Dipeptidase, renal

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),... 

Fig. 4.2 Hydrolytic activity of cauxin on 3-MBCG and proposed metabolic pathways for the conversion of 3-MBG to felinine in the cat kidney. The 3-MBCG (20 mM) was incubated with or without cauxin (1.5 mg/ml) at 38°C for 6 h, and the reaction mixtures were analyzed by thin layer chromatography with ninhydrin staining. y-GTP, y-glutamyl transferase RDP, renal dipeptidase a, 3-mercapto-3-methylbutyl formate b, 3-mercapto-3-methyl-l-butanol c, 3-methyl-3-methylthio-1-butanol and d, 3-methyl-3-(2-methyldisulfanyl)-l-butanol...

H. Kropp, J. G. Sundelof, R. Hajdu, F. M. Kahan, Metabolism of Thienamycin and Related Carbapenem Antibiotics by the Renal Dipeptidase, Dehydropeptidase I , Antimi-crob. Agents Chemother. 1982, 22, 62-70. 

B. J. Campell, L. J. Forrester, W. L. Zahler, M. Burks, /3-Lactamase Activity of Purified and Partially Characterised Human Renal Dipeptidase , J. Biol. Chem. 1984, 259, 14586-14590. 

H. Mikami, M. Ogashiwa, Y. Saino, M. Inoue, S. Mitsuhashi, Comperative Stability of Newly Introduced /3-Lactam Antibiotics to Renal Dipeptidase , Antimicrob. Agents Chemother. 1982, 22, 693-695. 

There are many dipeptidases [EC 3.4.13.x]. Cytosol nonspecific dipeptidase [EC 3.4.13.18] (also referred to as peptidase A, glycylglycine dipeptidase, glycylleucine dipeptidase, and A -)3-alanylarginine dipeptidase) catalyzes the hydrolysis of dipeptides. Membrane dipeptidase [EC 3.1.13.19] (also known as microsomal dipeptidase, renal dipeptidase, and dehydropeptidase I) is a zinc-dependent enzyme (a member of the peptidase family M19) that also catalyzes the hydrolysis of dipeptides. 

Pharmacology This product is a formulation of imipenem, a thienamycin antibiotic, and cilastatin sodium, the inhibitor of the renal dipeptidase, dehydropeptidase-1, which is responsible for the extensive metabolism of imipenem when it is administered alone. Cilastatin prevents the metabolism of imipenem, increasing urinary recovery and decreasing possible renal toxicity. The bactericidal activity of imipenem results from the inhibition of cell-wall synthesis, related to binding to penicillin-binding proteins (PBP). 

An antibiotic drug that is itself nontoxic may have metabolites that are toxic, diminishing its usefulness. For example, imipenem is hydrolyzed by renal dipeptidase to a metabohte that is inactive against bacteria but is toxic to humans. Coadministration of cilastatin inhibits the renal dipeptidase, which both prevents the formation of the toxic metabolite and decreases imipenem clearance, prolonging the half-life of the drug. 

Answer You decide that a metabolite of imipenem is responsible for the sudden toxicity. You add a second drug, cilastatin, to the patient s regimen. Coadministration of cilastatin inhibits renal dipeptidase, the enzyme responsible for the metabolism of imipenem. This prevents the formation of the toxic metabolite and decreases the clearance of imipenem. The side effect disappears within 12 hours and the patient recovers from the infection. 

Chemical Class Carbapenem renal dipeptidase inhibitor (cilistatin) thienamycin... 

Renal dipeptidase -antibiotic metabolization [ANTIBIOTICS - BETA-LACTAMS - CARBAPENEMS AND PENEMS] (Vol 3) -degradation of antibiotics [ANTIBIOTICS - BETA-LACTAMS - BETA-LACTAMASE INHIBITORS] (Vol 3)... 

Penem ff-Lactamase Inhibitors. The synthesis and antibacterial properties of penems have been reviewed. Like die 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. 

Title Design and Synthesis of Renal Dipeptidase Inhibitors S.R. Khan et al., US Patent 6,927,212 (August 9, 2005) Assignee The Johns Hopkins University Utility Treatment of Colon Tumors... 

Invention Significance Renal dipeptidase (RDP) is a zinc-containing... 

Kropp H, Sundelof JG, Hajdu R, Kahan EM. Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase-1. Antimicrob Ag Chemother 1982 22 62-70. 

Renal dipeptidase (from porcine Wdney cortex) [9031-96-3] M, 47,000 [EC 3.4.13.11]. Purified by homogenising the tissue, extracting with Triton X-100, elimination of insoluble material, and ion-exchange, size exclusion and affinity chromatography. [Hitchcock et al. Anal Biochem 163 219 1987.]... 

Meropenem (Merrem IV) is a dimethylcarbamoyl pyro-lidinyl derivative of thienamycin. It does not require coadministration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity is similar to that of imipenem except that it may be less likely to cause seizures (0.5% of meropenem- and 1.5% of imipenem-treated patients seized). Its in vitro activity is similar to that of imipenem, with activity against some imipenem-resistant P. aeruginosa but less activity against Gram-positive cocci. Chnical experience with meropenem demonstrates therapeutic equivalence with imipenem. 

MEROPENEM Meropenem (merrem iv) is a derivative of thienamycin that does not require coadministration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity and clinical efficacy are similar to imipenem, except that it may be less likely to cause seizures. 

Human renal dipeptidase lITU Znl 3.3 HiS2a/i 1 Asp2ba 102 Glup H2O ... 

Another zinc metalloenzyme, renal dipeptidase, was recently... 

Initial optimization of the general route was performed during the synthesis of porcine renal dipeptidase GPI anchor. The target molecule features the pseudopentasaccharide core, two mandatory phosphodiesters, the common P-GalNAc side branch at C4 position of ManI, and an additional phosphoethanolamine unit at C2 position of Manl. 

---