substratechanneling

Substrate channeling is a process in biochemistry in which intermediates produced by one enzyme are transferred directly to the next enzyme in a metabolic pathway without fully equilibrating with the surrounding solution. This direct handoff can occur within a single enzyme that contains multiple active sites, or more commonly within a multi-enzyme complex or metabolon where enzymes are physically associated.

The mechanisms of substrate channeling fall into several categories. In internal channeling, a substrate is passed through a physical tunnel or conduit formed by the protein structure, sometimes between active sites within a single multi-domain enzyme. In complex-mediated channeling, enzymes form transient assemblies that bring consecutive steps into close proximity, reducing diffusion of intermediates into bulk solvent. Additional forms include substrate tethering by flexible arms or cofactor domains (as seen in some dehydrogenase or synthase systems) and, at the cellular level, compartmentalization within microcompartments or organelles that concentrate pathway components.

Examples and evidence include well-studied cases such as tryptophan synthase, where indole is transferred directly between subunits, and the pyruvate dehydrogenase complex, which uses swinging arms to shuttle reaction intermediates between active sites. Fatty acid synthases and purine biosynthetic assemblies also illustrate channeling concepts. Experimental support comes from kinetic analyses, structural studies revealing physical interfaces and channels, and observations of enhanced pathway flux or protection of labile intermediates.

Substrate channeling is thought to improve catalytic efficiency, increase overall flux, prevent side reactions, and enable coordinated regulation of sequential steps. It has implications for metabolic engineering and synthetic biology, where designing channeling between enzymes can optimize production pathways.