Cathepsins are proteases ( enzymes that degrades proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes. Thus, the activity of this family lies almost entirely within those organelles. There are, however, exceptions such as cathepsin K, which works extracellularly after secretion by osteoclasts in bone resorption. Cathepsins have a vital role in mammalian cellular turnover, e.g. bone resorption. They degrade polypeptides and are distinguished by their substrate specificities.
Classification of cathepsins
Cathepsins are a type of enzyme which includes many different classes of proteases. Several of the cathepsins are cysteine proteases, while others are either serine or aspartic proteases. Cathepsins are classified into various categories based on criteria, such as expression, localization/distribution, activity, and the catalytic type of protease. Using localization, and expression cathepsins are divided into two groups, lysosomal, and extra lysosomal, or tissue specific. Cathepsins primarily act as lysosomal proteolytic enzymes, and include seven enzymes: cathepsins C, O, F, H, M, B, and L. Tissue specific cathepsins include cathepsins K, Q, J, M, R, X, W, S, P, and V.
Cathepsin proteases are synthesized in the cell as inactive pre-pro-enzymes in the ribosomes on the endoplasmic reticulum (E.R). The pre-pro-cathepsins are activated by co and post translational changes. The activation involves the cleavage of a propeptide portion, which blocks the active site of enzyme. The inactive form gets N-glycosylated in Golgi complex after the cleavage of pre-peptide segments. The N-glycosylated enzyme migrates to lysosomes for activation by mannose-6-phosphate signaling pathway. Proenzymes of some cysteine proteases, such as cathepsins B and L, undergo autocatalysis to active enzymes in the acidic environment of lysosomes. Whereas, some cathepsins, such as cathepsins X, D, and C, require proteolytic activation by other peptidases. Enhanced activation or autocatalysis, in presence of glycosaminoglycans (GAGs) was observed of many cathepsins, such as cathepsins B and S, as well as in cathepsin K. A direct proportionality between concentration of such accelerators and rate of autocatalysis is observed in cathepsin B activation. Concentration and co-localization of chondroitin sulfates with inactive forms of the enzyme enables activation of procathepsin.
Role of cathepsins in neurodegenerative Alzheimer’s Disease
Lysosomal aspartic proteinases, such as cathepsins D, and E, and cysteine proteinases cathepsins B, and L, were observed in aged amyloid plaques in AD patient brain. High concentrations of these enzymes were observed with age and in AD condition. The cleavage of substrate βAPP around its carboxy terminal (carboxy peptidase activity) by cathepsin B suggested its γ-secretase activity at low pH. This led to hypothesis of their promising APP digestive activity. Increased intracellular mRNA expression of cathepsins D was observed in pyramidal nerves of brain of AD. Cathepsin B is suspected to cause AD as it processes β amyloid precursor protein (βAPP) to amyloid-β peptide in brains of AD. On the other hand the exocytozed active enzymes may degrade amyloid toxic plaques, and reduce their quantity.42 Increased processing of APP, and reduction of degradation of amyloid-β (AB) peptide fragments increases AB peptide concentrations, which degenerate neurons, and develops AD. Degradation of amyloid β peptides by cathepsin B to the lesser extent leads to AD. Cysteine cathepsin H, L, and S expression in AD, and down syndrome brains, were studied. Cathepsins L, and H are expressed in astrocytes, whereas cathepsin S is expressed throughout the brain regardless of disease. However, transfection of renal cells with cathepsin S, APP coding genes lead to the raise of β- peptide levels, and development of AD.
Role of cathepsins in cancer metastasis
Numerous cathepsins, such as B, C, H, L, D, Z, S, etc., are also involved in various stages of cancer progression, including tumor growth, metastasis, and invasion due to their angiogenic proteolytic activities. Cysteinyl cathepsins, such as cathepsin B, K, and L, are expressed in almost all cells and parts of the body. However, high extracellular concentration of these cathepsin proteases and diminished quantities of their inhibitors were observed in developing tumors. Extra cellular matrix degradation by cathepsin B, H, L, and S, are involved in metastasis of neoplasm. Cathepsins B, D, and L were observed in acidic environment of tumors. Over-expression of cathepsin D was observed in almost all types of cancer, such as gastric, lung, epithelial, prostrate, and breast. Cathepsin K was found in prostate, breast cancer and cathepsin B was found to involve in metastasis of breast, bone, and lung tumors.
Dornbush, Padraick J. Compound discovery and expression of a putative cathepsin D-like protease in Trichomonas vaginalis. Diss. UNIVERSITY OF THE PACIFIC, 2014.
Hema Latha Sarepalla. Synthesis of acetyl-pro-phe-argininal thio-semicarbazone HCl as a Cathepsin B inhibitor. Department of Chemistry Western Illinois University. 2015