Abstract
Several reversible inhibitors selective for human monoamine oxidase B (MAO B) that do not inhibit MAO A have been described in the literature. The following compounds: 8-(3-chlorostyryl)caffeine, 1,4-diphenyl-2-butene, and trans,trans-farnesol are shown to inhibit competitively human, horse, rat, and mouse MAO B with K(i) values in the low micromolar range but are without effect on either bovine or sheep MAO B or human MAO A. In contrast, the reversible competitive inhibitor isatin binds to all known MAO B and MAO A with similar affinities. Sequence alignments and the crystal structures of human MAO B in complex with 1,4-diphenyl-2-butene or with trans,trans-farnesol provide molecular insights into these specificities. These inhibitors span the substrate and entrance cavities with the side chain of Ile-199 rotated out of its normal conformation suggesting that Ile-199 is gating the substrate cavity. Ile-199 is conserved in all known MAO B sequences except bovine MAO B, which has Phe in this position (the sequence of sheep MAO B is unknown). Phe is conserved in the analogous position in MAO A sequences. The human MAO B I199F mutant protein of MAO B binds to isatin (K(i) = 3 microM) but not to the three inhibitors listed above. The crystal structure of this mutant demonstrates that the side chain of Phe-199 interferes with the binding of those compounds. This suggests that the Ile-199 "gate" is a determinant for the specificity of these MAO B inhibitors and provides a molecular basis for the development of MAO B-specific reversible inhibitors without interference with MAO A function in neurotransmitter metabolism.
Highlights
Two isoforms of monoamine oxidase (MAO),1 MAO A and monoamine oxidase B (MAO B), exist in humans and are both ϳ60-kDa outer-mito
Another study has established that 1,4-diphenyl-2-butene (Ki ϭ 35 M), a contaminant of polystyrene bridges used for MAO B crystallization, and 1,4-diphenyl-1,3-butadiene (Ki ϭ 7 M) are potent, competitive MAO B-specific reversible inhibitors [6, 7]
MAO B from bovine and sheep liver mitochondria and recombinant human MAO A were not inhibited by these compounds
Summary
Two isoforms of monoamine oxidase (MAO), MAO A and MAO B, exist in humans and are both ϳ60-kDa outer-mito-. Another study has established that 1,4-diphenyl-2-butene (Ki ϭ 35 M), a contaminant of polystyrene bridges used for MAO B crystallization, and 1,4-diphenyl-1,3-butadiene (Ki ϭ 7 M) are potent, competitive MAO B-specific reversible inhibitors [6, 7]. Because none of these compounds (see Scheme 1 for their respective structures) inhibit MAO A, a more detailed study of the molecular basis for their specificities could provide opportunities to develop MAO B-selective inhibitors with potential neuroprotective properties. Previous studies on the catalytic and inhibitor properties of rat [11] and of human [12] I199F MAO B mutant proteins show clear differences with the respective native enzymes which could not be readily interpreted in molecular detail
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