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Serine Proteases and Regulators


The Introduction of Serine Proteases

Serine Proteases and Regulators

Serine proteases are a class of important proteolytic enzymes with serine as the active center. They play an important and extensive physiological role in biological organisms. They act as regulators by activation or inhibition of proproteinase. Serine protease also plays an important role in embryonic development, tissue remodeling, cell differentiation, angiogenesis and pathogen invasion. It can be seen that serine protease has extensive research and application value.

The Structure and Function of Serine Protease

The serine protease superfamily has many members, and their active sites contain Ser, His, and Asp, and have the same catalytic mechanism, but their differences with the substrate binding sites determine their specificity for the substrate. In fact, it is due to the small changes in the structure of serine proteases that cause their functional evolution. The serine protease is structurally a full beta protein and the core structure is composed of two very similar domains (N domain and C domain). Because of the structural differences between the two domains, they have different roles in function and evolution. Two of the three major residues in the catalytic center of the serine protease (Asp 102, His 57) are located in the N-terminal domain, but the most important Ser 195 is in the C-terminal domain, and other important functional sites are located in the C-terminal domain, including oxygen-ion pores that stabilize catalytic intermediates(Gly 193 , Ser 195), substrate-specific pockets( Ser 189 , Gly 216 ,Gly 226 ), and backbone substrate binding sites( Ser 214 , Trp 215 , Gly 216). The C-terminal domain also contains two important conserved disulfide bonds, and the C-terminal domain contains most of the functional sites, so the C-terminal domain performs the main catalytic function of serine proteases; while the main function of N-terminal domain may be to cooperate with the C-terminal domain to ensure structural stability.

Research Progress of Serine Protein Application and Regulatory Agent

Serine proteases have a wide range of applications in the treatment of cardiovascular diseases. The fibrinolytic active serine protease-Nattokinase, produced by Bacillus natto can directly act on cross-linked fibrin by oral administration while increasing the activity of endogenous plasmin. The sputum fibrinolytic enzyme extracted from the earthworm has plasminogen activity which directly dissolves fibrin, and has plasminogen-activated activity of urokinase, thereby dissolving old thrombus and inhibiting new thrombus formation. Snake venom serine proteases are chymotrypsin-like serine proteases, most of which act on coagulation/fibrinolysis systems. Serine proteases are also used in basic research on fungi. The ability of pathogenic fungi to secrete endogenous and exogenous extracellular proteases in vitro or in the process of infecting a host has attracted widespread attention. Using the cell chip technology combined with immunohistochemistry, the expression of serine protease in the cells of various Cryptococcus neoformans strains can be detected, and the role of serine protease in the pathogenesis of Cryptococcus neoformans can be compared horizontally. Serpin protease inhibitors are a class of proteins with a common origin, a conserved amino acid sequence and a spatial structure that are highly differentiated. A typical serpin has the following characteristics, including a single-chain protein of 350 to 500 amino acids consisting of a conserved protein body and a reaction center loop exposed outside the body. Serpin has a high degree of target enzyme specificity; many serpins use cofactors such as heparin to recognize target enzymes together with RCL and regulate the inhibitory activity of serpin on target enzymes. Unlike other protease inhibitors, which can only bind to the target enzyme through non-covalent bonds, serpin can bind closely to the target enzyme through covalent bonds; the main function of serpin, which has protease activity, is to inhibit serine proteases. A small number of serpins also inhibit caspase and some cysteine proteases. Serpin with inhibitory activity is composed of the protein body and the reaction center loop exposed outside the protein body. The protein body of serpin is very conservative, which usually has three beta-folds and eight or nine alpha helixes. The beta-folds are named sA-sC and the alpha helix is named hA-hI. The reaction center loop is located between beta-folds A and C and is exposed to the main body of serpin protein with sites that can be specifically recognized by target enzyme, which is called P1.

References:

  1. Chen H, Davids J A, Zheng D, et al. The serpin solution; targeting thrombotic and thrombolytic serine proteases in inflammation. Cardiovascular & Hematological Disorders Drug Targets. 2013, 13(2).
  2. Pham C T. Neutrophil serine proteases fine-tune the inflammatory response. Int J Biochem Cell Biol. 2008, 40(6):1317-1333.
  3. Wiedow O, Meyerhoffert U. Neutrophil serine proteases: potential key regulators of cell signaling during inflammation. Journal of Internal Medicine. 2010, 257(4):319-328.

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