Molecular Recognition at the Active Site of Catechol‐ O ‐methyltransferase (COMT): Adenine Replacements in Bisubstrate Inhibitors

2011 ◽  
Vol 17 (23) ◽  
pp. 6369-6381 ◽  
Author(s):  
Manuel Ellermann ◽  
Ralph Paulini ◽  
Roland Jakob‐Roetne ◽  
Christian Lerner ◽  
Edilio Borroni ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Active Site ◽  
Bisubstrate Inhibitors

Molecular Recognition at the Active Site of Factor Xa: Cation-π Interactions, Stacking on Planar Peptide Surfaces, and Replacement of Structural Water

2011 ◽  
Vol 18 (1) ◽  
pp. 213-222 ◽  
Author(s):  
Laura M. Salonen ◽  
Mareike C. Holland ◽  
Philip S. J. Kaib ◽  
Wolfgang Haap ◽  
Jörg Benz ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Active Site ◽  
Factor Xa ◽  
Structural Water ◽  
Π Interactions

scholarly journals Residue Accessibility, Hydrogen Bonding, and Molecular Recognition:  Metal−Chelate Probing of Active Site Histidines in Chymotrypsins

Biochemistry ◽  
1997 ◽  
Vol 36 (51) ◽  
pp. 16355-16356
Author(s):  
Patrick P. Berna ◽  
Nadir T. Mrabet ◽  
Jozef Van Beeumen ◽  
Bart Devreese ◽  
Jerker Porath ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Recognition ◽  
Active Site ◽  
Metal Chelate

scholarly journals Structures of bacterial kynurenine formamidase reveal a crowded binuclear zinc catalytic site primed to generate a potent nucleophile

2014 ◽  
Vol 462 (3) ◽  
pp. 581-589 ◽  
Author(s):  
Laura Díaz-Sáez ◽  
Velupillai Srikannathasan ◽  
Martin Zoltner ◽  
William N. Hunter
Keyword(s):  
Molecular Recognition ◽  
Active Site ◽  
Catalytic Properties ◽  
Catalytic Site ◽  
Plausible Mechanism

Catalytic properties and structures of three bacterial kynurenine formamidases are presented. The dimeric enzyme possesses an uncommon fold and crowded binuclear zinc active site. Fluorescence and structure of a complex inform on molecular recognition and a plausible mechanism is proposed.

Quantitative Distinctions of Active Site Molecular Recognition by P-Glycoprotein and Cytochrome P450 3A4

2001 ◽  
Vol 14 (12) ◽  
pp. 1596-1603 ◽  
Author(s):  
Er-jia Wang ◽  
Karen Lew ◽  
Mary Barecki ◽  
Christopher N. Casciano ◽  
Robert P. Clement ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Molecular Recognition ◽  
Active Site ◽  
Cytochrome P450 3A4 ◽  
P Glycoprotein

Residue Accessibility, Hydrogen Bonding, and Molecular Recognition:  Metal−Chelate Probing of Active Site Histidines in Chymotrypsins†

Biochemistry ◽  
1997 ◽  
Vol 36 (23) ◽  
pp. 6896-6905 ◽  
Author(s):  
Patrick P. Berna ◽  
Nadir T. Mrabet ◽  
Jozef Van Beeumen ◽  
Bart Devreese ◽  
Jerker Porath ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Molecular Recognition ◽  
Active Site ◽  
Metal Chelate

scholarly journals Evolutionary repurposing of a sulfatase: A new Michaelis complex leads to efficient transition state charge offset

2018 ◽  
Vol 115 (31) ◽  
pp. E7293-E7302 ◽  
Author(s):  
Charlotte M. Miton ◽  
Stefanie Jonas ◽  
Gerhard Fischer ◽  
Fernanda Duarte ◽  
Mark F. Mohamed ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Transition State ◽  
Active Site ◽  
High Reactivity ◽  
Fine Tuning ◽  
Binding Modes ◽  
Evolutionary Trajectory ◽  
Multiple Substrates ◽  
Enzyme Substrate ◽  
Multiple Substrate

The recruitment and evolutionary optimization of promiscuous enzymes is key to the rapid adaptation of organisms to changing environments. Our understanding of the precise mechanisms underlying enzyme repurposing is, however, limited: What are the active-site features that enable the molecular recognition of multiple substrates with contrasting catalytic requirements? To gain insights into the molecular determinants of adaptation in promiscuous enzymes, we performed the laboratory evolution of an arylsulfatase to improve its initially weak phenylphosphonate hydrolase activity. The evolutionary trajectory led to a 100,000-fold enhancement of phenylphosphonate hydrolysis, while the native sulfate and promiscuous phosphate mono- and diester hydrolyses were only marginally affected (≤50-fold). Structural, kinetic, and in silico characterizations of the evolutionary intermediates revealed that two key mutations, T50A and M72V, locally reshaped the active site, improving access to the catalytic machinery for the phosphonate. Measured transition state (TS) charge changes along the trajectory suggest the creation of a new Michaelis complex (E•S, enzyme–substrate), with enhanced leaving group stabilization in the TS for the promiscuous phosphonate (βleavinggroup from −1.08 to −0.42). Rather than altering the catalytic machinery, evolutionary repurposing was achieved by fine-tuning the molecular recognition of the phosphonate in the Michaelis complex, and by extension, also in the TS. This molecular scenario constitutes a mechanistic alternative to adaptation solely based on enzyme flexibility and conformational selection. Instead, rapid functional transitions between distinct chemical reactions rely on the high reactivity of permissive active-site architectures that allow multiple substrate binding modes.

Sign in / Sign up

Export Citation Format

Share Document