Small molecules peptide hydrolysis

This enzyme [EC 3.4.22.25] catalyzes the hydrolysis of peptide bonds with a preference for Gly-Xaa in proteins and small molecule substrates. The enzyme, a member of the peptidase family Cl, is isolated from the papaya plant, Carica papaya. It is not inhibited by chicken cys-tatin, unlike most other homologs of papain. 

In E. coli, many proteins are degraded by an ATP-dependent protease called Lon (the name refers to the long form of proteins, observed only when this protease is absent). The protease is activated in the presence of defective proteins or those slated for rapid turnover two ATP molecules are hydrolyzed for every peptide bond cleaved. The precise role of this ATP hydrolysis is not yet clear. Once a protein has been reduced to small inactive peptides, other ATP-independent proteases complete the degradation process. 

In the first catabolic stage, digestion, food is broken down in the mouth, stomach, and small intestine by hydrolysis of ester, glycoside (acetal), and peptide (amide) bonds to jdeld primarily fatty acids, simple sugars, and amino acids. These smaller molecules are further degraded in the cytoplasm of cells to yield acetyl groups attached by a thiol ester bond (Section 21.9) to the large carrier molecule coenzyme A. The resultant compound, aceiyl coenzyme A acetyl CoA), is an intermediate in the breakdown of all main classes of food molecules. 

The foregoing section indicates some reasons why peptide-based drugs are needed. If a peptide hormone is not produced in sufficient quantities or is defective in structure, then a replacement is required. Peptides, especially very small molecules, have a very short half life in the body. The reason for this is the ubiquitous occurrence of proteolytic enzymes that effect hydrolysis of peptides to the constituent amino acids. Although longer peptides, especially those with structural features such as disulphide bonds, survive longer in vivo, they are more likely to stimulate the body s immune system to produce antibodies and effect removal of the peptides. This is particularly likely to occur with molecules that differ structurally from the naturally occurring hormones. Thus, treatment of juvenile-onset diabetes mellitus with insulins from animal sources can occasionally stimulate the patient s immune system... 

The assessment of stability in biotechnology-derived products such as peptides for preformulation is similar to that of the small-molecule drug. Degradation subjected to hydrolysis, oxidation, and deamination influenced by pH, temperature, and buffer species may be studied in the same manner. Protein in solution is not inherently stable. As chemical reactions are retarded in the solid state, a freeze-dried formulation is more suitable for protein product. 

The above principle is amply illustrated by the small molecule systems discussed in Section III. The roles proposed for zinc ion in the three enzyme systems discussed in Section IV also adhere to this principle. The accumulated experimental evidence makes it highly probable that zinc ion has a Lewis acid catalytic function both in the horse liver alcohol dehydrogenase-catalyzed reduction of aldehydes, and in the carboxypeptidase A-catalyzed hydrolysis of peptides. In contrast, the accumulated experimental evidence supports a role for zinc ion involving the enhancement of water nucleophilicity via inner sphere coordination in the carbonic anhydrase-catalyzed hydration of CO 2. The substrates for... 

Some phosphatases are nonspecific, catalyzing the hydrolysis of a wide variety of substrates. Other phosphatases are small-molecule specific and hydrolyze a particular small-molecule phosphate ester or structurally similar substrates. Phosphoprotein-specific phosphatases accept particular phosphorylated proteins or peptides as substrates. The phosphoprotein-specific phosphatases can be subdivided into subgroups those specific for proteins phosphorylated on tyrosine those specific for proteins phosphorylated on serine or threonine and the so-called dual-specific enzymes, which accept both classes of phosphorylated proteins. More recently, a group of protein histidine phosphatases has been described. 

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