Hubálek Frantisek, Binda Claudia, Khalil Ashraf, Li Min, Mattevi Andrea, Castagnoli Neal, Edmondson Dale E
Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA.
J Biol Chem. 2005 Apr 22;280(16):15761-6. doi: 10.1074/jbc.M500949200. Epub 2005 Feb 14.
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.
文献中已描述了几种对人单胺氧化酶B（MAO B）具有选择性且不抑制MAO A的可逆抑制剂。以下化合物：8-（3-氯苯乙烯基）咖啡因、1,4-二苯基-2-丁烯和反式，反式-金合欢醇已显示出在低微摩尔范围内以K(i)值竞争性抑制人、马、大鼠和小鼠的MAO B，但对牛或羊的MAO B或人MAO A无作用。相比之下，可逆竞争性抑制剂异吲哚酮以相似亲和力与所有已知的MAO B和MAO A结合。人MAO B与1,4-二苯基-2-丁烯或反式，反式-金合欢醇复合物的序列比对和晶体结构为这些特异性提供了分子见解。这些抑制剂跨越底物和入口腔，异亮氨酸-199的侧链旋转出其正常构象，表明异亮氨酸-199是底物腔的门控。除牛MAO B在此位置为苯丙氨酸（羊MAO B的序列未知）外，异亮氨酸-199在所有已知的MAO B序列中保守。苯丙氨酸在MAO A序列的类似位置保守。MAO B的人MAO B I199F突变蛋白与异吲哚酮结合（K(i)=3 microM），但不与上述三种抑制剂结合。该突变体的晶体结构表明苯丙氨酸-199的侧链干扰了这些化合物的结合。这表明异亮氨酸-199“门”是这些MAO B抑制剂特异性的决定因素，并为开发不干扰神经递质代谢中MAO A功能的MAO B特异性可逆抑制剂提供了分子基础。
