The low-barrier hydrogen bond in enzymic catalysis

Cleland WW, Frey PA, Gerlt JA. The low barrier hydrogen bond in enzymic catalysis. J Biol Chem. 1998 273 25529-25532. 

B. Schwartz and D.G. Drucckhammer, A simple method for determining the relative strengths of normal and low-barrier hydrogen bonds in solution Implications to enzyme catalysis, J. Am. Chem. Soc., 117 (1995) 11902. 

The topologically defined region(s) on an enzyme responsible for the binding of substrate(s), coenzymes, metal ions, and protons that directly participate in the chemical transformation catalyzed by an enzyme, ribo-zyme, or catalytic antibody. Active sites need not be part of the same protein subunit, and covalently bound intermediates may interact with several regions on different subunits of a multisubunit enzyme complex. See Lambda (A) Isomers of Metal Ion-Nucleotide Complexes Lock and Key Model of Enzyme Action Low-Barrier Hydrogen Bonds Role in Catalysis Yaga-Ozav /a Plot Yonetani-Theorell Plot Induced-Fit Model Allosteric Interaction... 

Hydrogen bonds appear to be essential in all enzyme-catalyzed reactions, although why they are essential and how they promote function is an open question. In recent years a specific hypothesis for their involvement in catalysis has emerged so-called low-barrier hydrogen bonds (LBHB) have been proposed to lower the transition state energy for many enzymatic reactions, including those of serine protease, citrate... 

So-called low-barrier hydrogen bonds [1] may also play a role in catalysis effected by hydrolases, but their catalytic role is less secure [2-5] relative to the role of transition state proton bridges. It is indeed ironic that while the structural origins of catalytically-questionable LBHBs can be determined with certainty, the structural origins of catalytically-critical TSPBs are elusive. The implications of the latter point will be the topic of the final section of this chapter where we examine several cases in which the results of solvent isotope effect studies that may have been interpreted in the context of the hydrolase chemistry, in fact reflect rate-limiting product release or conformational isomerization of the enzyme. 

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