Cathepsin (English name: cathepsin) is found in the cells of various animal tissues (especiallylysosomeSome) are the main members of the cysteine protease family. More than 20 kinds of protease have been found in the biological world. There are 11 kinds of protease in the human bodyosteoporosis, arthritis and other major diseases are closely related, and are a class of target proteases that have attracted much attention in recent years.
Protease is the main participant of protein hydrolysis in human body, which can be divided into endopeptidase, peptide terminal lyase, aminopeptidase and carboxypeptidase according to its substrate specificity;According to its proteolysis mechanism, it is classified asSerine protease、Cysteine protease、Aspartate protease, threonine protease andMetalloproteinase。Cysteine protease has been studied extensively.It widely exists in viruses, bacteria, fungi, protozoa and protozoa, plants, mammals and people, and its largest subgroup isPapainCysteine like protease[1]。Papain cysteine protease in mammals belongs to cathepsin, which is a kind of intracellular protease mainly existing in lysosomes. It is easy to be activated in weak acid environment, and is a kind of glycoprotein unstable in alkaline and neutral solutions (except cathepsin D, E, S)[2]。
classification
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Since the concept of cathepsin was proposed in the 1920s, cathepsin A and cathepsin Z have been reported so far.According to the classification of protein hydrolysis mechanism, most cathepsin members belong to cysteine protease, and a few are aspartic protease (cathepsin D, E) and serine protease (cathepsin A, G); according to the classification of substrate specificity, cathepsin also includes endopeptidase cathepsin BF 、H 、K 、L、S 、V ，Peptide terminal lyase cathepsin B, C, H, X, aminopeptidase cathepsin C, H, carboxypeptidase cathepsin B, X[2]。
synthesis
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At present, human cathepsin is mainly divided into two sub groups, one is cathepsin L protease or ERW FNIN motif protease, which mainly includes cathepsin L (Cat-L, the same below), V, K, S and H;The other is cathepsin B protease which only includes Cat-B.
Cathepsin is hydrolyzed from inactive precursor enzyme, and its synthesis pathway in vivo is as follows: first, it is synthesized in the form of precursor enzyme on the ribosome binding membrane, and then it enters the endoplasmic reticulum through transferrin, and then enters the Golgi apparatus. At the same time, it forms mannose-6 phosphoprotein through glycosylation and phosphorylation,Finally, through the recognition of mannose-6 phosphate specific receptor on lysosome, it is indirectly transported to lysosome[2]。Same as allPapainclassCysteine proteaseSimilarly, the precursor enzyme of cathepsin is also composed of signal peptide, precursor peptide and catalytic domain containing mature protease activity center.The length of the signal peptide is between 10 and 20 amino acid residues. It is responsible for transporting the ribosome expressed proenzyme protein to the endoplasmic reticulum, and after the endoplasmic reticulum is hydrolyzed, it forms a proenzyme containing only the precursor peptide and the catalytic domain.The amino acid residues of precursor peptides differ greatly (between 36 and 315). They occupy the active center of the enzyme, so that the zymogen has no catalytic activity, and is then transported into the intracellular lysosome. Under the acidic conditions of the lysosome, the precursor peptide is automatically hydrolyzed to remove the precursor peptide and produce an active mature histoproteinase.
Introduction to common tissue proteins
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Cathepsin B
Cathepsin B (CTBB) is a cysteine proteolytic enzyme in lysosome. Its catalytic effect is realized by Cys and His, and it is easily inhibited by sulfhydryl reagents, also known as sulfhydryl enzyme. It belongs to papain family. It is active at pH 3.0~7.0 and irreversibly inactivated under alkaline conditions[3]。
CTSB exists in bacteria, viruses, protozoa, plants and mammals, and in liver, spleen, kidney, bone, nerve cells, interstitial fibroblasts, macrophages, etc[3]。CB plays an essential role in the pathway of lysosomal protein degradationPlasma protein, hormones and phagocytized bacteria enter the cell and are dissolved in the enzyme bodyProteolytic enzymeHydrolysisIntracellular digestionSo as to maintain an accurate balance between protein synthesis and degradation.
In recent years, it has been found that cathepsin B (CB) is related to tumor invasion and metastasis. CB can be directly dissolved or indirectly activated to dissolve in the process of cancer cell metastasisExtracellular matrix, such as collagenLaminin, basement membrane and other components of the enzyme to promote tumor cells to infiltrate into deep tissue, thus opening a channel for the movement of cancer cells.The study found that CB was found in many tumor cells, such as gastric cancer, lung cancer, intestinal cancer, breast cancerprostatic cancerAnd renal cell carcinoma;The mRNA expression is related to the histological type and differentiation stage of the cancer, but the protein level is opposite. This difference may have some regulation at the transcriptional and post transcriptional levels, thus affecting the final expression;The expression of CB in pericancerous interstitial cells and vascular endothelial cells increased. Under normal circumstances, interstitial fibroblasts and macrophages can also secrete CB, but the expression of CB in cancer stage increased significantly, indicating that in the process of cancer invasion and metastasis, the excessive synthesis and leakage of CB in macrophages may also participate in the diffusion mechanism of cancer cells[3]。
Tissue Protein D
Cathepsin D (CTSD) is an aspartic lysosomal endopeptidase discovered by Westley in 1979[4], widely found in vertebrates, fungiRetrovirusAnd plant viruses, its normal function is to hydrolyze proteins in the acidic environment of lysosomes8 ～ 5. Within the range of 0, CTSD (the optimal pH value is 4) can degrade hormones, polypeptide precursors, polypeptides, structures andFunctional proteinQuality, but when pH is greater than 5Inactive at 5[5]。
Cathepsin D participates in a variety of physiological activities in vivo: Cathepsin D participates in substrate hydrolysis CTSD, as an endopeptidase, can degrade peptides and proteins in lysosomes;Cathepsin D is involved in epidermal differentiation. It has been found that CTSD can activate transglutaminase-1 (TG-1) through hydrolysis, thus promoting the cross connection of keratinized membrane proteins, and ultimately inducing skin epidermal differentiation and regeneration;Cathepsin D participates in cell apoptosis.In addition to having various physiological functions, CTSD is also closely related to a variety of clinical diseases, such as Alzheimer's disease, atherosclerosis, and congenital muscle diseases[6]。
Tissue protein K
In 1994, cathepsin K cDNA was cloned from rabbits, andOsteoclastMedium significant expression[7]。Cathepsin K is a protein composed of 329 amino acids, including three parts: 15 amino acid amino terminal region, 99 amino acid pro peptide and 215 amino acid catalytic unit.Cathepsin K is not only present in osteoclasts, but also activated and expressed in skin, heart, skeletal muscle, lung, placenta, ovary, testis, small intestine and colon.
Tissue protein K andosteoporosisofIn absorption lacunae, activated osteoclasts almost exclusively express mature cathepsin K.In activated osteoclasts, high levels of activated enzymes polarize the cell fold margin, lysosomal vesicles fuse with the cell membrane fold margin, and cathepsin K is released out of the cell.Cathepsin K degrades type I and II collagen, especially type I collagen, in the acidic microenvironment of the absorption pit[8]。
Tissue protein L
Cathepsin L(cathepsin L, CTSL) is a major member of the lysosomal cysteine protease family, which has a very unique synthesis and transport mode.The lysosome CTSL contains a signal peptide and is translated from the first AUG start site of ORF.First, the signal peptide pulls the synthesized CTSL precursor zymogen to the endoplasmic reticulum.Then, the peptide bond between the signal peptide and the precursor peptide on the endoplasmic reticulum breaks, releasing the signal peptide and the CTSL proenzyme containing the precursor peptide and mature peptide.Finally, with the help of precursor peptides, CTSL protein folds and curls to form disulfide bonds.In the endoplasmic reticulum, the CTSL zymogen, which only contains precursor peptide and mature peptide, must be removed under specific conditions and form the correct spatial structure to show enzyme activity.Usually, the CTSL zymogen is cut by itself in the acidic environment of the intracellular body or lysosome, or formed active through the processing of other proteases
Mature enzyme of[9]。
cathepsin inhibitor
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Endogenous protein inhibitor[2]
(1) Precursor peptide: YesCysteine proteaseA component of the zymogen structure, which occupies the active center of the enzyme,
It prevents the enzyme from combining with the substrate, so that it cannot play a catalytic role.
(2) Cystatin family: this family of inhibitors has poor selectivity to target protease, and it includes three major categories: cystatin, stefins and kininogens.
(3) Serpin family, namely serine protease inhibitors, is a class of protein inhibitors with cross activity to a variety of cathepsins.
(4) Thyropins class:ThyroglobulinType 1 domain binding inhibitor is a cathepsin inhibitor that has been identified in recent years, and its selectivity is higher than that of Cystatin family inhibitors.
(5) α 2-macroglobulin: it is a universal protease inhibitor.
(6) Cytotoxic T-lymphocyte antigen-2 β:Cathepsin LAnalogue of precursor peptide, which may play an inhibitory role on cathepsin in a way similar to that of precursor peptide.
Synthetic peptide inhibitor
Such as aldehydes, ketones, nitriles, epoxy succinyl, vinyl sulfones, etc.
Other natural inhibitors
Plant Cystatins Phytostatins, which have inhibitory effect on cysteine protease[2]。
