Metal-coordinating substrate analogs as inhibitors of metalloenzymes.
A group of active-site metal coordinating inhibitors of zinc proteases (carboxypeptidase A, thermolysin, Bacillus cereus neutral protease, and angiotensin-converting enzyme) have been synthesized and their properties investigated. Their general structures are R-SH and R-NH-PO2(O phi)H, where-S- or -O- serve as metal ligands and R refers to an amino acid or peptide group designed to interact with substrate recognition sites. These inhibitors can be extremely potent; thus, N-(2-mercaptoacetyl)-D-phenylalanine, e.g., inhibits carboxypeptidase A with a Kiapp of 2.2 x 10(-7) M. The spectral response of cobalt(II)-substituted thermolysin or carboxypeptidase A to the sulfur-containing inhibitors signals the direct interaction of the mercaptan with the metal. An S leads to Co(II) charge transfer band is generated near 340 nm and is detected by absorption, circular dichroism, and magnetic circular dichroism. The cobalt(II) spectra indicate both inner sphere coordination with sulfur and 4-coordination in the enzyme-inhibitor complex. Thus, the metal undergoes a simple substitution reaction, the inhibitor most likely displacing water at the fourth coordination site.
D000806:Angiotensin-Converting Enzyme Inhibitors; D001665:Binding Sites; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D055598:Chemical Phenomena; D002621:Chemistry; D002942:Circular Dichroism; D003035:Cobalt / Q000494:pharmacology*; D007700:Kinetics; D008667:Metalloproteins / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors; D013057:Spectrum Analysis; D013438:Sulfhydryl Compounds; D013820:Thermolysin / Q000037:antagonists & inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D008667:Metalloproteins; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D003035:Cobalt; D002268:Carboxypeptidases; D013820:Thermolysin