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ing through the Golgi, nucleus, and endosomes. They are generally bound to a lipid
membrane through a lipid anchor, such as a myristoyl group or farnesyl group, and
regulate the assembly and activity of protein complexes at these sites. The small G
protein Ras, for example, is involved in regulation of cellular proliferation by a
number of hormones called growth factors (Fig. 9.14). It is attached to the plasma
membrane by a farnesyl group (see Chapter 6, section IV.B.). The activity of Ras is
regulated by a guanine nucleotide exchange protein called SOS (son of sevenless).
When SOS is in its active conformation, it binds to Ras, thereby activating dissoci-
ation of GDP and binding of GTP. When Ras binds GTP, it is activated, allowing it
to bind and activate a protein kinase called Raf. The net effect will be the activation
of transcription of certain genes. (Rho, Arf, Rab, and Ran are illustrated in Chapter
10, and the function of Ras is discussed in greater detail in Chapter 11).
D. Proteolytic Cleavage
Although many enzymes undergo some cleavage during synthesis, others enter
lysosomes, secretory vesicles or are secreted as proenzymes, which are precursor
proteins that must undergo proteolytic cleavage to become fully functional. Unlike
most other forms of regulation, proteolytic cleavage is irreversible.
Most of the proteases involved in
The precursor proteins of proteases (enzymes that cleave specific peptide bonds)
blood clotting are zymogens, such
are called zymogens. To denote the inactive zymogen form of an enzyme, the name
as fibrinogen and prothrombin,
is modified by addition of the suffix ogen or the prefix pro. The synthesis of
which circulate in blood in the inactive form.
zymogens as inactive precursors prevents them from cleaving proteins prematurely
They are cleaved to the active form (fibrin
at their sites of synthesis or secretion. Chymotrypsinogen, for example, is stored in
and thrombin, respectively) by other pro-
vesicles within pancreatic cells until secreted into ducts leading to the intestinal
teases, which have been activated by their
lumen. In the digestive tract, chymotrypsinogen is converted to chymotrypsin by the
attachment to the site of injury in a blood
proteolytic enzyme trypsin, which cleaves off a small peptide from the N-terminal
vessel wall. Thus, clots form at the site of
injury and not randomly in circulation. region (and two internal peptides). This cleavage activates chymotrypsin by causing
Association Exchange of GTP Ras-GTP
1 2 3
of SOS and Ras for bound GDP binds Raf
Ras GDP Ras GTP
GDP GTP
SOS
(GEF)
Raf
Fig. 9.14. The monomeric G protein Ras. When SOS is activated, it binds to Ras, a
monomeric G protein anchored to the plasma membrane. SOS is a guanine nucleotide
exchange protein that activates the exchange of GTP for bound GDP on Ras. Activated Ras
containing GTP binds the target enzyme Raf, thereby activating it.
CHAPTER 9 / REGULATION OF ENZYMES 151
a conformational change in the spacing of amino acid residues around the binding
site for the denatured protein substrate and around the catalytic site.
IV. REGULATION THROUGH CHANGES IN AMOUNT
OF ENZYME
Tissues continuously adjust the rate at which different proteins are synthesized to
vary the amount of different enzymes present. The expression for Vmax in the
Michaelis-Menten equation incorporates the concept that the rate of a reaction is pro-
The maximal capacity of MEOS
portional to the amount of enzyme present. Thus, the maximal capacity of a tissue
(cytochrome P450-2E1) is increased
can change with increased protein synthesis, or with increased protein degradation.
in the liver with continued ingestion
of ethanol through a mechanism involving
A. Regulated Enzyme Synthesis
induction of gene transcription. Thus, Al Mar-
tini has a higher capacity to oxidize ethanol
Protein synthesis begins with the process of gene transcription, transcribing the
to acetaldehyde than a naive drinker (a per-
genetic code for that protein from DNA into messenger RNA. The code in messen-
son not previously subjected to alcohol).
ger RNA is then translated into the primary amino acid sequence of the protein.
Nevertheless, the persistance of his elevated
Generally the rate of enzyme synthesis is regulated by increasing or decreasing the
blood alcohol level shows he has saturated
rate of gene transcription, processes generally referred to as induction (increase)
his capacity for ethanol oxidation (V-maxed
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