Chemists at the University of Buffalo (UB) have identified what they say is a central mechanism responsible for the action of enzymes.
The research, reported in a paper selected as a “2007 Hot Article” by the journal Biochemistry, provides insight into why catalysis is so complex and may help pave the way for improving the design of synthetic catalysts.
The more that is known about catalysis, the better chances we have of designing active catalysts.—John P. Richard, University of Buffalo
While attempts to design catalysts of non-biological reactions with enzyme-like activity have been somewhat successful, the catalysis that results is far less efficient than that produced by reactions with enzymes.
Protein catalysts are distinguished by their enormous molecular weights, ranging from 10,000 to greater than 1,000,000 Daltons, whereas a synthetic molecule with a weight of 1,000 would be considered large, according to Richard. The recent results by Richard and co-author Tina Amyes provide insight into why effective catalysis requires such large molecules.
The chemistry between an enzyme and a substrate occurs where groups of amino acid residues interact with the substrate. Catalysis starts with molecular recognition of the substrate by the catalyst. But enzymes also have domains that interact with the non-reacting parts of the substrate, according to Richard.
Amyes and Richard provide evidence that interactions between enzymes and non-reacting portions of the substrate are critical for large catalytic rate accelerations.
A flexible loop on the enzyme wraps around the substrate, burying it in an environment that’s favorable for catalysis. In order to bury the substrate, certain interactions are necessary that allow the loop to wrap around the substrate and that’s what the phosphate groups on the substrate are doing. We’ve shown that these interactions are critical to the process of making reactions faster.—John Richard
To conduct the research, Richard and Amyes developed a specialized and technically difficult assay for enzyme activity that uses nuclear magnetic resonance spectroscopy to detect chemical reactions that would normally be invisible.
Richard and Amyes have applied their method during the past 10 years to a wide variety of chemical and enzymatic reactions with results published in approximately 25 papers in Biochemistry and The Journal of the American Chemical Society. Richard’s work on enzymes has been supported continuously since 1987 by grants from the National Institutes of Health.
“Enzymatic Catalysis of Proton Transfer at Carbon: Activation of Triosephosphate Isomerase by Phosphite Dianion”; Tina L. Amyes and John P. Richard; Biochemistry 2007, 46, 5841-5854