Transpeptidase

IB 90,000 250 (8) transglycosylase, major transpeptidase of cell elongation essential for cylindrical cell wall synthesis rapid lysis... 

Resistance can also arise when target enzymes, ie, the PBPs, and in particular the transpeptidases, are modified. Target-mediated cephalosporin resistance can involve either a reduced affinity for an existing PBP, or the acquisition of a supplementary, P-lactam insensitive PBP (139). 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

P-Lactam antibiotics exert their antibacterial effects via acylation of a serine residue at the active site of the bacterial transpeptidases. Critical to this mechanism of action is a reactive P-lactam ring having a proximate anionic charge that is necessary for positioning the ring within the substrate binding cleft (24). 

Preliminary investigations involving a P-lactam-sensitive, bifimctional D-alanyl-carboxypeptidase—transpeptidase (C Pase—T Pase) from Streptomjces R61 have identified the three-dimensional stmcture and catalytic site of interaction with penicillins (63). 

Although most /3- lactam antibiotics bind covalently to some or all of the same six proteins, there are decided differences among them in terms of their relative affinities. For example, cefoxitin (see Table 1 for structures) fails to bind to protein 2 while cephacetrile binds very slowly to proteins 5 and 6. Cephaloridine binds most avidly to protein 1, the transpeptidase, and inhibits cell elongation and causes lysis at its minimum inhibitory concentration. On the other hand, cephalexin binds preferentially to protein 3 and causes inhibition of cell division and filament formation (75PNA2999, 77MI51002). 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

The biological activity of penicillins and cephalosporins is due to the presence of the strained /3-lactam ring, which reacts with and deactivates the transpeptidase enzyme needed to synthesize and repair bacterial cell walls. With the wall either incomplete or weakened, the bacterial cell ruptures and dies. 

This insertion is accomplished by an enzyme called transpeptidase. -Lactam antibiotics function as substrates for the transpeptidase, thereby establishing selective inhibition of bacterial cell wall synthesis. The structural similarity between -lactam antibiotics and the alanylalanine unit is remarkable as can be seen in Figure 6.8. 

Figure 6.8 Pendllins are similar to the bacterial peptidogiycan terminal alanylalanine moiety. Because of this similarity, the enzyme transpeptidase recognizes 8-lactam antibiotics as substrate. As a result of this the 8-lactam is incorporated in the peptide chain thereby making peptide-peptide cross-linking impossible. The occurrence of this phenomenon stops the construction of the bacterial cell wall.

In contrast to macrolides, the targets of (3-lactams, the penicillin binding proteins (PBPs) require several mutations in order to become resistant while simultaneously maintaining their viable function as cell wall transpeptidases/transglycosidases. Thus, in order to achieve clinically relevant resistance Streptococcus pneumoniae uses a unique strategy to rapidly accumulate several point mutations. Due to its natural competence for transformation during respiratory tract... 

Antithyroid drags have several side effects. The most frequent side effects are maculopapular rashes, pruritus, urticaria, fever, arthralgia and swelling of the joints. They occur in 1-5% of patients [1, 2]. Loss of scalp hair, gastrointestinal problems, elevations of bone isoenzyme of alkaline phosphatase and abnormalities of taste and smell are less common. The incidence of all these untoward reactions is similar with MMI and PTU. Side effects of MMI are dose-related, whereas those of PTU are less clearly related to dose [1]. PTU may cause slight transient increases of serum aminotransferase and y-glutamyl transpeptidase concentrations but also severe hq atotoxicity whereas methimazole or carbimazole can be associated with cholestasis. The side... 

Frere JM et al (1975) Kinetics of interactions between the exocellular DD-carboxypeptidase-transpeptidase from Streptomyces R61 and (3-lactam antibiotics. Eur J Biochem 57 343-351... 

A comparison of the structures of penicillin and Dalanyl-Dalanine (cf. structures 41 and 42) shows that there is a great deal of similarity between the two molecules. Penicillin is essentially an acylated cyclic dipeptide of Dcysteine and Dvaline (84). As such, it contains a peptide bond, that of the /3-lactam ring, that can acylate the enzyme. Labeling studies of the peptidoglycan transpeptidase of Bacillus subtilis indicate that radioactive penicillin reacts with a sulfhydryl group of a cysteine residue of the enzyme (86). 

Bondar, R. J. L. and Moss, G. A. Enhancing effect of glutamate on apparent serum Y glutamyl transpeptidase activity. Clin. Chem. (1974), 20, 317-319. 

Rosalki. S. B. Rau, D. Serum Y"giutamyl-transpeptidase activity in alcoholism. Clin. Chim. Acta (1972), 39, 41-47. 

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