Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

PROTEIN FUNCTION
149
FATTY ACID SYNTHASE
acyl carrier
domain
N
C
(A)
2
1
4
enzyme domains
5
3
termination
domain (TE)
TE
1
(D)
20 nm
1
PYRUVATE DEHYDROGENASE COMPLEX
3
4
2
5
2
3
2
1
4
(B) 5 nm
(C) etc.
(E)
3
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.)
MBoC6 n3.150/3.50
(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 CO 2 and H 2 O (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