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A proof-of-concept is provided to prove that Cys59 offers a molecular target to differentiate the type-I EcMetAP enzyme from type-II MetAP enzymes, and therefore small molecules that target Cys59 represent a new class of antibiotic. The experimental data indicate that type-I MetAPs could be specifically inhibited by covalent modification of Cys residues thus supporting the hypothesis.

Linear free energy relationships [beta(sub nuc) and beta(sub Ig)] (LFER) and kinetic isotope effects (KIE) for the reactions of oxyanions with aryl dimethylphosphinothioates is measured to resolve the mechanistic ambiguity on the hydrolysis of aryl phosphinothioate esters. The LFER and KIE data are found to be consistent with a combined reaction and disfavor a stepwise mechanism.

Earlier work on the hydrolysis of aryl phosphinothioate esters has led to contradictory mechanistic conclusions. To resolve this mechanistic ambiguity, we have measured linear tree energy relationships (βnuc and βIg) and kinetic isotope effects for the reactions of oxyanions with aryl dimethylphosphinothioates. For the attack of nucleophiles on 4-nitrophenyl dimethylphosphinothioate, βnuc 0.47 ± 0.05 for phenoxide nucleophiles (pKa < 11) and βnuc = 0.08 ± 0.01 for hydroxide and alkoxide nucleophiles (pKa ≥ 11). Linearity of the plot in the range that straddles the pKa of the leaving group (4-nitrophenoxide, pKa 7.14) is indicative of a concerted mechanism. The much lower value of βnuc for the more basic nucleophiles reveals the importance of a desolvation step prior to rate-limiting nucleophilic attack. The reactions of a series of substituted aryl dimethylphosphinothioate esters give the same value of βIg with the nucleophiles HO- (β = -0.54 ± 0.03) and PhO- (β = -0.52 ± 0.09). A significantly better Hammett correlation is obtained with σ- than with σ or σ°, as expected for a transition state involving rate-limiting cleavage of the P-OAr bond. The 18O KIE at the position of bond fission (18k = 1.0124 ± 0.0008) indicates the P-O bond is ∼40% broken, and the 15N KIE in the leaving group (15k= 1.0009 ± 0.0003) reveals the nucleofuge carries about a third of a negative charge in the transition state. Thus, both the LFER and KIE data are consistent with a concerted reaction and disfavor a stepwise mechanism. [ABSTRACT FROM AUTHOR]

Dinuclear [(TPyA)FeII(THBQ(2-))FeII(TPyA)](BF4)2 (1) possesses hydrogen bonding interactions that form a 1-D chain, and pi-pi interactions between the 1-D chains that give rise to a 2-D supramolecular-layered structure, inducing hysteresis in the spin crossover behavior; 1 has shown spin crossover behavior around 250 K with thermal hysteresis and ferromagnetic interactions at low temperature.