhibitor complexes. The PDB codes for each structure are in parentheses. The protein molecule is rotated approximately 90° around an axis perpendicular to the plane of picture with respect to Figure 4. The residues lining the cavity are in gray ball-and-stick with carbon, oxygen, nitrogen and sulfur atoms in black, red, blue and yellow, respectively. Water molecules included in the cavity are represented as green spheres. The flavin is in yellow and the inhibitor molecule is in blue.

General Reaction Scheme for MAO Catalysis.

Proposed Mechanism for Mofegiline Inhibition of Human MAO B

Reaction of Rimoldi’s Amine with MAO B.

Proposed Mechanisms for O₂ Reaction in the Oxidative Half Reaction of MAO Catalysis.