Papain-like peptidases: structure, function, and evolution

Abstract

Papain-like cysteine peptidases are a diverse family of peptidases found in most known organisms. In eukaryotes, they are divided into multiple evolutionary groups, which can be clearly distinguished on the basis of the structural characteristics of the proenzymes. Most of them are endopeptidases; some, however, evolved into exopeptidases by obtaining additional structural elements that restrict the binding of substrate into the active site. In humans, papain-like peptidases, also called cysteine cathepsins, act both as non-specific hydrolases and as specific processing enzymes. They are involved in numerous physiological processes, such as antigen presentation, extracellular matrix remodeling, and hormone processing. Their activity is tightly regulated and dysregulation of one or more cysteine cathepsins can result in severe pathological conditions, such as cardiovascular diseases and cancer. Other organisms can utilize papainlike peptidases for different purposes and they are often part of host-pathogen interactions. Numerous parasites, such as Plasmodium and flukes, utilize papain-like peptidases for host invasion, whereas plants, in contrast, use these enzymes for host defense. This review presents a state-of-the-art description of the structure and phylogeny of papain-like peptidases as well as an overview of their physiological and pathological functions in humans and in other organisms.

A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods

“…4b) Interaction of compound 1 with other cysteine peptidases. To determine the selectivity of compound 1 we have evaluated its inhibitory activity against other cysteine peptidases, including human cathepsins L, S and V that are closely related to cathepsin K as well as human cathepsin B, a ubiquitous and widely studied cysteine cathepsin 32 , and papain as the archetypal representative of the family. The azocasein assay was used for the comparison, because this substrate is effectively cleaved by all tested peptidases.…”

Structural and Functional Characterization of the Major Allergen Amb a 11 from Short Ragweed Pollen

“…4A) (22). When crystal structures of pro-rAmb a 11, pro-Der p 1 (Protein Data Bank code 1XKG) (23), and propapain (Protein Data Bank code 3TNX) (18) were superposed (Fig.…”

Synthesis of Novel 5-(N-Boc-N-Benzyl-2-aminoethyl)-7-oxo- 4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides and Their Inhibition of Cathepsins B and K

“…31 All compounds were initially tested for their activity at a concentration of 100 µM. As shown in Table 2, compound 5a had the strongest inhibitory effect on cathepsin K, with an IC 50 value of 25 ± 5 µM under the experimental conditions used in the assay and complete (100%) inhibition was observed at concentrations of 600 µM or higher.…”