Substrate channeling: Molecular bases

Substrate channeling (or tunneling) is the process of non-covalent direct transfer of a reaction intermediate from the active site of one enzyme to the catalytic center of a second enzyme without prior dissociation into the bulk solvent. Substrate channeling can occur within protein matrix tunnels or along electrostatic highways crossing the surface of multifunctional enzymes, of tightly associated multienzyme complexes, or of transient multienzyme complexes. Substrate channeling has been proposed (i) to decrease the transit time of reaction intermediates, (ii) to prevent the loss of reaction intermediates by diffusion, (iii) to protect labile reaction intermediates from solvent, (iv) to sequester reaction intermediates that are toxic to the cell, (v) to circumvent unfavorable equilibria, (vi) to forestall the entrance of reaction intermediates into competing metabolic pathways, (vii) to prevent the build-up of excess reaction intermediates, and (viii) to closely regulate a block of consecutive reactions within a metabolic pathway or in a multistep catalytic cycle. The three-dimensional structures of Escherichia coli carbamoyl-phosphate synthetase and Leishmania major dihydrofolate reductase-thymidylate synthase beautifully exemplify the concept of substrate channeling.