Zymogen Proenzyme

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). 

To prevent self-digestion, the pancreas releases most proteolytic enzymes into the duodenum in an inactive form as proenzymes (zymogens). Additional protection from the effects of premature activation of pancreatic proteinases is provided by proteinase inhibitors in the pancreatic tissue, which inactivate active enzymes by complex formation (right). 

Normally, thrombin is present in the blood as an inactive proenzyme (see p. 270). Prothrombin is activated in two different ways, both of which represent cascades of enzymatic reactions in which inactive proenzymes (zymogens, symbol circle) are proteolytically converted into active proteinases (symbol sector of a circle). The proteinases activate the next proenzyme in turn, and so on. Several steps in the cascade require additional protein factors (factors 111, Va and Villa) as well as anionic phospholipids (PL see below) and Ca "" ions. Both pathways are activated by injuries to the vessel wall. 

Many proteins are formed as inactive precursors and become activated by proteolysis. The inactive precursors are termed proenzymes, zymogens or - for hormones like e.g. insulin - prehormones. Processing to the active form occius in a cell- and tissue-specific way and usually requires a specific protease. Activation can also occur intramolecu-larly by autoproteolysis. In most cases, short sequences of the protease substrate serve as a recognition signal for the attack of the processing protease. Of the numerous examples of proteolytic processing of proteases only the digestive proteases will be discussed in more detail. 

The digestive enzymes trypsin, chymotrypsin, elastase, and proteinase E are related serine proteases. All three are synthesized in the pancreas which secretes 5-10 g per day of proteins, mostly the inactive proenzymes (zymogens) of digestive enzymes.191,192... 

Figure 12-8 Cascade of reactions that activate pancreatic proteases. Enteropeptidase, or trypsin, cleaves the proenzyme (zymogen) at specific sites.

The most thoroughly investigated pancreatic lipase is from the pig. Most of our knowledge of the structure and properties of this enzyme comes from P. Desnuelle and his co-workers in Marseille (3) (Table III). The lipase occurs in two similar forms, isoenzymes Lipase A and Lipase B. There is no known proenzyme (zymogen). The enzyme does not react with diisopropylfluorophosphate (DFP), the standard inhibitor... 

Caspases, a family of aspartate-specific cysteine proteases, are essential in the initiation and execution of apoptosis (Creagh et al., 2003 Cohen, 1997). They are expressed as inactive proenzymes (zymogens) that become active during apoptosis. Out of 14 caspase enzymes, caspase-3 appears to be the major effector of neuronal apoptosis induced by a variety of stimuli as well as traumatic injuries (Fig. 4.4). A role for caspase-3 in injury-induced neuronal cell death has been established using semispecific peptide caspase inhibitors. Caspases not only cleave other downstream caspases but also a variety of enzymes, cytokines, cytoskeletal, nuclear, and cell cycle regulatory proteins (Cohen, 1997). Their activities in brain and spinal cord tissues are regulated by the occurrence in zymogens form, by members of Bcl-2 family, and certain cellular inhibitor of apoptosis proteins (cIAPs). 

Caspases are a family of at least 14 aspartate-specific cysteine proteases that are essential in the initiation and execution of apoptosis (Creagh et al., 2003 Cohen, 1997). Caspases are normally expressed as inactive proenzymes (zymogens) that become activated during apoptosis (Zhivotovsky et al., 1999). All members of the caspase family share a number of amino acid residues crucial for substrate binding... 

Activation of proenzymes (zymogens) (see Pepsin, Tlypsin, Chymotrypsin). 

These are inactive forms of enzymes—proenzymes. Zymogens convert to active enzymes under the influence of various agents such a pH changes or other enzymes. Examples of... 

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

Pepsin This acid-stable endopeptidase is secreted by the serous cells of the stomach as an inactive zymogen (or proenzyme), pepsinogen. In general, zymogens contain extra amino acids in... 

Chymotrypsinogen consists of a single 245-residue chain. The amino acid residues in chymotrypsin, trypsin, and elastase are usually all numbered according to their position in this zymogen. Inactive proenzymes are formed as precursors to enzymes of many different classes and are activated in a variety of ways. A part of the polypeptide chain of the proenzymes is often folded over the active site, interacting in a nonsubstrate-like fashion and blocking the site.197a... 

Zymogens of cysteine proteases usually have a long terminal extension which is removed, sometimes by autoactivation. Propapain has a 107-residue extension.343 The 322-residue cathepsin B carries an unusually short 62-residue extension in its proenzyme form.315 343 344 In every case the N-terminal extension folds into a domain, one of whose functions is to block the active site cleft. 

Phospholipase A2 catalyzes the hydrolysis of the 2-acyl linkage of all phospholipids. It is secreted as a zymogen by the pancreas, and converted to the active enzyme via a specific tryptic cleavage of the Arg-Ala link which removes an N-terminal heptapeptide from the proenzyme. Phospholipase A2 is one example of the way in which the metabolism of phospholipids is sensitive to calcium at several key points. 

Enzymes are found embedded in cell walls and membranes as well as occuring in the various fluids found in living organisms. A number of enzymes are produced in specific areas of the body by the metabolism of inactive protein precursors known as proenzymes or zymogens. 

Several enzymes are synthesized as larger inactive precursor forms called proenzymes or zymogens. Activation of zymogens involves irreversible hydrolysis of one or more peptide bonds. 

Some enzymes are synthesized in an inactive precursor form known as proenzymes or zymogens, which are activated at a physiologically appropriate time and place. 

The pancreatic enzyme it stored and secreted as a proenzyme with an additional seven residues at the N-tcmiinus, The proenzyme serves, like the other pancreatic proteinase zymogens, to prevent aotodigestion of the pancreatic cells. Upon secretion into the gastrointestinal tract, trypsin cleaves off these seven residues to produce the enzymatic form with full activity on insoluble substrates. On monomeric substrates, however, there is little difference between the catalytic activity of the proenzyme and of the activated enzyme [34],... 

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