β-Lactam Compounds. Inhibitors of Transpeptidases, β-Lactamases and Elastases: A Review

Abstract

Listen

Translate article

Abstract: There are three classes of serine proteases that specifically recognise and cleave the cyclic amide bond of the four membered P­ lactam ring. One class is the bacterial D-alanyi-D-alanine transpeptidases/ carboxypeptidases or D,D-peptidase enzymes, which are the inhibitory targets for p-lactam antibiotics. The second group are the bacterial P­ lactamases, which catalyse the hydrolysis of the P-lactam antibiotics, yielding biologically inactive products.The third group are elastases, particularly the mammalian human leukocyte elastase which is a serine protease that uses the catalytic triad of Ser-195, His-57 and Asp-102, to catalyse the cleavage of the amide bonds of peptides and various proteins, including elastin, the connective tissue of the lung. The mechanism by which the three classes of enzymes cleave amide bond involves the nucleophilic addition of the hydroxyl group of an active site serine to the carbonyl carbon of the cleavable P-lactam bond and formation of a tetrahedral intermediate that collapses to an acyl­ enzyme intermediate. P-Lactamases differ from D,D-peptidases in that they catalyse the dea­ cylation step very efficiently. Although P-lactamases resemble elastases in the formation of an acyl-enzyme intermediate via the enzyme active-site serine, they differ in that the cooperating residues are lysine and glutamic acid for class A P-lactamases, and histidine and aspartic acid for elastases. The mechanism of action of these three types of enzymes has been supported by X-ray crystallographic determination and/or by electrospray ionization mass-spectrometry. Kinetic studies were used to decide whether a postulated intermediate lies on the reaction pathway. Application of site-directed mutagenesis has led to new insights into the mechanism of catalysis by P-lactamases. This review takes examples, mostly from P-lactam compounds developed as elastase inhibitors, to illustrate how an understanding of physico-chemical properties and an appreciation of the molecular shape and electronic properties can lead to a better insight into molecular recognition processes. The synthetic methods employed in the synthesis of lead P-lactam compounds as elastase inhibitors are also discussed.