Glutamate .gamma.-Semialdehyde as a Natural Transition State Analog Inhibitor of Escherichia coli Glucosamine-6-phosphate Synthase

Biochemistry ◽  
1995 ◽  
Vol 34 (36) ◽  
pp. 11515-11520 ◽  
Author(s):  
Stephen L. Bearne ◽  
Richard Wolfenden
Keyword(s):  
Escherichia Coli ◽  
Transition State ◽  
Transition State Analog ◽  
Phosphate Synthase

scholarly journals Crystal structure of phenylalanine-regulated 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase from Escherichia coli

Structure ◽  
1999 ◽  
Vol 7 (7) ◽  
pp. 865-875 ◽  
Author(s):  
Igor A Shumilin ◽  
Robert H Kretsinger ◽  
Ronald H Bauerle
Keyword(s):  
Crystal Structure ◽  
Escherichia Coli ◽  
Phosphate Synthase

Renin inhibitors. Synthesis of transition-state analog inhibitors containing phosphorus acid derivatives at the scissile bond

1989 ◽  
Vol 32 (7) ◽  
pp. 1652-1661 ◽  
Author(s):  
Mark C. Allen ◽  
Walter Fuhrer ◽  
Brian Tuck ◽  
Roy Wade ◽  
Jeanette M. Wood
Keyword(s):  
Transition State ◽  
Phosphorus Acid ◽  
Transition State Analog ◽  
Renin Inhibitors ◽  
Scissile Bond

scholarly journals A crystallographic study of the Toho-1 β-lactamase acylation mechanism

2014 ◽  
Vol 70 (a1) ◽  
pp. C1207-C1207
Author(s):  
Leighton Coates
Keyword(s):  
Hydrogen Bonding ◽  
Transition State ◽  
Active Site ◽  
Catalytic Mechanism ◽  
Substrate Binding ◽  
Ligand Complex ◽  
Transition State Analog ◽  
Hydrogen Bonding Interactions ◽  
Active Site Region ◽  
Neutron Crystallography

β-lactam antibiotics have been used effectively over several decades against many types of highly virulent bacteria. The predominant cause of resistance to these antibiotics in Gram-negative bacterial pathogens is the production of serine β-lactamase enzymes. A key aspect of the class A serine β-lactamase mechanism that remains unresolved and controversial is the identity of the residue acting as the catalytic base during the acylation reaction. Multiple mechanisms have been proposed for the formation of the acyl-enzyme intermediate that are predicated on understanding the protonation states and hydrogen-bonding interactions among the important residues involved in substrate binding and catalysis of these enzymes. For resolving a controversy of this nature surrounding the catalytic mechanism, neutron crystallography is a powerful complement to X-ray crystallography that can explicitly determine the location of deuterium atoms in proteins, thereby directly revealing the hydrogen-bonding interactions of important amino acid residues. Neutron crystallography was used to unambiguously reveal the ground-state active site protonation states and the resulting hydrogen-bonding network in two ligand-free Toho-1 β-lactamase mutants which provided remarkably clear pictures of the active site region prior to substrate binding and subsequent acylation [1,2] and an acylation transition-state analog, benzothiophene-2-boronic acid (BZB), which was also isotopically enriched with 11B. The neutron structure revealed the locations of all deuterium atoms in the active site region and clearly indicated that Glu166 is protonated in the BZB transition-state analog complex. As a result, the complete hydrogen-bonding pathway throughout the active site region could then deduced for this protein-ligand complex that mimics the acylation tetrahedral intermediate [3].

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