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8 Enzyme Regulation: Covalent Modification and Genetic Control

8 Enzyme Regulation: Covalent Modification and Genetic Control

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SECTION 19.8



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

zymogens.

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 (inactive)



S–S



S–S

Trypsin



Dipeptides



Chymotrypsin (active)



S–S



S–S



Chymotrypsinogen (a zymogen) at top, and the active enzyme chymotrypsin at

bottom.





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.

2 ATP



2 ADP



Serine

–OH group

Phosphorylase

kinase



HO



OH

Phosphorylase b

(less active)



2–O



Phosphorylase a

(more active)



Phosphoprotein

phosphatase



2 HOPO32–



OPO32–



3PO



2 H2O



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.



645



Zymogen A compound that becomes

an active enzyme after undergoing a

chemical change.



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646



CHAPTER 19



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



Angiotensinconverting

enzyme

(ACE)



Angiotensin I



Asp-Arg-Val-Tyr-Ile-His-Pro-Phe + His-Leu

Angiotensin II



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.

Resembles a

terminal proline



O

N

O



C



C

CH



O–



Bonds to Zn2+

in ACE



CH2



SH



CH3

Captopril

(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

HIV protease.





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

ritonavir?



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SECTION 19.9



Vitamins, Antioxidants, and Minerals



647



genetic Control

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

its synthesis.



ProBlEM 19.16

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

Learning Objectives:

• 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

synthesize them.



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.



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648



CHAPTER 19



Enzymes and Vitamins



Water-Soluble 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

tablet form.





O

CH2OH

O



HOHC



O



HN



NH



HC



CH



H2C



CH



OH



OH



(CH2)4



COO–



S



Vitamin C

(Ascorbic acid)



Biotin



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.

OH



OH



NH2



H

N+

+N



O



CH2



O



OH



C



P



O



O–

C



O

Nicotinamide



Niacin

(Nicotinic acid)



N



O



O



P



O



CH2



O



N



N



N



O–



NH2

OH



O



OH



Nicotinamide adenine dinucleotide (NAD+), a coenzyme



NH2



H2C



H2C



OH



O



P



H3C



C



CH3



H3C



C



CH3



HO



C



H



HO



C



H



C



O



C



O



O–



O



P



O



CH2



H2C



O



O

–O



H2C



C



OH



P

O–



H2C



O



H2C



C



O



NH



Pantothenic acid



Figure 19.10



The vitamin-derived portions of NAD + and coenzyme A.



N



O–



NH



NH







N



O



O



CH2



CH2



Coenzyme A



SH



OH

O



N

N



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