Opinion
Enzyme catalysis: a new definition accounting for noncovalent substrate- and product-like states

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Abstract

Biological catalysis frequently causes changes in noncovalent bonding. By building on Pauling's assertion that any long-lived, chemically distinct interaction is a chemical bond, this article redefines enzyme catalysis as the facilitated making and/or breaking of chemical bonds, not just of covalent bonds. It is also argued that nearly every ATPase or GTPase is misnamed as a hydrolase and actually belongs to a distinct class of enzymes, termed here ‘energases’. By transducing covalent bond energy into mechanical work, energases mediate such fundamental processes as protein folding, self-assembly, G-protein interactions, DNA replication, chromatin remodeling and even active transport.

Section snippets

Reactions involving changes in noncovalent-bonding interactions

There is a diverse range of biochemical processes that involves reactant-like and product-like states representing rearrangements in noncovalent-bonding interactions (Table 1). Tabulated are reactions that: (1) strictly involve noncovalent interactions; (2) are mechanistically linked to the Gibbs free energy of ATP or GTP hydrolysis, or to another thermodynamic driving force such as a solute gradient; and (3), for example proteins such as GroEL and GroES, that catalyze the noncovalent folding

A more encompassing definition of enzyme catalysis

As there are so many instances in which biological catalysis is not attended by changes in covalent bonding, I offer a broader definition: enzymes catalyze the making and/or breaking of chemical bonds by promoting substrate and/or product access to the transition state. (This statement deliberately avoids specifying how an enzyme promotes catalysis; for example, by stabilizing enzyme transition states, destabilizing the ground state, reorganizing active-site solvent molecules, enabling

Energases: a distinct class of enzyme-catalyzed reactions

Discoveries of the past two decades have convincingly demonstrated the pervasiveness of mechanochemical proteins that transduce the Gibbs free energy of nucleotide hydrolysis into some form of useful work. The product of these reactions can be described as a form of translational movement, rotation or solute gradient. Under normal physiological conditions, nucleotide hydrolysis is stoichiometrically coupled to the production of an increment of useful work. ‘Energase’ is offered as a new term

Energases that modify enzyme performance

The free energy of nucleoside 5′-triphosphate hydrolysis can also produce substrate-like and product-like conformational states that alter an enzyme's ability to catalyze a reaction. Two notable examples are ATP sulfurylase (ATP+sulfate→AMP–sulfate+pyrophosphate), which transduces the energy of GTP hydrolysis to modulate both substrate binding and catalytic performance 21, and nicotinate phosphoribosyltransferase (nicotinate+phosphoribosylpyrophosphate→nicotinate

Concluding remarks

Although the systematic classification of enzymes on the basis of organic chemistry was logical, modern biochemistry has shown that metabolism necessarily includes many other reactions that must be written in terms of changes in the strength of noncovalent interactions. The involvement of molecular motors in contractile processes, intracellular organelle trafficking and cell crawling constitutes just another branch of metabolism, as does the building up and tearing down of macromolecular and

Acknowledgements

I am indebted to the following for examining the manuscript and offering valuable advice: Linda Bloom, Robert Cohen, Perry Frey, Herbert Fromm, Benjamin Horenstein, Giulio Magni, Dexter Northrop, Dale Poulter, Silverio Ruggieri, David Silverman, Peter von Hippel and Richard Wolfenden.

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