Proenzyme

Renatns, M., Engh, R. A., Stubbs, M. T, et al., 1997. Lysine-156 promotes the anomalons proenzyme activity of tPA X-ray crystal structure of singlechain human tPA. EMBO Journal 16 4797-4805. 

So far ten catalytically active caspases have been reported in mouse (caspase-1, -2, -3, -6, -7, -8, -9, -11, -12,-14) and eleven in human (caspase-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -14) (Fig. 1). Caspases are expressed as inactive proenzymes that contain an amino-terminal prodomain of variable length followed by two domains with conserved sequences a large subunit ( 20 kDa, p20) and a small carboxy-terminal subunit ( 10 kDa, plO). Caspases can be divided according to absence (-3, -6, -7, -14) or presence (-1, -2, -8, -9, -10, -11, -12) of an extended prodomain containing protein-protein interaction motifs belonging to the death domain (DD) superfamily, in particular the death effector domains (DED) and the caspase activation and recruitment domains (CARD). 

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). 

Certain enzymes, proenzymes, and their substrates are present at all times in the circulation of normal individuals and perform a physiologic function in the blood. Examples of these functional plasma enzymes include lipoprotein Upase, pseudocholinesterase, and the proenzymes of blood coagulation and blood clot dissolution (Chapters 9 and 51). The majority of these enzymes are synthesized in and secreted by the liver. 

Proenzymes Facilitate Rapid Mobilization of an Activity in Response to Physiologic Demand... 

Selective proteolysis of catalytically inactive proenzymes initiates conformational changes that form the... 

Complement is not a single protein but comprises a group of functionally linked proteins that interact with each other to provide mar of the effector functions of humoral immunity and inflammation. Most of the components of the system are present in the serum as proenzymes, i.e. enzyme precursors. Activation of a complement molecule occurs as a result of proteolytic cleavage of the molecule, which in itself confers proteolytic activity on the molecule. Thus, many components of the system serve as the substrate of a prior component and, in turn, activate a subsequent component. This pattern of sequential activation results in the system being called the complement cascade. ... 

A completely distinct enzyme has been found in a number of organisms, which carry out the metabolism of amino acids. In this group, a pyruvoyl group is covalently bound to the active enzyme that is produced from a proenzyme in a self-maturation process (Toms et al. 2004). The proenzyme contains a serine residue that undergoes rearrangement to an ester followed by conversion into the (3-chain of the enzyme and a dehydroalanine residne that forms the A-terminal pyruvoyl group of the a-chain. This type of enzyme has been fonnd for a number of important decarboxylations ... 

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

The fluidity of blood is a result of the inhibition of a complex series of enzymic reactions in the coagulation cascade (see Fig. 10). When triggered either intrinsically (by contact with foreign surfaces ), or extrinsically (by tissue factors from damaged cells), inactive proenzymes (factors XII, XI, IX, and X) are transformed into activated pro-teinases (XHa, XIa, IXa, and Xa, respectively). Each proteinase catalyzes the activation of the following proenzyme in the sequence, up to formation of thrombin (Factor Ha), another proteinase that catalyzes partial... 

Becker JW, Marcy AI, Rokosz LL, Axel MG, Burbaum JJ, Fitzgerald PMD, Cameron PM, Esser CK, Hagmann WK, Hermes JD, Springer JP. Stromelysin-1 Three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme. Prot Sci 1995 4 1966-1976. 

Trypsinogen, the inactive proenzyme form of trypsin has no water molecules in its unordered active site cf. Fehlhammer, H., Bode, W., Huber, R. ibid. Ill, 415 (1977)... 

The pepsin, activated by cleavage of a proenzyme, has two putative active site domains comprising hydrophobic-hydrophobic-Asp-Thr-Gly amino acids, is potentially glycosylated and has a free cysteine residue which may allow it to form dimers, as in the case of human and Plasmodium falciparum-derived aspartyl proteases (Longbottom et al., 1997). However,... 

KIO. Kobayashi, H., Schmitt, M., Goretzki, L., Chuchowolski, N., Calvete, J., Karamer, M., Gunzler, W. A., Janicke, F., and Graeff, H., Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (pro-uPA). J. Biol. Chem. 266, 5147-5152 (1991). 

PI. Pagano, M., Dalet-Fumeron, V., and Engler, R., The glycosylation state of the precursors of the cathepsin-iike proteinase from human malignant ascitic fluid Possible implication in the secretory pathways of these proenzymes. Cancer Lett. 45, 13-19 (1989). 

The protein-based clotting process is a classic example of an enzyme cascade (see Figure 5.23). The clotting factors (which are designated with a Roman numeral, I to XIII) are synthesized in the liver and circulate in the blood as inactive precursors, strictiy, proenzymes. Most of the clotting factors are serine protease enzymes, that is they are enzymes which cleave other proteins (substrates) by a mechanism which involves a serine residue at the active site. 

These proteolytic enzymes are all endopeptidases, which hydrolyse links in the middle of polypeptide chains. The products of the action of these proteolytic enzymes are a series of peptides of various sizes. These are degraded further by the action of several peptidases (exopeptidases) that remove terminal amino acids. Carboxypeptidases hydrolyse amino acids sequentially from the carboxyl end of peptides. They are secreted by the pancreas in proenzyme form and are each activated by the hydrolysis of one peptide bond, catalysed by trypsin. Aminopeptidases, which are secreted by the absorptive cells of the small intestine, hydrolyse amino acids sequentially from the amino end of peptides. In addition, dipeptidases, which are structurally associated with the glycocalyx of the entero-cytes, hydrolyse dipeptides into their component amino acids. 

Pancreatic secretions. In the acinar cells, the pancreas forms a secretion that is alkaline due to its HCOa content, the buffer capacity of which is suf cient to neutralize the stomach s hydrochloric acid. The pancreatic secretion also contains many enzymes that catalyze the hydrolysis of high-molecular-weight food components. All of these enzymes are hydrolases with pH optimums in the neutral or weakly alkaline range. Many of them are formed and secreted as proenzymes and are only activated in the bowel lumen (see p. 270). 

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). 

Trypsinogen plays a key role among the proenzymes released by the pancreas. In the bowel, it is proteolytically converted into active trypsin (see p. 176) by enteropeptidase, a membrane enzyme on the surface of the en-terocytes. Trypsin then autocatalytically activates additional trypsinogen molecules and the other proenzymes (left). 

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. 

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