Dipeptidases

Penem B-Lactamase Inhibitors. The synthesis and antibacterial properties of penems, the trivial name for the 4-thia-l-azabicyclo[3.2.0]hept-2-ene ring system (24), have been reviewed (107,108). Like the closely related carbapenems, many of the penems are potent antibacterials. Additionally, penems are also susceptible to degradation by renal dipeptidase, but to a lesser extent. The limited -lactamase inhibitory data available for penems are presented in Table 4. SCH-29,482 [77646-83-4] (24, R = H, R = CH(OH)CH2, R = SCH2H ), C2qH23NO S2, is reported to be an inhibitor of type I Cephases and the OXA-2 enzyme (109). Compounds [101803-54-7] and [101914-68-5] (24, R = H, R = CH2CH(OH),... 

An exopeptidase that can only degrade a dipeptide. Examples are carnosine dipeptidase I (MEROPS M20.006), which degrades carnosine (beta-Ala-His), and membrane dipeptidase (MEROPS Ml9.001), which is important in the catabolism of glutathione, degrading the dipeptides Cys-Gly. Dipeptidases are included in Enzyme Nomenclature sub-subclass 3.4.13. 

Gener ally, a family of peptidases contains either exopeptidases or endopeptidases, but there are exceptions. Family Cl contains not only endopeptidases such as cathepsin L, but also the aminopeptidase bleomycin hydrolase. Some members of this family can act as exopeptidases as well as endopeptidases. For example, cathepsin B also acts as a peptidyl-dipeptidase, and... 

An exopeptidase that sequentially releases dipeptides from the C-terminus of a protein or peptide. An example is angiotensin-converting enzyme (also known as peptidyl-dipeptidase A MEROPS XM02-001), which plays an important role in the control of blood pressure by converting angiotensin I to angiotensin II. Peptidyl-dipeptidases are included in Enzyme Nomenclature sub-subclass 3.4.15. 

L-Dihydroxyphenylalanine 4-Dihydroxyphenylethylamine Dimeric Transcription Factors Dioxins Dipeptidase Dipeptidylpeptidase Dipeptidylpeptidase IV Direct Thrombin Inhibitors Discharge of Neurons... 

Penicillin Binding Protein Pentasaccharide Peptide Mass Fingerprint Peptide YY Peptidoglycans Peptidyl Transferase Center Peptidyl-Dipeptidase PERI... 

Other interesting examples of proteases that exhibit promiscuous behavior are proline dipeptidase from Alteromonas sp. JD6.5, whose original activity is to cleave a dipeptide bond with a prolyl residue at the carboxy terminus [121, 122] and aminopeptidase P (AMPP) from E. coli, which is a prohne-specific peptidase that catalyzes the hydrolysis of N-terminal peptide bonds containing a proline residue [123, 124]. Both enzymes exhibit phosphotriesterase activity. This means that they are capable of catalyzing the reaction that does not exist in nature. It is of particular importance, since they can hydrolyze unnatural substrates - triesters of phosphoric acid and diesters of phosphonic acids - such as organophosphorus pesticides or organophosphoms warfare agents (Scheme 5.25) [125]. 

There are two main classes of proteolytic digestive enzymes (proteases), with different specificities for the amino acids forming the peptide bond to be hydrolyzed. Endopeptidases hydrolyze peptide bonds between specific amino acids throughout the molecule. They are the first enzymes to act, yielding a larger number of smaller fragments, eg, pepsin in the gastric juice and trypsin, chymotrypsin, and elastase secreted into the small intestine by the pancreas. Exopeptidases catalyze the hydrolysis of peptide bonds, one at a time, fi"om the ends of polypeptides. Carboxypeptidases, secreted in the pancreatic juice, release amino acids from rhe free carboxyl terminal, and aminopeptidases, secreted by the intestinal mucosal cells, release amino acids from the amino terminal. Dipeptides, which are not substrates for exopeptidases, are hydrolyzed in the brush border of intestinal mucosal cells by dipeptidases. 

The second example of property space applications concerns the dipephde camo-sine (P-alanine-L-histidine, see Fig. 1.4) which represents the archetype of a series of histidine-containing dipeptides whose full physiological role remains poorly understood despite extensive studies in recent years [18-20]. Carnosine is synthesized by carnosine synthetase and hydrolyzed by dipeptidases (also called camosi-nases) which belong to the metalloproteases [21]. 

Metallo proteases Exopeptidase group Peptidyl dipeptidase-A (ACE) Aminopeptidase-M Carboxypeptidase-A... 

Proline dipeptidase cleaves dipepetides where proline is adjacent to the N-terminal residue. The enzyme is a homodimer, with one Co ion tightly bound in each subunit. However, it has been shown that an additional Co11 ion must be added (per subunit) for activity. This second ion is relatively weakly bound and may be substituted by Mn11 with somewhat attenuated activity. Curiously, the active site ligands identified in metallohydrolases such as MetAP are conserved in this enzyme despite a generally low sequence similarity. 

The intestinal mucosal peptidases are distributed in the brush border and cytosol of the absorptive cell. There are, however, distinct differences between the brush border and cytosolic peptidases [75], The tetrapeptidase activity is associated exclusively with the brush border enzyme. Furthermore, brush border peptidases exhibit more activity against tripeptides than dipeptides, whereas the cytosolic enzymes show greater activity against dipeptides. Studies have demonstrated that more than 50% of dipeptidase activity was detected in the cytosol [76] and just 10% in the brush border membrane [77]. The brush border enzymes include... 

O Noren, H Sjostrom, L Josefsson. Studies on a soluble dipeptidase from pig intestinal mucosa. I. Purification and specificity. Biochem Biophys Acta 327 446-456, 1973. 

M Das, AN Radhakrishnan. Substrate specificity of a highly active dipeptidase purified from monkey small intestine. Biochem J 128 463-465, 1972. 

O Noren, E Dabelsteen, H Sjostrom, L Josefsson. Histological localization of two dipeptidases in the pig small intestine and liver, using immunofluorescence. Gastroenterology 72 87-92, 1977. 

Rajotte D, Ruoslahti E. Membrane dipeptidase is the receptor for a lung-targeting peptide identified by in vivo phage display. J Biol Chem 1999 274 11593-11598. 

Several different types of proteases hydrolyze intact storage proteins first into large fragments and then into smaller peptides and amino acids within the protein body. The peptides are transported to the cytosol where other enzymes, e. g. amino-peptidases, carboxypeptidases, dipeptidases and tripeptidases, cleave them and eventually form a pool of free amino acids [11]. 

Formed by sequential enzymatic cleavage by renin and then peptidyl dipeptidase (kinase 11)... 

Lowers blood pressure in hypertensive patients by inhibition of peptidyl dipeptidase... 

---