Figure 3–54 How unstructured regions of polypeptide chain serving as tethers allow reaction intermediates to be passed from one active site to another in large multienzyme complexes. (A–C) The fatty acid synthase in mammals. (A) The location of seven protein domains with different activities in this 270 kilodalton protein. The numbers refer to the order in which each enzyme domain must function to complete each two-carbon addition step. After multiple cycles of two-carbon addition, the termination domain releases the final product once the desired length of fatty acid has been synthesized. (B) The structure of the dimeric enzyme, with the location of the five active sites in one monomer indicated. (C) How a flexible tether allows the substrate that remains linked to the acyl carrier domain (red) to be passed from one active site to another in each monomer, sequentially elongating and modifying the bound fatty acid intermediate (yellow). The five steps are repeated until the final length of fatty acid chain has been synthesized. (Only steps 1 through 4 are illustrated here.) (D) Multiple tethered subunits in the giant pyruvate dehydrogenase complex (9500 kilodaltons, larger than a ribosome) that catalyzes the conversion of pyruvate to acetyl CoA. As in (C), a covalently bound substrate held on a flexible tether (red balls with yellow substrate) is serially passed through active sites on subunits (here labeled 1 through 3) to produce the final products. Here, subunit 1 catalyzes the decarboxylation of pyruvate accompanied by the reductive acetylation of a lipoyl group linked to one of the red balls. Subunit 2 transfers this acetyl group to CoA, forming acetyl CoA, and subunit 3 reoxidizes the lipoyl group to prepare it for the next cycle. Only one-tenth of the subunits labeled 1 and 3, attached to the core formed by subunit 2, are illustrated here. This important reaction takes place in the mammalian mitochondrion, as part of the pathway that oxidizes sugars to CO2 and H2O (see page 82). (A–C, adapted from T. Maier et al., Quart. Rev. Biophys. 43:373–422, 2010; D, from J.L.S. Milne et al., J. Biol. Chem. 281:4364–4370, 2006.) the cell, the concentration of reactants in that compartment may be increased by 10 times compared with a cell with the same number of enzyme and substrate molecules, but no compartmentalization. Reactions limited by the speed of diffusion can thereby be speeded up by a factor of 10.
The Cell Regulates the Catalytic Activities of Its Enzymes
A living cell contains thousands of enzymes, many of which operate at the same time and in the same small volume of the cytosol. By their catalytic action, these enzymes generate a complex web of metabolic pathways, each composed of chains of chemical reactions in which the product of one enzyme becomes the substrate of the next. In this maze of pathways, there are many branch points (nodes) where different enzymes compete for the same substrate. The system is complex (see Figure 2–63), and elaborate controls are required to regulate when and how rapidly each reaction occurs.