9p1b

Publication Abstract from PubMed

Mandelate racemase (MR) catalyzes the Mg(2+)-dependent interconversion of (R)- and (S)-mandelate and has been employed as a model enzyme to demonstrate that an enzyme catalyzing the deprotonation of a carbon acid substrate may be inhibited by boronic acids. We report a detailed structure-activity-based study of the ability of various boronic acid derivatives to competitively inhibit MR. 2-Naphthylboronic acid (K(i) = 0.32 +/- 0.01 muM), furan-3-boronic acid (K(i) = 10 +/- 1 muM), and thiophene-3-boronic acid (K(i) = 1.27 +/- 0.06 muM) were potent inhibitors of MR, while 1-naphthylboronic acid (K(i) = 28 +/- 3 muM) and nitrogen-heterocycles (e.g., isoxazole, indole, 1H-indazole, pyridine, and pyrimidine) bearing boronic acid groups were generally weaker inhibitors. A chlorine substituent on the pyridine (i.e., 2-chloro-pyridine-5-boronic or 2-chloro-pyridine-4-boronic acids) or pyrimidine (i.e., 2-chloro-pyrimidine-5-boronic acid) ring enhanced the binding affinity by 3- to 27-fold. Surprisingly, benzoxaboroles, including the antifungal agent tavaborole (i.e., 5-fluorobenzoxaborole, K(i) = 1.06 +/- 0.09 muM), were also potent competitive inhibitors of MR. The pH-dependence of the inhibition by benzoxaborole suggested that the species with the tetrahedral, sp(3)-hybridized boron atom was the more potent inhibitor. Interestingly, (11)B NMR spectroscopy and X-ray crystallography revealed that aryl boronic acids and benzoxaboroles interact with MR via different binding modes. Unlike phenylboronic acid, which forms an N(epsilon2)-B bond with His 297 at the active site, the 1.8-A resolution structure of the MR-tavaborole adduct revealed the presence of an N(zeta)-B bond between the bound tavaborole and Lys 166 at the active site.

Inhibition of Mandelate Racemase by Boron-Based Inhibitors: Different Binding Modes for Benzoxaboroles Versus Boronic Acids.,Hayden JA, Jabin A, Kuehm OP, Moncrief JG, St Maurice M, Bearne SL Biochemistry. 2025 Dec 30. doi: 10.1021/acs.biochem.5c00655. PMID:41467460^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.