Tải bản đầy đủ - 0trang
8 Enzyme Regulation: Covalent Modification and Genetic Control
Enzyme Regulation: Covalent Modification and Genetic Control
of such enzymes, known as zymogens or proenzymes, requires a chemical reaction that
splits off part of the molecule. Blood clotting, for example, is initiated by activation of
Other examples of zymogens include trypsinogen, chymotrypsinogen, and proelastase, precursors of enzymes that digest proteins in the small intestine. Produced in the
pancreas, these enzymes must be inactive when they are synthesized so that they do not
immediately digest the pancreas. Each zymogen has a polypeptide segment at one end
that is not present in the active enzymes. The extra segments are snipped off to produce
trypsin, chymotrypsin, and elastase, the active enzymes, when the zymogens reach the
small intestine, where protein digestion occurs.
Chymotrypsinogen (a zymogen) at top, and the active enzyme chymotrypsin at
One danger of traumatic injury to the pancreas or the duct that leads to the small
intestine is premature activation of these zymogens inside pancreatic cells, resulting in
acute pancreatitis, a painful and potentially fatal condition in which the activated enzymes attack the pancreas.
Another mode of covalent modification is the reversible addition of phosphoryl groups
1 ¬ PO3 2- 2 to a serine, tyrosine, or threonine residue. Kinase enzymes catalyze the addition of a phosphoryl group supplied by ATP (phosphorylation). Phosphatase enzymes
catalyze the removal of the phosphoryl group (dephosphorylation). This control strategy
swings into action, for example, when glycogen stored in muscles must be hydrolyzed to
glucose that is needed for quick energy, a process known as glycogenolysis. Two serine
residues in glycogen phosphorylase, the enzyme that initiates glycogen breakdown, are
phosphorylated. Only with these phosphoryl groups in place is glycogen phosphorylase
active. The groups are removed, changing both the shape and charge on the enzyme, once
the need to break down glycogen for quick energy has passed.
The curved arrows shown above are used frequently in biochemical equations in
later chapters. While the focus of the main reaction arrow is on changes in the major biomolecule reactant, the participation of other reactants needed to accomplish the
chemical change is shown by the curved arrows adjacent to the main reaction arrow.
Coenzymes and energy-providing molecules like ATP are often included in this manner. Here, the top curved arrow shows that the reaction in the forward direction requires
ATP to supply the phosphoryl groups and produces ADP. The bottom curved arrow
shows that water is needed for the reverse reaction, the hydrolysis that removes the
phosphoryl groups as hydrogen phosphate anions.
Zymogen A compound that becomes
an active enzyme after undergoing a
Enzymes and Vitamins
CHEMiStry in ACtion
Enzyme Inhibitors as Drugs
Consider the medical possibilities when the chemical structures of a substrate and the active site to which it binds are
known. A drug designer can create a molecule similar in structure to the substrate so that it binds to the active site and acts
as an inhibitor. Inhibiting a particular enzyme can help treat a
variety of medical conditions.
The family of drugs known as angiotensin-converting
enzyme (ACE) inhibitors is a good example of enzyme inhibitors that help treat a medical condition. Angiotensin II, the
octapeptide illustrated next, is a potent pressor—it elevates
blood pressure, in part by causing contraction of blood vessels. Angiotensin I, is an inactive precursor of angiotensin II. To
become active, two amino acid residues—His and Leu—must
be cut off the end of angiotensin I, a reaction catalyzed by ACE.
This reaction is part of a normal pathway for blood pressure
control and is accelerated when blood pressure drops because
of bleeding or dehydration. Inhibition of ACE activity lowers
high blood pressure to more normal levels.
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe + His-Leu
The first ACE inhibitor on the market, captopril, was developed by experimenting with modifications of the proline-like
structure. Success was achieved by introducing an ¬ SH
group that binds to the zinc ion in the active site.
Bonds to Zn2+
(an ACE inhibitor)
Several other ACE inhibitors have subsequently been
developed, and they are now common medications for patients
with high blood pressure.
The development of enzyme inhibitors also plays a continuing, major role in the battle against acquired immunodeficiency syndrome (AIDS). The battle is far from won, but two
important AIDS-fighting drugs are enzyme inhibitors. The first,
known as AZT (azidothymidine, also called zidovudine), resembles in structure a molecule essential to reproduction of the
AIDS-causing human immunodeficiency virus (HIV). Because
Ritonavir, an enzyme inhibitor, in the active site of
AZT is accepted by an HIV enzyme as a substrate, it prevents
the virus from producing duplicate copies of itself.
The most successful AIDS drug thus far inhibits a protease, an enzyme that cuts a long protein chain into smaller
pieces needed by the HIV. Protease inhibitors, such as ritonavir, cause dramatic decreases in the virus population and AIDS
symptoms. The success is only achieved, however, by taking a
“cocktail” of several drugs, including AZT. The cocktail is expensive and requires precise adherence to a schedule of taking
20 pills a day. These conditions make it unavailable or too
difficult for many individuals to use.
Many drugs are enzyme inhibitors. For example, topiramate, a carbonic anhydrase inhibitor, is prescribed to treat
seizure disorders and also to prevent migraines. Sildenafil
(Viagra) inhibits a specific phophodiesterase responsible
for some forms of erectile dysfunction. And most antibiotics
inhibit enzymes involved in microbial growth and reproduction.
CiA Problem 19.1 The primary structure of angiotensin II has
Pro-Phe at the C-terminal end of the octapeptide. An ACE inhibitor from the South American pit viper is a pentapeptide with
a C-terminal proline and is a mild ACE inhibitor. Captopril has a
modified proline structure and is also a mild ACE inhibitor.
(a) Why do you suppose that a mild ACE inhibitor is more
valuable for the treatment of high blood pressure than
a very potent ACE inhibitor? (Hint: How much should
blood pressure change at once?)
(b) What structural modifications to the pit viper peptide
might make it a more powerful ACE inhibitor? (Hint:
Compare protein structures at C-terminal end.)
CiA Problem 19.2 AZT (zidovudine) inhibits the synthesis of
the HIV virus RNA because AZT resembles substrate molecules. Which kind of inhibition is most likely taking place
in this reaction?
CiA Problem 19.3 Ritonavir inhibits the action of HIV protease. What kind of inhibition is imposed on HIV protease by
Vitamins, Antioxidants, and Minerals
The synthesis of all proteins, including enzymes, is regulated by genes (Chapter 27)
and is a strategy that controls enzyme availability. Genetic control is especially useful
for enzymes needed only at certain stages of development. Mechanisms controlled by
hormones (Section 28.2) can accelerate or decelerate enzyme synthesis. For example,
lactase, needed to digest lactose is not synthesized in most adults because adults have a
more varied diet than infants and do not need to digest milk sugar. Conversely, fetuses
and infants do not metabolize ethanol because alcohol dehydrogenase, the necessary
enzyme, is under genetic control and does not appear until later in life.
In summary, we have described the most important strategies that control the activity of enzymes. In any given biochemical pathway in a healthy individual, several of
these strategies are likely occurring simultaneously at any given moment.
Genetic (enzyme) control Regulation
of enzyme activity by control of the
synthesis of enzymes.
Summary: Mechanisms of Enzyme Control
Inhibition, which is either reversible or irreversible. Reversible inhibition that occurs
away from the active site is termed uncompetitive inhibition, while reversible inhibition
that occurs at the active site and often involves molecules that mimic substrate structure
is termed competitive inhibition. Irreversible inhibition occurs due to covalent bonding of the inhibitor to the enzyme. Competitive inhibition is a strategy often utilized in
medications, and irreversible inhibition is a mode of action of many poisons.
Feedback control is exerted on an earlier reactant by a later product in a reaction
pathway and is made possible by allosteric control. The feedback molecule binds
to a specific enzyme early in the pathway in a way that alters the shape and therefore the efficiency of the enzyme.
Production of inactive enzymes (zymogens), which must be activated by cleaving a
portion of the molecule.
Covalent modification of an enzyme by addition and removal of a phosphoryl
group, with the phosphoryl group supplied by ATP.
Genetic control, whereby the amount of enzyme available is regulated by limiting
Which type of enzyme regulation is best for the following situations?
(a) An enzyme that becomes overactive during a disease
(b) An enzyme needed only when there is low blood glucose
(c) An enzyme that springs into action when a traumatic injury occurs
(d) An enzyme needed only during adolescence
19.9 Vitamins, Antioxidants, and Minerals
• Describe the two classes of vitamins, the reasons vitamins are necessary in the diet,
and the results of vitamin excesses or deficiencies.
• Identify antioxidants and explain their function.
• Identify essential minerals, explain why minerals are necessary in the diet, and explain
the results of mineral deficiencies.
Long before the reasons were understood, people knew that lime and other citrus juices
cure scurvy, meat and milk cure pellagra, and cod-liver oil prevents rickets. Eventually, researchers discovered that these diseases are caused by deficiencies of vitamins—
organic molecules required in only trace amounts that must be obtained through the diet.
Vitamins are a dietary necessity for humans because our bodies do not have the ability to
The role of vitamin C in collagen
synthesis was examined in Section 18.11.
Vitamin An organic molecule,
essential in trace amounts that must be
obtained in the diet because it is not
synthesized in the body.
Enzymes and Vitamins
Vitamins are grouped by solubility into two classes: water-soluble and fat-soluble.
The water-soluble vitamins, listed in Table 19.5, are found in the aqueous environment inside cells, where most of them are needed as components of coenzymes.
Over time, an assortment of names, letters, and numbers for designating vitamins
have accumulated. Structurally, the water-soluble vitamins have ¬ OH, ¬ COOH,
or other polar groups that make them water soluble, but otherwise they range from
simple molecules like vitamin C to large, complex structures like vitamin B12.
Most vitamins are components of coenzymes, but some function as coenzymes
themselves. Vitamin C is biologically active without any change in structure from the
molecules present in foods. Similarly, biotin is connected to enzymes by an amide bond
at its carboxyl group but otherwise undergoes no structural change from dietary biotin.
A myriad of vitamin pills in capsule and
Other water-soluble vitamins are incorporated into coenzymes. The vitaminderived portions of two of the most important coenzymes, NAD+ and coenzyme A, are
illustrated in Figure 19.10. Table 19.5 includes the functions, deficiency symptoms, and
major dietary sources of water-soluble vitamins.
Nicotinamide adenine dinucleotide (NAD+), a coenzyme
The vitamin-derived portions of NAD + and coenzyme A.