Enzymes proenzymes

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. 

Allosteric control involves the reversible binding of a compound to an allosteric site referred to as a regulatory site on the enzyme. These compounds may be either one of the compounds involved in the metabolic pathway (feedback regulators) or a compound that is not a product of the metabolic pathway. In both cases, the binding usually results in conformational changes, which either activate or deactivate the enzyme. Proenzymes also act as a form of enzyme control. 

The blood is a fluid connective tissue with a matrix called plasma. Plasma proteins are in solution unlike the other connective tissues that occur in insoluble forms like fibres thus, proteins in solution in the plasma make the plasma slightly denser than water. The blood is composed of plasma (46—63%) and formed elements (37—54%). The plasma is composed of water (92%), plasma proteins (7%) and other solutes (1 %). The formed elements of blood are composed of red blood cells (RBCs) (99.9%), and the remaining 0.1% is platelets and white blood cells (WBCs). The water dissolves and transports organic and inorganic molecules, formed elements and heat from one part of the body to the other. The plasma proteins are composed of albumins (60%), globulins (35%), transport ions, hormones, and hpids, which have an immune function, fibrinogen (4%) and regulatory proteins (<1% enzymes, proenzymes and hormones). Other solutes of blood are composed of electrolytes (major ones are Na" ", K" ", Ca " ", Mg " ",... 

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... 

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... 

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). 

Hypothetical hierarchy of reactions (A) those that fail to yield amplification and (B) those that can achieve any level of amplification, depending only on the number of cycles and the kinetic parameters of the active enzymes formed by successive conversions of proenzyme into active enzymes. 

The classical example is blood clotting, where successive steps involving enzyme-catalyzed proteolysis converts an inactive (or weakly active) proenzyme into its highly active form. Although unknown at the time of Wald s classical report, kinase-type and nucleotidyltransferase-type reactions (See Enzyme Cascade Kinetics) are frequently the source of biological signal transduction and amplification. 

A precursor or storage form of an enzyme, sometimes used synonymously with proenzyme, in which the precursor is converted to the active (or more active) enzyme... 

Non-pyridoxal Phosphate Dependent. Figure 2 depicts the postulated mechanism for a non-pyridoxal phosphate catal) zed decarboxylation of histidine to histamine involving a pyruvoyl residue instead of pyridoxal -5 - phosphate (20). Histidine decarboxylases from Lactobacillus 30a and a Micrococcus sp. have been shown to contain a covalently bound pyruvoyl residue on the active site. The pyruvoyl group is covalently bound to the amino group of a phenylalanine residue on the enzyme, and is derived from a serine residue (21) of an inactive proenzyme (22). The pyruvoyl residue acts in a manner similar to pyridoxal phosphate in the decarboxylation reaction. 

FIGURE 6.9 The classical pathway of complement activation is initiated by binding of Clq to antibody on a surface such as a bacterial surface. Multiple molecules of IgG bound on the surface of a pathogen allow the binding of a single molecule of Clq to two or more Fc pieces. The binding of Clq activates the associated Clr, which becomes an active enzyme that cleaves the proenzyme Cls, generating a serine protease that initiates the classical complement cascade. 

The MMPs are secreted as inactive proenzymes, which are activated by proteolytic cleavage. Once activated they are subject to control by tissue inhibitors of metalloproteinases (TIMPs). It is the imbalance between the active enzymes and the TIMPs that leads to destructive tissue degradation that potent directed pharmaceuticals can overcome. These enzymes have been the target of... 

There is very little information on the process by which the enzyme(s) which catalyze the formation of O is activated. Whether activation represents covalent modification of a proenzyme, translocation to the subcellular site where it gains access to its substrate(s), insertion of a necessary cofactor, association of active subunits, or still another process remains to be determined. The rapidity with which activation occurs seems too rapid to represent synthesis of protein de novo. 

The rate of protein degradation also differs from enzyme to enzyme and depends on the conditions in the cell protein half-lives vary from a few minutes to many days. Some proteins are tagged for degradation in pro-teasomes (discussed in Chapter 28) by the covalent attachment of ubiquitin (recall the case of cyclin see Fig. 12-44). Some proteins are synthesized as inactive forms, or proenzymes, that become active only when a proteolytic event removes an inhibitory sequence in the proenzyme. 

Genetic factors influence the rate of not only synthesis of proteins but also their breakdown, i.e., the rate of turnover. As we have seen in Chapter 10, some enzymes are synthesized as inactive proenzymes which are later modified to active forms, and active enzymes are destroyed, both by accident and via deliberate hydrolytic pathways. Protein antienzymes may not only inhibit enzymes but may promote their breakdown.35 An example is the antienzyme that controls ornithine decarboxylase, a key enzyme in the synthesis of the polyamines that are essential to growth.36,37 As with all cell constituents, the synthesis of enzymes and other proteins is balanced by degradation. 

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... 

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... 

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