Inhibition of the dapE-Encoded N-Succinyl-L,L-diaminopimelic Acid Desuccinylase from Neisseria meningitidis by L-Captopril. Biochemistry 2015 Aug 11;54(31):4834-44
Date
07/18/2015Pubmed ID
26186504Pubmed Central ID
PMC4671288DOI
10.1021/acs.biochem.5b00475Scopus ID
2-s2.0-84938704618 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
Binding of the competitive inhibitor L-captopril to the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Neisseria meningitidis (NmDapE) was examined by kinetic, spectroscopic, and crystallographic methods. L-Captopril, an angiotensin-converting enzyme (ACE) inhibitor, was previously shown to be a potent inhibitor of the DapE from Haemophilus influenzae (HiDapE) with an IC50 of 3.3 μM and a measured Ki of 1.8 μM and displayed a dose-responsive antibiotic activity toward Escherichia coli. L-Captopril is also a competitive inhibitor of NmDapE with a Ki of 2.8 μM. To examine the nature of the interaction of L-captopril with the dinuclear active site of DapE, we have obtained electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) data for the enzymatically hyperactive Co(II)-substituted forms of both HiDapE and NmDapE. EPR and MCD data indicate that the two Co(II) ions in DapE are antiferromagnetically coupled, yielding an S = 0 ground state, and suggest a thiolate bridge between the two metal ions. Verification of a thiolate-bridged dinuclear complex was obtained by determining the three-dimensional X-ray crystal structure of NmDapE in complex with L-captopril at 1.8 Å resolution. Combination of these data provides new insights into binding of L-captopril to the active site of DapE enzymes as well as important inhibitor-active site residue interaction's. Such information is critical for the design of new, potent inhibitors of DapE enzymes.
Author List
Starus A, Nocek B, Bennett B, Larrabee JA, Shaw DL, Sae-Lee W, Russo MT, Gillner DM, Makowska-Grzyska M, Joachimiak A, Holz RCAuthor
Brian Bennett D.Phil. Professor and Chair in the Physics department at Marquette UniversityMESH terms used to index this publication - Major topics in bold
Angiotensin-Converting Enzyme InhibitorsBacterial Proteins
Captopril
Catalytic Domain
Circular Dichroism
Crystallography, X-Ray
Lyases
Neisseria meningitidis