scholarly journals Interactions between active-site-serine β-lactamases and compounds bearing a methoxy side chain on the α-face of the β-lactam ring: kinetic and molecular modelling studies

1993 ◽  
Vol 293 (3) ◽  
pp. 607-611 ◽  
Author(s):  
A Matagne ◽  
J Lamotte-Brasseur ◽  
G Dive ◽  
J R Knox ◽  
J M Frère
Keyword(s):  
Water Molecule ◽  
Molecular Modelling ◽  
Side Chain ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Class A ◽  
Molecular Modelling Studies ◽  
Lactam Ring ◽  
Modelling Studies

The interactions between three class A beta-lactamases and compounds bearing a methoxy side chain on the alpha-face of the beta-lactam ring (cefoxitin, moxalactam and temocillin) have been studied. When compared with the situation prevailing with good substrates, both acylation and deacylation steps appeared to be severely impaired. Molecular modelling studies of the structures of the Henri-Michaelis complexes and of the acyl-enzymes indicate a major displacement of the crystallographically observed water molecule which connects the glutamate-166 and serine-70 side chains and underline the role of this water molecule in both reaction steps.

Molecular modelling studies of side-chain rotation in substituted triazine rings

2002 ◽  
Vol 602-603 ◽  
pp. 59-70 ◽  
Author(s):  
Helen E. Birkett ◽  
Julian C. Cherryman ◽  
A. Margaret Chippendale ◽  
Paul Hazendonk ◽  
Robin K. Harris
Keyword(s):  
Molecular Modelling ◽  
Side Chain ◽  
Molecular Modelling Studies ◽  
Modelling Studies

Interaction of β-lactamases I and II from Bacillus cereus with semisynthetic cephamycins. Kinetic studies

1991 ◽  
Vol 279 (1) ◽  
pp. 111-114 ◽  
Author(s):  
J Martin Villacorta ◽  
P Arriaga ◽  
J Laynez ◽  
M Menendez
Keyword(s):  
Bacillus Cereus ◽  
Kinetic Studies ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Class A ◽  
Rate Determining Step ◽  
Class B ◽  
Lactam Ring ◽  
Beta Lactamase Ii

The influence of C-6 alpha- or C-7 alpha-methoxylation of the beta-lactam ring in the catalytic action of class A and B beta-lactamases has been investigated. For this purpose the kinetic behaviour of beta-lactamases I (class A) and II (class B) from Bacillus cereus was analysed by using several cephamycins, moxalactam, temocillin and related antibiotics. These compounds behaved as poor substrates for beta-lactamase II, with high Km values and very low catalytic efficiencies. In the case of beta-lactamase I, the substitution of a methoxy group for a H atom at C-7 alpha or C-6 alpha decreased the affinity of the substrates for the enzyme. Furthermore, the acylation of cephamycins was completely blocked, whereas that of penicillins was slowed down by a factor of 10(4)-10(5), acylation being the rate-determining step of the process.

scholarly journals The diversity of the catalytic properties of class A β-lactamases

1990 ◽  
Vol 265 (1) ◽  
pp. 131-146 ◽  
Author(s):  
A Matagne ◽  
A M Misselyn-Bauduin ◽  
B Joris ◽  
T Erpicum ◽  
B Granier ◽  
...  
Keyword(s):  
Catalytic Properties ◽  
Amino Acid Sequences ◽  
Side Chain ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Class A ◽  
Wide Range ◽  
Class C ◽  
Range Of Variation ◽  
Sequence Similarities

The catalytic properties of four class A beta-lactamases were studied with 24 different substrates. They exhibit a wide range of variation. Similarly, the amino acid sequences are also quite different. However, no relationships were found between the sequence similarities and the substrate profiles. Lags and bursts were observed with various compounds containing a large sterically hindered side chain. As a group, the enzymes could be distinguished from the class C beta-lactamases on the basis of the kappa cat. values for several substrates, particularly oxacillin, cloxacillin and carbenicillin. Surprisingly, that distinction was impossible with the kappa cat./Km values, which represent the rates of acylation of the active-site serine residue by the beta-lactam. For several cephalosporin substrates (e.g. cefuroxime and cefotaxime) class A enzymes consistently exhibited higher kappa cat. values than class C enzymes, thus belying the usual distinction between ‘penicillinases’ and ‘cephalosporinases’. The problem of the repartition of class A beta-lactamases into sub-classes is discussed.

scholarly journals Inhibition of class C β-lactamases by (1′R,6R)-6-(1′-hydroxy)benzylpenicillanic acid SS-dioxide

1985 ◽  
Vol 225 (2) ◽  
pp. 435-439 ◽  
Author(s):  
G C Knight ◽  
S G Waley
Keyword(s):  
Side Chain ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Lactam Ring ◽  
Class C ◽  
Hydrolysis Of

beta-Lactamases, enzymes that catalyse the hydrolysis of the beta-lactam ring in beta-lactam antibiotics, are divided into three classes, A, B and C, on the basis of the structures so far determined. There are relatively few effective inhibitors of class C beta-lactamases. A beta-lactam sulphone with a hydroxybenzyl side chain, namely (1′R,6R)-6-(1′-hydroxy)benzylpenicillanic acid SS-dioxide (I), has now been studied. The sulphone is a good mechanism-based inhibitor of class C beta-lactamases. At pH8, the inhibition of a Pseudomonas beta-lactamase is irreversible, and proceeds at a rate that is about one-tenth the rate of concurrent hydrolysis. The labelled enzyme has enhanced u.v. absorption and is probably an enamine. At a lower pH, however, inhibition is transitory.

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