Zymogen

Allosteric interactions control the behavior of proteins through reversible changes in quaternary structure, but this mechanism, effective though it may be, is not the only one available. A zymogen, an inactive precursor of an enzyme, can be irreversibly transformed into an active enzyme by cleavage of covalent bonds. 

The changes in primary structure that accompany the conversion of chymo-tiypsinogen to a-chymotrypsin bring about changes in the tertiary structure. The enzyme is active because of its tertiary structure, just as the zymogen is inactive because of its tertiary structure. The three-dimensional structure of 

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Factor XI. Factor XI is a Hver-synthesized glycoprotein that circulates in a zymogen form as a dimer. It is converted to its active serine protease form by Factor Xlla in the presence of high molecular weight kininogen. Calcium is not required for this activation step. 

Factor XIII. Factor XIII circulates in the blood as a zymogen composed of two pairs of different polypeptide chains designated A and B. Inert Factor XIII has a molecular weight of 350,000 daltons and is converted to its active transglutaminase form in the presence of thrombin and calcium. Activated Factor XIII, Xllla, induces an irreversible amide exchange reaction between the y-glutamine and S-lysine side chains of adjacent fibrin... 

Protein G. This vitamin K-dependent glycoproteia serine protease zymogen is produced ia the Hver. It is an anticoagulant with species specificity (19—21). Proteia C is activated to Proteia by thrombomodulin, a proteia that resides on the surface of endothefial cells, plus thrombin ia the presence of calcium. In its active form, Proteia selectively iaactivates, by proteolytic degradation. Factors V, Va, VIII, and Villa. In this reaction the efficiency of Proteia is enhanced by complex formation with free Proteia S. la additioa, Proteia activates tissue plasminogen activator, which... 

Specialized controls Enzyme regulation is an important matter to cells, and evolution has provided a variety of additional options, including zymogens, isozymes, and modulator proteins. 

BLOOD CLOTTING. The formation of blood clots is the result of a series of zymogen activations (Figure 15.5). The amplification achieved by this cascade of enzymatic activations allows blood clotting to occur rapidly in response to injury. Seven of the clotting factors in their active form are serine proteases ... 

Why do you suppose proteolytic enzymes are often synthesized as inactive zymogens ... 

The enzymatic activity of these potentially harmful enzymes is tightly controlled. Once transcribed into protein, MMPs are expressed as inactive zymogens and require distinct activation processes to convert them into active enzymes. After secretion, MMP-activity is regulated by the noncovalent binding of tissue inhibitors of metalloproteinases ( TIMPs) as shown in Fig. 2 for MMP-2 and TIMP-2. Four TIMPs have been identified so far TIMP-1, TIMP-2, TIMP-3, and TIMP-4. All known MMPs can be inhibited by at least one of the four known TIMPs. Nevertheless, individual differences with regard to bond strength and thus the magnitude of inhibition of a particular MMP do exist. 

A proteolytic cascade occurs when one peptidase activates the next in a proteolytic pathway, and this in turn activates the next and so on. This is a mechanism to amplify the initial signal, because one peptidase molecule can activate many zymogen molecules. Examples of proteolytic cascades include blood coagulation, activation of digestive peptidases in the intestine, and apoptosis. 

Plasmin, a serine protease (83 kDa), can degrade fibrin, and its degradation products (FDP) are soluble in the blood. Plasmin is formed from its proenzyme (zymogen, precursor), plasminogen (92 kDa), synthesized by the liver, and secreted into the blood circulation, where its concentration is 2 pM. Plasminogen is converted to plasmin by plasminogen activators (serine proteases). 

Zymogen is a precursor protein that is converted to an active protease when one or more of its peptide bonds are cleaved. Zymogens involved in coagulation include factors II (prothrombin), VII, IX, X, and XI. 

Zollinger-Ellison Syndrome Zona Glomemlosa Zymogen... 

The proteases are secreted as inactive zymogens the active site of the enzyme is masked by a small region of its peptide chain, which is removed by hydrolysis of a specific peptide bond. Pepsinogen is activated to pepsin by gastric acid and by activated pepsin (autocatalysis). In the small intestine, trypsinogen, the precursor of trypsin, is activated by enteropeptidase, which is secreted by the duodenal epithelial cells trypsin can then activate chymotrypsinogen to chymotrypsin, proelas-tase to elastase, procarboxypeptidase to carboxypepti-dase, and proaminopeptidase to aminopeptidase. 

Factor XIa in the presence of activates factor IX (55 kDa, a zymogen containing vitamin K-dependent y-carboxyglutamate [Gla] residues see Chapter 45), to the serine protease, factor IXa. This in turn cleaves an Arg-Ile bond in factor X (56 kDa) to produce the two-chain serine protease, factor Xa. This latter reaction requires the assembly of components, called the tenase... 

Many coagulation factors are zymogens of serine proteases, becoming activated during the overall process. 

Autolysis of the pancreas can occur when zymogens are activated in the pancreas before being released into the duodenum. Acute pancreatitis can result from the initial injury to the zymogen-producing cells, which is followed by neutrophil invasion of the pancreas, and that ends in further activation of enzymes within the pancreas. This cascade of events can be destructive to the pancreas and harmful to the patient. 

Zymogen A proenzyme the inactive or nearly inactive precursor of an enzyme that is converted into an active enzyme by proteolysis. 

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