Class A beta-lactamase

M. Ishiguro, S. Imajo, Modeling Study on a Hydrolytic Mechanism of Class A beta-Lactamases , J. Med. Chem. 1996, 39, 2207-2218. 

Y. Yang, B. A. Rasmussen, D. M. Shlaes, Class A beta-Lactamases-Enzyme-Inhibitor Interactions and Resistance , Pharmacol. Ther. 1999, 83, 141 -151. 

Y. Yang, K. Janota, K. Tabei, N. Huang, M. M. Siegel, Y. I. Lin, B. A. Rasmussen, D. M. Shlaes, Mechanism of Inhibition of the Class A beta-Lactamases PCI and TEM-1 by Tazobactam. Observation of Reaction Products by Electrospray Ionization Mass Spectrometry , J. Biol. Chem. 2000, 275, 26674-26682. 

Hermann JC, L Ridder, AJ Mulholland, H-D Holtje (2003) Identification of Glul66 as the general base in the acylation reaction of class A beta-lactamases through QM/MM modeling. J. Am. Chem. 

Hermann JC, L Ridder, H-D Holtje, AJ Mulholland (2006) Molecular mechanisms of antibiotic resistance QM/MM modelling of deacylation in a class A beta-lactamase. Organic Biomolecular Chemistry 4 (2) 206-210... 

Meroueh SO, Fisher JF, Schlegel HB, Mobashery S. Ab initio QM/MM study of class A beta-lactamase acylation dual participation of Glul66 and Lys73 in a concerted base promotion of Ser70. J. Am. Chem. Soc. 2005 127 15397-15407. 

A, Stemmier AJ, Stemmier TL, Mobashery S. The importance of 47. a critical protonation state and the fate of the catalytic steps in class A beta-lactamases and penicillin-binding proteins. J. Biol. 48. Chem. 2004 279 34665-34673. 

In the case of penicillin G, the outward rotation about the C3-C4 bond can occur vithout conflict with protein side chains. It relaxes the strained conformation along this bond previously enforced by the four-membered ring. Moreover, this rotation improves hydrophobic contact of the dimethyl and the sulfur part of the thiazolidine ring of penicillin with two leucine side chains, thus offering an additional driving force for the outward rotation. Experimental evidence is provided by the observed rotation of 35.2° in this direction about the C3-C4 bond that occurs in the acyl-enzyme complex formed between benzyl penicillin and a mutant class A beta-lactamase (RTEM-1) blocked in deacylation [9]. 

Inspection of class A beta-lactamase crystal structures indicated that a water molecule in an equivalent position would be much less activated because there is a serine residue replacing the tyrosine of class C enzymes [7,11]. Attack in a class A enzyme occurs from the opposite side of the ester, with activation of the water molecule occurring through an extension of the hydrogen bond network that is not present in class C enzymes. Hence, rotation about C3-C4 is less critical to the mechanism of deacylation in these enzymes and restricting the rotation should have less impact on the stability of the acyl-enzyme complex. 

M. Galleni, G. Amicosante, J. M. Frere, A Survey of the Kinetic Parameters of Class C beta-Lactamases. Cephalosporins and Other beta-Lactam Compounds , Biochem. J. 1988, 255, 123-129. 

This experimental result offers a convincing rationalization for the slow deacylation of aztreonam in class C beta-lactamases. 

Crichlow GV, Nukaga M, Doppalapudi VR. et al Inhibition of class c beta-lactamases Structure of a re-... 

Monobactam, a new class of natural beta-lactam antibiotics, was found from a beta-lactamase screen. Aztreonam, a chemically synthesized monobactam, is in clinical use. 

Several classes of (3-lactamases, often encoded in transmissible plasmids, have spread worldwide rapidly among bacteria, seriously decreasing the effectivenss of penicillins and other (3-lactam anti-biotics.t y Most (3-lactamases (classes A and C) contain an active site serine and are thought to have evolved from the dd transpeptidases, but the B typey has a catalytic Zn2+. The latter, as well as a recently discovered type A enzyme,2 hydrolyze imipenem, currently one of the antibiotics of last resort used to treat infections by penicillin-resistant bacteria. Some (3-lactam antibiotics are also powerful inhibitors of (3-lactamases.U/aa/bb These antibiotics may also have uses in inhibition of serine proteasesCC/dd such as elastase. Some antibiotic-resistant staphylococci produce an extra penicillin-binding protein that protects them from beta lactams.ee Because of antibiotic resistance the isolation of antibiotics from mixed populations of microbes from soil, swamps, and lakes continues. Renewed efforts are being... 

K Bush. Metallo-beta-lactamases a class apart. Clin Infect Dis 27(Suppl 1) S48-S53, 1998. 

Moxifloxacin is an 8-methoxyquinolone with enhanced potency against important Gram-positive pathogens, notably Streptococcus pneumoniae (penicillin-resistant and penicillin-susceptible strains), and class activity against Gram-negative bacteria. Its activity is not affected by beta-lactamases. Moxifloxacin may therefore represent a promising alternative for treatment of respiratory tract infections (1). 

Sanschagrin, F., Levesque, R. C. (2005). A specific peptide inhibitor of the class B metallo-beta-lactamase L-1 from Stenotrophomonas maltophilia identified using phage display. J. Antimicrob. Chemother., 55, 252-255. 

Bush K. 1998. Metallo-beta-lactamases a class apart. Clin Infect Dis 27 S48-S53. Siemann S, Brewer D, Clarke AJ, Dmitrienko GI, Lajoie G, Viswanatha T. 2002. lMP-1 metallo-beta-lactamase effect of chelators and assessment of metal requirement by electrospray mass spectrometry. Biochim Biophys Acta 1571 190-200. 

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