Sulfamide derivatives as transition state analogue inhibitors for carboxypeptidase A.
3-Phenyl-2-sulfamoyloxypropionic acid (2), 2-benzyl-3-sulfamoylpropionic acid (3), and N-(N-hydroxysulfamoyl)phenylalanine (5) have been synthesized and evaluated as inhibitors for carboxypeptidase A (CPA) to find that they inhibit the enzyme competitively with the Ki values in the microM range, suggesting that their binding modes to CPA are analogous to each other, and resemble the binding mode of N-sulfamoylphenylalanine (1) that has been established by the X-ray crystallographic method to form a complex with CPA in a manner reminiscent of the binding of a transition state in the catalytic pathway. It was concluded thus that they are a new type of transition state analogue inhibitors for CPA. (R)-N-Hydroxy-N-sulfamoyl-beta-phenylalanine (8) was shown to be also a potent CPA inhibitor (Ki = 39 microM), the high potency of which may be ascribed to the involvement of the hydroxyl in the binding of CPA, most likely forming bidentate coordinative bonds to the zinc ion in CPA together with the sulfamoyl oxygen atom.
Park
Jung Dae
JD
Center for Integrated Molecular System and Division of Molecular and Life Sciences, Pohang University of Science and Technology, San 31 Hyoja-dong, Namku, Pohang 790-784, Korea.
Kim
Dong H
DH
D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors*; D007700:Kinetics; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology*
D011480:Protease Inhibitors; D013451:Sulfonic Acids; C005741:sulfamic acid; D043422:Carboxypeptidases A