ODCase proficiency

The mechanism of the enzymatic decarboxylation of orotidine 5 -mono-phosphate (OMP) to uridine 5 -monophosphate (UMP) (see Fig. 1) is an intriguing problem for which many solutions have been offered. Even before 1995 when Wolfenden and Radzicka declared OMP decarboxylase (ODCase) to be the most proficient enzyme [1], several different mechanisms had been proposed. Since that time, other mechanisms have been advocated. Curiously, the appearance of crystal structures for various wild-type and mutant ODCases has led not to a definitive picture of catalysis, but to even more conjecture and controversy concerning the mechanism. 

Figure 3 compares the proficiencies (kcat/K]v[/kun) of ODCase, several other enzyme decarboxylases [2], and some antibody decarboxylases [3]. The proficiencies of the decarboxylase enzymes, including a variety of amino acid decarboxylases, are nearly equal. Many decarboxylases employ iminium intermediates formed by reaction of an amino acid with a cofactor such as pyruvoyl or pyridoxal, or by reaction of a -keto ester with an active-site lysine residue. These intermediates have been found to be so reactive that the... 

For ODCase, non-covalent mechanisms have often been proposed, as reflected in three of the mechanisms shown in Fig. 2. This is the crux of the attention showered on ODCase how can this enzyme achieve its rate acceleration without the use of cofactors, metals, or acid-base catalysis From Wolfenden s measurements of the uncatalyzed reaction of 1-methylorotic acid in water, he calculated the rate enhancement (kcat/kun) in the enzyme to be 1.4x10, corresponding to a reduction of AG of 24 kcal/mol [1]. He also reported the catalytic proficiency to be 2x10 meaning that the enzyme-transition state complex is an impressive 32 kcal/mol more stable than the fi-ee enzyme and transition state in water (i.e., the effective binding free energy of the transition state out of water is 32 kcal/mol) [1] The experimental free energy of activation is 15 kcal/mol for this decarboxylation in ODCase. 

Despite intense experimental and theoretical efforts, the mystery surrounding the proficiency of ODCase has not yet been solved. This summary of the experimental facts and their imphcations, analysis of the structural data available from various crystal structures, description of the various computational studies performed on this problem, and discussion of the important mechanisms that have been proposed, shows the exciting challenges that remain in understanding the action of one of nature s most proficient enzymes. 

How can an enzyme that apparently does not utilize cofactors or covalent intermediates be one of the most proficient enzymes known This is the mystery of orotidine monophosphate decarboxylase (ODCase). In this volume, experts in the field of enzyme catalysis describe their efforts to understand this puzzling enzyme. 

Houk and coworkers provide a survey of the known biochemical, structural, and computational studies on ODCase. In particular, they examine what recent theoretical studies have discovered about the origins of catalysis in ODCase, including the possibility that dynamic effects and/or iminium ion formation might actually be important contributors to ODCase s proficiency. 

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