Cama Evis, Shin Hyunshun, Christianson David W
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
J Am Chem Soc. 2003 Oct 29;125(43):13052-7. doi: 10.1021/ja036365b.
Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to form L-ornithine plus urea. Chiral L-amino acids bearing sulfonamide side chains have been synthesized in which the tetrahedral sulfonamide groups are designed to target bridging coordination interactions with the binuclear manganese cluster in the arginase active site. Syntheses of the amino acid sulfonamides have been accomplished by the amination of sulfonyl halide derivatives of (S)-(tert-butoxy)-[(tert-butoxycarbonyl)amino]oxoalkanoic acids. Amino acid sulfonamides with side chains comparable in length to that of L-arginine exhibit inhibition in the micromolar range, and the X-ray crystal structure of arginase I complexed with one of these inhibitors, S-(2-sulfonamidoethyl)-L-cysteine, has been determined at 2.8 A resolution. In the enzyme-inhibitor complex, the sulfonamide group displaces the metal-bridging hydroxide ion of the native enzyme and bridges the binuclear manganese cluster with an ionized NH(-) group. The binding mode of the sulfonamide inhibitor may mimic the binding of the tetrahedral intermediate and its flanking transition states in catalysis. It is notable that the ionized sulfonamide group is an excellent bridging ligand in this enzyme-inhibitor complex; accordingly, the sulfonamide functionality can be considered in the design of inhibitors targeting other binuclear metalloenzymes.
精氨酸酶是一种双核锰金属酶，催化L-精氨酸水解生成L-鸟氨酸和尿素。已合成了带有磺酰胺侧链的手性L-氨基酸，其中四面体磺酰胺基团旨在靶向与精氨酸酶活性位点中的双核锰簇的桥联配位相互作用。氨基酸磺酰胺的合成是通过对(S)-(叔丁氧基)-[(叔丁氧羰基)氨基]氧代链烷酸的磺酰卤衍生物进行胺化来完成的。侧链长度与L-精氨酸相当的氨基酸磺酰胺在微摩尔范围内表现出抑制作用，并且已测定了精氨酸酶I与这些抑制剂之一S-(2-磺酰胺基乙基)-L-半胱氨酸复合的X射线晶体结构，分辨率为2.8 Å。在酶-抑制剂复合物中，磺酰胺基团取代了天然酶的金属桥连氢氧根离子，并用一个离子化的NH(-)基团桥连双核锰簇。磺酰胺抑制剂的结合模式可能模拟催化过程中四面体中间体及其侧翼过渡态的结合。值得注意的是，离子化的磺酰胺基团在这种酶-抑制剂复合物中是一种出色的桥连配体；因此，在设计针对其他双核金属酶的抑制剂时可以考虑磺酰胺官能团。
