Models of enzymatic catalysis

Traditional models of enzymatic catalysis

Models proposed for enzymes with active sites located on the protein surface.

Traditional models of enzymatic catalysis

Traditional models of enzymatic catalysis. (A) The lock-key model; (B) The induced-fit model; (C) The selected-fit model

Keyhole-lock-key model

Keyhole-lock-key model [1] proposed for enzymes with active sites buried inside the core and connected with a surface by tunnels.

Keyhole-Lock-Key model

The keyhole-lock-key model. Key = ligand; Lock = active site; Keyhole = tunnel.

Tunnels are present in all six classes of enzymes.The existence of tunnels, keyholes, is not restricted to a certain enzyme class, but is widespread all over the protein world.

Tunnels in enzymes

Tunnels in six representatives of all enzyme classes.



Protein tunnels

The tunnel connects a protein buried cavity with bulk solvent. The shape of the protein tunnel is approximated as a pipeline with a varying width of cross section. This approximation is useful for estimation of the largest probe accessing the deepest site in the pocket. The size of a probe able to access internal cavity is limited by radius of tunnel gorge, i.e., the most narrow place in the tunnel (bottleneck).



Tunnel represented as a set of intersecting spheres. Yellow sphere marks the tunnel bottleneck, blue residues form this bottleneck.

The tunnels facilitate the transport of small molecules, ions and water solvent in a large variety of proteins.

Engineering implications

Recognition of the substrate by the enzyme with buried active site can be seen as a two-step process: passage of the substrate via the tunnel and fit to the active site. Targeting tunnels by site-directed or saturation mutagenesis has wide practical applications in protein engineering. Altering the size, physico-chemical properties or dynamics of tunnels can lead to significant changes in activity, specificity, stereoselectivity and stability. Compared to mutations in the active site, engineering of tunnel residues provide higher chances of obtaining functional variants.

References

[1] Prokop et al. "Engineering of protein tunnels: keyhole-lock-key model for catalysis by the enzymes with buried active sites." Lutz, S., Bornscheuer, UT (Eds.), Protein Engineering Handbook, Wiley-VCH, Weinheim (2012): 421-464.



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