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Proteinase
A proteinase exhibiting chymotrypsin-like specificity was purified by Huntley et al. [1] from sheep gastric mucosa and isolated mucosal mast cells, and classified as a serine endopeptidase [2].
From: Handbook of Proteolytic Enzymes (Third Edition), 2013
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Industrial Biotechnology and Commodity Products
O.P. Ward, in Comprehensive Biotechnology (Second Edition), 2011
Abstract
Proteases are ubiquitous in biosystems where they have diverse roles in the biochemical, physiological, and regulatory aspects of cells and organisms. Proteases represent the largest segment of the industrial enzyme market where they are used in detergents, in food processing, in leather and fabric upgrading, as catalysts in organic synthesis, and as therapeutics. Microbial protease overproducing strains have been developed by conventional screening, mutation/selection strategies and genetic engineering, and wholly new enzymes, with altered specificity or stability have been designed through techniques such as site-directed mutagenesis and directed evolution. Complete sequencing of the genomes of key Bacillus and Aspergillus workhorse extracellular enzyme producers and other species of interest has contributed to enhanced production yields of indigenous proteases as well as to production of heterologous proteases. With annual protease sales of about $1.5–1.8 billion, proteases account for 60% of the total enzyme market. Detergent proteases, with an annual market of about $1 billion account for the largest protease application segment. Subtilisin Carlsberg and related subtilisin serine proteases represent the first generation of detergent proteases with pH optima of 9–10. The second generation, having higher pH optima (10–11) and greater temperature stability, is produced from alkalophilic strains including Bacillus clausii and B. halodurans. The third generation consists of detergent proteases whose active sites and/or stability have been modified by protein engineering. The principal applications of proteases in food processing are in brewing, cereal mashing, and beer haze clarification, in the coagulation step in cheese making, in altering the viscoelastic properties of dough in baking and in production of protein hydrolysates. In organic synthesis, proteases have application in synthesis and/or hydrolysis of peptide, ester, and amide bonds involving carboxylic acids and are effective tools for resolution of pairs of enantiomers. Proteases have applications in nutrition as digestive aids and in therapy in thrombosis and cancer treatment. Hyperproteolytic endogenous activity may play significant roles in abnormal physiological functioning as well as in microbial and viral pathophysiological conditions and this has created substantial momentum for development of protease inhibitors as therapeutic agents against disease-causing proteases.
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Biochemistry and Molecular Biology
M.R. Kanost, T.E. Clarke, in Comprehensive Molecular Insect Science, 2005
4.7.1 Introduction and History
Proteases (peptidases) are enzymes that hydrolyze peptide bonds in proteins. Exopeptidases cleave a terminal amino acid residue at the end of a polypeptide; endopeptidases cleave internal peptide bonds. Hooper (2002) provides a useful introduction to the general properties of proteases. Proteases can be classified based on the chemical groups that function in catalysis. In serine proteases the hydroxyl group in the side chain of a serine residue in the active site acts as a nucleophile in the reaction that hydrolyzes a peptide bond, whereas in cysteine proteases the sulfhydryl group of a cysteine side chain performs this function. In aspartic acid proteases and metalloproteases, a water molecule in the active site (positioned by interacting with an aspartyl group or a metal ion, respectively) functions as the nucleophile that attacks the peptide bond. Proteases are classified on this basis of catalytic mechanism in a system developed by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC3/4/). However, proteases can have the same catalytic mechanism but will be unrelated in amino acid sequence, as products of convergent evolution. The MEROPS classification system groups proteases into families based on sequence similarity (Rawlings and Barrett, 1999) (http://merops.sanger.ac.uk).
A protease cleaves a peptide bond, called the scissile bond, between two amino acid residues named P1 and P1′ (Schechter and Berger, 1967). Residues on the N-terminal side of the scissile bond are numbered in the C to N direction, whereas residues on the C-terminal side of the scissile bond (the "prime" side) are numbered in the N to C direction (Figure 1). The substrate specificity of most endopeptidases is highly dependent on the nature of the side chain of the P1 residue, but the sequence of other residues near the scissile bond can also affect binding of the substrate to the active site and thus influence substrate specificity.

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Figure 1. The Schechter and Berger (1967) notation for protease cleavage sites. The arrow designates the scissile peptide bond between amino acid residues P1 and P1′.
Insects produce abundant proteases that function in digestion of dietary proteins in the gut. Such proteases are thoroughly discussed in 00053. This chapter focuses on nondigestive proteases, which have many diverse roles in insect biology. These proteases often function in cascade pathways, in which one protease activates the zymogen form of another protease, leading to amplification of an initial signal that may involve a few molecules and finally generating a very large number of effector molecules at the end of the pathway. The complement and blood coagulation pathways in mammals are well-understood examples of this type of protease cascade, which also occur in insect embryonic development and insect immune responses (Jiang and Kanost, 2000; Krem and DiCerra, 2002; see Chapter 4.5). Details of the organization and regulation of such pathways in insect biology are beginning to be understood. This chapter will include an emphasis on the current state of knowledge in this rapidly developing area.
Insect proteases have previously been reviewed by Law et al. (1977), Applebaum (1985), Terra et al. (1996), and Reeck et al. (1999). These reviews deal primarily with proteases as they function in the digestion of food. Only quite recently has much detailed information appeared about proteases with other functions in insect biology. An exception is cocoonase, the first insect protease that was purified and well-characterized biochemically. Cocoonase is a serine protease from silk moths that functions to hydrolyze silk proteins in the cocoon, enabling the adult moth to emerge (Kafatos et al., 1967a, 1967b). It digests sericin, the silk protein that cements fibroin threads together (see Chapter 2.11). A specialized tissue called the galea, derived from modified mouthparts, synthesizes and secretes the zymogen form, prococoonase (Kafatos, 1972). On the surface of the galea, prococoonase is activated by cleavage at a specific site by an unknown protease in the molting fluid (Berger et al., 1971). Sequencing of an amino terminal fragment and the peptide containing the active site Ser residue indicated that the activation and catalytic mechanisms of coccoonase were quite similar to those of mammalian trypsin (Felsted et al., 1973; Kramer et al., 1973). It is surprising that no molecular cloning has apparently yet been carried out for this historically important insect protease.
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Molecular Cell Biology
K. Ji, B.F. Sloane, in Encyclopedia of Cell Biology, 2016
Abstract
Proteases of five human clans have been shown to play causal roles in cancer. Proteases were originally implicated due to their ability to degrade extracellular matrices traversed by invading tumor cells. The literature documenting high levels and activities of proteases in cancers and causal roles for proteases in mouse models of cancer is extensive. Nonetheless, targeting proteases therapeutically has not been very effective. This may reflect in part the use of broad-spectrum protease inhibitors that targeted both pro-tumor and antitumor proteases. This may also reflect the complexity of the protease web and the connectivity among proteases and their endogenous inhibitors.
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SENP6 and SENP7 Peptidases
David Reverter, in Handbook of Proteolytic Enzymes (Third Edition), 2013
Name and History
SENP6 and SENP7 comprise a subclass of SUMO proteolytic enzymes within the ULP/SENP peptidase family (family C48). All members from the ULP/SENP family contain an ~220 amino acid domain that belongs to the clan CE of cysteine peptidases. ULP (Ubiquitin-like-specific protease) was the first name given to these proteins in budding yeast, where they were first discovered [1]. SENPs (SUMO1/sentrin/SMT3-specific proteases) are the names given to this family in humans, named purely on the basis of sequences found in databases [2]. Most of the ULP/SENP family members possess proteolytic activity at different levels toward the ubiquitin-like modifiers SUMO1, SUMO2 and SUMO3.
SENP6 (Sentrin-specific protease 6) is also named SUSP1 (SUMO-Specific Protease 1) and SSP1 (SUMO1-Specific Protease 1) [3]. SENP7 is alternatively named after SENP6 as SUSP2 (Sentrin/SUMO-Specific Protease 2) and SSP2 (SUMO1-Specific Protease 2).
ULP/SENP family members are multi-domain proteins. The C48 cysteine peptidase catalytic domain is typically located at the C-terminal part of the protein. An evolutionary relationship based on sequence alignment predictions of eukaryotic ULP/SENP family members shows three major branches [4]. The first branch corresponds to the SENP8/dennedylase family members, with activity towards Nedd8, another ubiquitin-like modifier [5–7]. The second branch includes yeast ULP1 and human SENP2, SENP2, SENP3 and SENP5. Within this branch the pairs SENP1 and SENP2, and SENP3 and SENP5 show a high degree of sequence similarity to each other. The third branch of the family includes yeast ULP2 and human SENP6 and SENP7, all showing a non-regular domain architecture, with long sequence insertions located inside the catalytic domain.
Vertebrate SENP6 and SENP7 constitute the most divergent subclass within the ULP/SENP family. In addition to the low sequence similarity within the catalytic domain with the other members, SENP6 and SENP7 include conserved sequence insertions in distinct positions within the catalytic domain. Despite these differences, SENP6 and SENP7 maintain the basic structural elements required for the peptidase activity for SUMO.
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Fungal Prions
In Virus Taxonomy, 2012
Genome organization and replication
Normally, protease A, as well as mature protease B, can carry out the cleavage-maturation of proprotease B. In a pep4 deletion mutant lacking protease A, protease B acts as a prion. Cells initially lacking mature active protease B give rise to progeny, nearly all of which lack the active enzyme. Cells initially carrying active mature protease B give rise to offspring, nearly all of which also have active protease B. Transmission of active protease B to a cell lacking it, converts the pro-protease B in the recipient to the active form. This activity is then passed on to progeny by continued auto-activation. About 1 in 105 cells spontaneously develops protease B activity.
The protease B precursor protein requires removal of both N-terminal and C-terminal extension for maturation.
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Caspases: Executioners of Apoptosis
S.J. Martin, in Pathobiology of Human Disease, 2014
Two Major Subgroups of Caspases Define Pro- or Anti-inflammatory Roles
The mammalian caspase family comprises a group of proteases that all share homology with the founding member of this family, interleukin-1β-converting enzyme (ICE), now known as caspase-1. The human caspase family contains 12 members, numbered according to their order of discovery (see Figure 2). All known caspases contain an active site cysteine residue and cleave their substrates after aspartate (Asp) residues, which gives rise to the name caspases (cysteine aspartate-specific proteases). Proteases that cleave their substrates after aspartate residues are very uncommon, and this substrate preference is shared with only one other known protease – granzyme B, a component of cytotoxic lymphocyte granules. As we shall see, granzyme B also plays a prominent role in apoptosis in certain settings and it is no accident that granzyme B shares a preference with the caspases for cleaving its substrates after aspartate residues.

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Figure 2. Human caspase domain organization. Long prodomain caspases function as initiator caspases and typically contain caspase recruitment domains (CARD) or death effector domain (DED) motifs. Note that caspase-4 and caspase-5 in humans are equivalent to caspase-11 in mouse. Caspase-12 (not depicted) is not expressed as a functional enzyme in the majority of humans but appears to be involved as a negative regulator of inflammation in mouse.
Caspases all have the same basic structure: a prodomain, a large subunit of ~ 20 kDa and a small subunit of ~ 10 kDa (Figures 2 and 3). The caspases can be broadly separated into two functional groups ('initiators' and 'effectors') on the basis of the lengths of their prodomain regions. Several caspases, the initiators, have long prodomains (caspase-1, caspase-2, caspase-8, caspase-9, and caspase-10) while the remainder (the effectors) have short prodomains.

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Figure 3. Caspase activation via dimerization and reorientation of the catalytic pocket.
The prodomain region regulates activation of initiator caspases by facilitating the association of these caspases with other proteins. During conversion of the caspases from their inactive to their active forms, the prodomain is often removed and a cut is introduced between the large and small subunits. This cut does not lead to separation of the large and small subunits, but rather to a subtle but important change in the conformation of the enzyme that allows the active site to achieve the correct configuration. In all cases, these internal cuts occur adjacent to an aspartic acid residue. This suggests that activation of caspases during apoptosis occurs via a protease cascade – with those caspases possessing long prodomains acting at the apex of the cascade (i.e., they initiate the cascade). Upon activation of the initiator caspases by recruitment to molecules that promote their aggregation, these caspases proceed to activate – via proteolytic processing – the 'effector' caspases, which then act upon cellular substrates to effect apoptosis.
As I have alluded to in the preceding text, not all caspases are involved in apoptosis but instead play important roles in the maturation of proinflammatory cytokines. Before we focus on the central role that certain caspases play in apoptosis, we will briefly discuss the inflammatory caspases and their involvement in the maturation of IL-1β and IL-18.
Some Caspases Promote Inflammation, While Others Oppose It
Mammalian caspases can be subdivided into two major subfamilies based on sequence homology to each other. Caspase-2, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and caspase-10 are the most closely related to the C. elegans caspase, CED-3, and all of these caspases play roles in apoptosis. The caspase subset most closely related to caspase-1 (caspase-1, caspase-4, caspase-5, caspase-11, and caspase-12) are engaged primarily in the regulation of inflammatory cytokine maturation, through either direct or indirect means. Thus, the latter caspases have a proinflammatory role. Caspase-1 (ICE) is largely responsible for the production of mature IL-1β and IL-18 by macrophages during immune responses to bacterial pathogens. Caspase-1 proteolytically processes the immature forms of these cytokines (pro-IL-1β and pro-IL-18) into their mature counterparts by clipping the inactive precursors of these proteins at one or two sites. Caspase-1 'knockout' mice do not exhibit any significant defects in the regulation of apoptosis but do show defects in the production of the aforementioned inflammatory cytokines upon bacterial infection. Other members of the caspase-1 subfamily (caspase-4, caspase-5, and caspase-12) have also been implicated in proinflammatory pathways rather than as participants in the cell death machinery; however, the latter proteases do not directly process interleukins but appear to be involved in fine-tuning the activation of caspase-1. Thus, as I outlined earlier, all members of the caspase family can be interpreted to have a role in the regulation of inflammation, with some members promoting inflammation (the caspase-1 subfamily), while other members oppose inflammation (the caspase-3/apoptosis subfamily).
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Kaposi's Sarcoma Virus Assemblin (Herpesvirus 8-type Assemblin)
Tina Shahian, Charles S. Craik, in Handbook of Proteolytic Enzymes (Third Edition), 2013
Distinguishing Features
KSHV Pr and other HHV proteases have a unique mechanism of concentration-dependent zymogen activation. This regulatory step acts as a switch to ensure the protease is turned on at the right stage of the viral life cycle. There are no human homologs of KSHV Pr. Recently a novel allosteric pocket was discovered at the dimer interface of KSHV Pr that is believed to be conserved across other HHV proteases [25,27]. Development of small molecule inhibitors that target this pocket, or other specific sites, can potentially lead the way to new therapeutics for herpesviral diseases.
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Nairovirus Deubiquitinylating Peptidase
Adolfo García-Sastre, Jesica M. Levingston Macleod, in Handbook of Proteolytic Enzymes (Third Edition), 2013
Related Peptidases
Arterivirus nsp2 proteases are also viral OTU proteases with the ability to deconjugate both Ub and ISG15 [24]. In contrast to the nairoviruses OTU proteases, the arterivirus nsp2 proteases participate in the processing of the viral polymerases. At the moment, no crystal structure is available for these proteases. It is also worthy to mention that other viral peptidases, as the adenoviral protease adenain [25] and the papain-like protease from SARS coronavirus [26,27] have ISG15 and Ub deconjugating activities, which have been suggested to suppress inflammatory and IFN responses of the host.
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Biochemistry of Hemostasis
N.V. BHAGAVAN, in Medical Biochemistry (Fourth Edition), 2002
36.8 Anticoagulant Subsystem—Activation of Protein C and Inactivation of Factors Va and Villa
The very large increases in the rates of activation of prothrombin and factor X that occur in the presence of factors Va and VIIIa respectively, make the hemostatic response both rapid and localized. However, if such rates were to continue unabated, the extension of the hemostatic plug into the blood vessel would occlude the vessel and result in ischemia and death to the adjacent cells and tissues. If the pathologically extended hemostatic plug is in the venous system, the separation of the occlusive plug (also designated clot, or red thrombus) can result in the clot being sent to the lungs with consequent pulmonary embolism. The proteinase activations of the procoagulant subsystem are opposed by the cofactor protein inactivations of the anticoagulant subsystem.
Protein C is activated by thrombin in the complex with thrombomodulin to produce activated protein C, the proteolytic inactivator of factors Va and VIIIa. The binding of thrombin to thrombomodulin changes thrombin from a procoagulant proteinase to an anticoagulant proteinase. Whereas the hemostatic reactions that prevent blood loss at the injury site are associated with the ruptured blood vessels, thrombomodulin is on the endothelium (Figure 36-15).

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FIGURE 36-15. (Also see color figure.) Anticoagulant subsystem. Activation of protein C occurs adjacent to the injury site; inactivation occurs on the exposed surface at the injury site. Protein C is activated through cleavage by thrombin at Arg169-lle170. Protein S is a 635-residue vitamin K-dependent protein that functions as a cofactor. There is a Gla domain and four EGF-like domains in the molecule, but no proteinase domain. Thrombomodulin is a 554-residue integral membrane protein. The extracellular region comprises residues 1-494, the transmembrane region residues 495-518, and the intracellular region residues 519-554. EGF-like structures are found from residue 224 to 459. In the color version of this figure, motifs and domains are color coded as follows: Gla domain (blue), EGF-like domain (magenta), activation peptide (yellow), and proteinase domain (green). Light chains are indicated in dark gray, heavy chains in light gray. Regions connecting the motifs are black.
Activation of protein C by thrombin occurs adjacent to the injury site; inactivation of factors Va and VIIIa occurs on the exposed surface at the injury site. Inactivation of activated factors Va and VIIIa occurs by proteolysis of two peptide bonds, both in each of the heavy chains (domains A1 and A2, Figure 36-6) of factors Va and VIIIa. The consequence of these cleavages is that the cofactor proteins become nonfunctional catalysts. The interaction of the activated cofactors with the proteinases in their respective complexes is eliminated because the interaction is a property of the factor Va and factor VIIIa heavy chains. The rates of proteolytic inactivation of factors Va and VIIIa are increased by participation of the cofactor protein, protein S. The increased rate of proteolysis with protein S (only about 500 times) is much less than observed with the cofactor proteins Va and VIIIa of the procoagulant subsystem (more than 10,000 times).
Mutations that result in amino acid substitution at the cleavage site in a protein substrate cause two changes in the proteolytic process. First, the rate of cleavage of the peptide bond is reduced because of the altered orientation of the substrate within the active site. Second, the altered substrate is very likely to be a competitive inhibitor of the proteinase responsible for the cleavage. Both of these effects are evident in the phenomenon called activated protein C resistance.
A mutation in the factor V gene, G to A at 1691, results in the replacement of the normal Arg residue at position 506 in the heavy chain of factor Va by a Gln residue. Individuals carrying this mutation, called factor V (Leiden) are at increased risk of venous thrombosis and venous thromboembolism. The inability of activated protein C to cleave Gln506 slows the cleavage of Arg306 in factor Va. A second mutation, factor V (Cambridge), that confers activated protein C resistance is at Arg306. As a result, the cleavage essential for complete inactivation of factor Va does not occur.
The factor V (Leiden) mutation is very common in individuals of western European origin. The prevalence is approximately 5% in the Western Hemisphere in Caucasians; the mutation is almost completely absent from Africans and almost entirely absent from Asians.
Anticoagulant Subsystem-Proteinase Inhibitors
Proteinase inactivation occurs by a stoichiometric reaction between proteinase and inhibitor that results in the formation of a "covalent" ester bond between the reactive site residue of the inhibitor (Arg393 in antithrombin) and the active site residue (Ser195 in the proteinase). The proteinases thrombin, factor Xa, factor IXa, and, less effectively, factor VIIa and factor XIa are all inactivated by antithrombin (Figure 36-16). Other SERPINS can inactivate procoagulant proteinases, heparin cofactor II can inactivate thrombin, and α I-proteinase inhibitor can inactivate factor Xa. An altered α I-proteinase inhibitor (α I-proteinase inhibitor inhibitor represent the helices Pittsburgh), in which an Arg has replaced Ala at the reactive site, is a good inhibitor of thrombin.

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FIGURE 36-16. (Also see color figure.) Proteinase inactivation by SERPINS. Proteinase inactivation occurs by reaction between proteinase and inhibitor, e.g., antithrombin. The proteinase is a stoichiometric reactant in this instance but is not a catalyst. This reaction results in the formation of a covalent bond between the reactive site residue of the inhibitor (Arg393 in antithrombin) and the active site residue (Ser195 in the proteinase). This complex formation prevents the proteinase from hydrolyzing any other peptide bond. Proteinases, thrombin, factor Xa, factor IXa, and, less effectively, factor VIIa and factor XIa are all inactivated by the plasma protein inhibitor antithrombin (previously designated antithrombin III). The product ATm is the cleaved form of antithrombin. It is formed in both the absence and presence of heparin, but more so in the presence. In the color version of this figure, the proteinase is indicated by green, the inhibitor by red, and the inactivated proteinase by gray. Stripes on the
(Figure 36-7).
Because inactivation of factors Va and VIIIa by activated protein C promotes the dissociation of the proteinases, cofactor protein inactivation complements the action of the proteinase inhibitors. This eliminates the "protection" that the proteinases have when bound to their cofactor proteins and substrates. Inactivation of proteinases by SERPINS occurs via a common mechanism that involves a Michaelis complex between the proteinase and the inhibitor (Figure 36-16). This mechanism applies to all serine proteinases of the hemostatic system, i.e., the procoagulant, anticoagulant, and fibrinolytic subsystem proteinases.
Mechanism of Action of Heparin as a Therapeutic Anticoagulant
The inactivation of procoagulant proteinases can be catalyzed by glycosaminoglycans, which are sulfated polysaccharide molecules found on the surface of the normal endothelial cells and in the basophilic granules of mast cells. The glycosaminoglycans act as catalysts, increasing the rates of inactivation of the proteinases as much as 100,000-fold. The therapeutic benefits of heparin in preventing and treating deep vein thrombosis are derived from its altering the balance between the procoagulant and anticoagulant subsystem reactions in favor of the anticoagulant subsystem.
Heparin is a polymer of repeating disaccharide "building blocks." All heparins bind to antithrombin; however, heparin molecules that contain a unique pentasaccharide sequence bind with particularly high affinity (designated high-affinity heparins). Heparins that contain this pentasaccharide sequence are also the most effective in catalyzing the inactivation of proteinases by antithrombin. This increased effectiveness of high-affinity heparins is due to a conformation change that they cause in the antithrombin molecule that makes the binding between antithrombin and heparin tighter.
The magnitude of the heparin-catalyzed increases in the rates of proteinase inactivation by antithrombin depends on the molecular weight of the high-affinity heparin molecules. Up to a molecular weight of about 20,000, the higher the molecular weight, the greater the increase in the rate of proteinase inactivation. Thrombin inactivation requires heparin molecules of sufficient molecular weight to permit the formation of a thrombin-heparinantithrombin complex. Factor Xa inactivation is less sensitive to the molecular weight of the heparin molecules, and factor Xa is the only proteinase that can be efficiently inactivated by the very low-molecular-weight high-affinity pentasaccharide (Figure 36-17). Here, in contrast to the situation of factor XI activation, the glycosaminoglycan is acting as a catalyst of an anticoagulant (proteinase inactivation) process.

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FIGURE 36-17. (Also see color figure.) Structure of heparin. Heparin is a polymer of repeating disaccharide units that contain one uronic acid and one hexosamine residue. The uronic acid residues may be either glucuronic acid or iduronic acid, both of which are monosaccharide acids that differ in their stereochemistry. The hexosamine residue is glucosamine. Both the uronic and hexosamine residues can be modified by 0- and N-sulfation and the glucosamine residue by N-acetylation. All heparins bind to antithrombin; however, heparin molecules that contain a unique pentasaccharide sequence bind with particularly high affinity (high-affinity heparins). Approximately 30% of the heparin molecules present in the commonly used therapeutic heparins have high affinity for antithrombin.
Inhibitors of the Contact Phase Proteinases
Several proteinase inhibitors inactivate the proteinases of the contact phase. Among the SERPINS are C-l inactivator, αI-proteinase inhibitor, and antithrombin. The target proteinases for these inhibitors are factor XIIa kallikrein, and factor XIa. The molecular mechanisms are the same as those described for the procoagulant and fibrinolytic system proteinases.
Another inhibitor is present in plasma that can inactivate thrombin, plasmin, and, to a much lesser extent, the other proteinases as well. This inhibitor, α2-macroglobulin, inhibits by a completely different mechanism from that of the SERPINS. It entraps the proteinases in a "cavity" that is created by the four subunits of the α2-macroglobulin molecule. The active sites of the entrapped proteinases are sterically hindered from protein substrates but are accessible to low-molecular-weight chromogenic substrates that are used in some laboratory coagulation tests for heparin and antithrombin.
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