l. Traducibilidad y equivalencia
2. Las primeras escuelas
2.1. La aproximación científica
Hormone Produced in Acts upon Function of hormone
Luteinizing hormone (LH)
Pituitary gland Ovaries or testes • In females stimulates ovulation
• In males stimulates secretion of testosterone
Follicle-stimulating hormone (FSH)
Pituitary gland Ovaries or testes • In females stimulates maturation of follicles in ovaries
• In males stimulates production of sperm Thyroid-stimulating
hormone (TSH)
Pituitary gland Thyroid gland Stimulates thyroid gland to secrete thyroxine (T4) and triiodothyronine (T3) Antidiuretic hormone
(ADH)
Pituitary gland Kidneys Controls retention of water in the kidneys
Triiodothyronine (T3) Thyroid gland A range of cells throughout the body
Regulates the basal metabolic rate and affects protein synthesis
Thyroxine (T4)
Insulin Pancreas Liver, muscle and fat
tissue cells
• Causes glucose to be taken up from the blood and to be stored in liver and muscle
• Stops use of fat as energy source Testosterone Testes, adrenal glands Range of organs
throughout body
• Growth of muscle mass, increased bone density, growth and strength
• Maturation of sex organs, male secondary sex characteristics, e.g.
deepening of voice, beard growth Adrenaline
(epinephrine)
Adrenal glands Heart, liver and many other organs
• Fight or flight response—boosts the supply of oxygen and glucose to the brain and muscles by range of actions
• Suppresses immune system and non-emergency bodily processes
Noradrenaline Adrenal glands Skeletal muscles • Fight or flight response
• Increases skeletal muscle readiness Aldosterone Adrenal glands Kidneys Increase reabsorption of ions and water in
the kidney
Progesterone • Ovaries
• Placenta (during pregnancy)
Uterus, cervix, and a range of other organs
• Supports pregnancy and prepares uterus for fertilized egg; also performs a range of anti-inflammatory functions
• Required for synthesis of aldosterone
Estrogens Ovaries Range of organs
throughout body
Huge range including stimulating
ovulation, promoting formation of female secondary sex characteristics, increasing
CHAPTER 2 HUMAN BIOCHEMISTRY The structure of cholesterol is similar to that of the sex hormones because
it is the precursor of these hormones. The part of the structure that is common to all is the steroid backbone—a series of four fused rings—three of which have six members and one with fi ve members. The difference between these
molecules lies in their functional groups. Progesterone and testosterone are very similar in structure; the only difference occurring on the fi ve-membered ring where testosterone has a hydroxyl group while progesterone has a methyl ketone group. Like testosterone, estradiol has a hydroxyl group on the fi ve-membered ring, but its fi rst ring has an aromatic ring structure and a hydroxyl group rather than the carbonyl group found in progesterone and testosterone.
Estradiol is also missing a methyl group between the fi rst two rings. Like estradiol, cholesterol has a hydroxyl group on its fi rst ring, but possesses the methyl group that estradiol is missing, and has a hydrocarbon chain in the position on the fi ve-membered ring that is occupied by other functional groups in the sex hormones.
HO
OH
estradiol
O
CH3 C
progesterone CH3
O CH3
CH3
O
CH3 OH
testosterone CH3
HO
CH3
CH3 CH H3C CH2
CH2 CH2
CH CH3
CH3
cholesterol
Figure 2.6.2 Thestructures of estradiol, progesterone, testosterone and cholesterol.
The co-operative actions of progesterone and estrogen regulate the menstrual cycle. At the beginning of the cycle, levels of estrogen and progesterone are low. The release of follicle-stimulating hormone (FSH) by the pituitary gland increases estrogen levels. At the midpoint of the menstrual cycle, the pituitary gland releases luteinizing hormone (LH), which stimulates ovum (egg) release and the increase of progesterone secretion—this is needed for the maintenance of a pregnancy. At the end of the menstrual cycle, hormone production
decreases and menstruation occurs.
B.6.2
Compare the structures of cholesterol and the sex hormones. © IBO 2007
B.6.3
Describe the mode of action of oral contraceptives. © IBO 2007
Blood levels of pituitary hormones
Blood levels of ovarian hormones
Ovary
Uterine lining
Time
2 4 6 8 10 12 14 16 18 20 2 24 26 28 2 Flow
phase 4–6 days
Flow phase
4–6 days Follicular phase
9–10 days
Luteal phase 13–15 days LH
FSH
progesterone estrogen
follicle ovulation corpus luteum
Figure 2.6.3 The relative levels of hormones during the menstrual cycle.
Oral contraceptives work by administering estrogens and progestins
(synthetically produced progestogens), which inhibit FSH and LH secretion by the pituitary gland and hence ovulation. Although progestins are the main hormones that inhibit follicle development and ovulation, estrogen has also been found to perform those functions, as well as reducing the incidence of breakthrough bleeding (an unpleasant side effect). A secondary mechanism of action of oral contraceptives is inhibition of sperm penetration through the cervix by changing the composition of the cervical mucus.
The structures of progesterone and synthetically produced progestogens are suffi ciently similar that they perform the same function in the human body. In fi gure 2.6.4 it can be seen that the major difference lies in the additional C2H group with a carbon–carbon triple bond that is present in the progestin.
O
CH3 C CH3
CH3
O
CH3 OH O
C C H
CHAPTER 2 HUMAN BIOCHEMISTRY Anabolic steroids are a class of steroid hormones related to testosterone.
The structure of these compounds is very similar to that of testosterone (see fi gure 2.6.5) and they mimic the action of testosterone. They increase protein synthesis within cells, which results in the build up of cellular tissue, especially in muscles. This build up is called anabolism.
Anabolic steroids may be used therapeutically to stimulate bone growth and appetite, and to induce puberty in males. It can be used to help patients with chronic wasting diseases such as cancer or AIDS, since it increases the muscle mass and the physical strength of the patient, helping them to resume normal activities. There are health risks involved with the use of steroids. These include an increased level of LDL cholesterol and the accompanying decrease in HDL levels, high blood pressure and liver damage.
Anabolic steroids may be put to controversial use in sports and bodybuilding.
They offer an advantage to the user by increasing muscle mass, but have side-effects such as increased bad temper, increased incidence of acne, trembling of the hands, premature balding and a decreased sperm count. Such use is banned by sporting bodies across the world. In a number of countries anabolic steroids are a controlled substance, meaning that their manufacture,
possession and use are regulated by the government.
1 a State the general role of hormones in the body.
b State the name of the type of gland that controls the production of hormones.
2 Refer to fi gure 2.6.2 to answer these questions.
a Identify one sex hormone that has a hydroxyl group.
b Identify one sex hormone that has a carboxyl group.
3 For each of the following hormones, describe where it is produced and outline its specifi c role in the body.
a Testosterone b Progesterone c Estradiol d Adrenaline e Thyroxine
4 Explain how an oral contraceptive can prevent a pregnancy from occurring.
5 Describe the effect achieved and the circumstances in which steroids may be:
a used effectively b abused.
B.6.4
Outline the use and abuse of steroids. © IBO 2007
O
CH3
CH3
OH
O
testosterone a synthetic steroid
CH3HO
CH3
CH3
Figure 2.6.5 The structure of anabolic steroids and testosterone is very similar.
Section 2.6 Exercises
Enzymes are proteins that act as biological catalysts, increasing reaction rates of biological processes without being used up in the process. Unlike inorganic catalysts, enzymes tend to be very specifi c in terms of the reactions they can catalyse. Their specifi city depends on their tertiary and quaternary structures (see p. 84). The ability of an enzyme to increase the rate of a biological process by as much as 107 times means that the concentrations of potentially dangerous substances such as hydrogen peroxide are reduced rapidly. Catalase is an enzyme that increases the rate of the decomposition of hydrogen peroxide, a corrosive by-product in the cells of many organisms.
Catalase enables the rapid decomposition of the hydrogen peroxide to water and oxygen. Inorganic catalysts such as manganese dioxide can also catalyse this reaction.
Compared with inorganic catalysts, enzymes:
• have faster reaction rates
• operate under milder conditions, that is low temperatures (37°C) and pressures and within narrow ranges of temperature and pH
• can be rendered inactive at temperatures below their operating temperature and can be denatured at higher than usual temperatures at which the three-dimensional structure of the enzyme is destroyed
• are very selective, generally dealing with only one set of reactants
(substrates). For example, lactase breaks down the disaccharide lactose, and a different enzyme, maltase, breaks down the disaccharide maltose.
One model to explain enzyme action is the lock and key model. An enzyme’s shape is seen to match that of the molecule whose reaction it catalyses. Figure 2.7.1 illustrates the reacting substance (the substrate) attaching to the active site (particular part of the enzyme to which the substrate can attach or bind) of the enzyme, forming an enzyme–substrate complex. The signifi cant dipoles and other charged areas in the enzyme interact with the substrate, weakening bonds within the substrate molecules. Reaction therefore occurs more readily than it would without the enzyme. The products detach from the enzyme, leaving it unchanged. This model is a simplifi cation of a very complex process.
enzyme
Substrate enters the enzyme’s active site.
Interactions occur between the enzyme and substrate, forming an enzyme–substrate complex.
Bonds break in the substrate.
The enzyme molecule is regenerated.
b c a
Products are released.
2.7 ENZYMES
HLB.7.1
Describe the characteristics of biological catalysts (enzymes). © IBO 2007
B.7.2
Compare inorganic catalysts and biological catalysts (enzymes). © IBO 2007
B.7.5
Describe the mechanism of enzyme action, including enzyme–substrate complex, active site and induced-fit model. © IBO 2007
Enzyme catalysis
Catalysis
CHAPTER 2 HUMAN BIOCHEMISTRY A more recent model of enzyme action which improves on the lock and key model
is the induced-fi t model. In this model, the enzyme changes shape as the substrate binds to the active site. Since enzymes are rather fl exible structures, the active site is continually reshaped by interactions with the substrate. This enables a more precise fi t to be achieved between the enzyme and substrate. When the products leave the enzyme, it returns to its original form.
enzyme substrate
enzyme–substrate complex
a a
b
c
b
c
Figure 2.7.2 The induced-fit model of enzyme action.
Enzyme effectiveness is infl uenced by temperature. An increase in
temperature causes an increase in reaction rate (as it does for most chemical reactions), but at elevated temperatures the rate of enzyme-catalysed reactions drops dramatically. At these elevated temperatures the enzyme is denatured, changes shape and so loses its catalytic power. Similarly, enzyme structure, and therefore enzyme action, may be altered by changes in pH. At different pH values the charges on amino acid side groups in the enzyme may alter,
affecting the bonds between them, and so denaturing the enzyme. The presence of heavy-metal ions can permanently alter the tertiary structure of an enzyme. Heavy metals such as Ag+, Hg2+, Pb2+ have strong affi nities for –SH groups and replace the hydrogen atoms in these groups. As the –SH group is part of the side chain of the amino acid cysteine, it is present in many enzymes, which may then be affected by heavy metals.
temperature (°C)
rate of reaction
0 20 40 60
pH
rate of reaction
4 6 8 10
Figure 2.7.3 The activity of enzymes is influenced by changes in temperature and pH.
Energy and enzymes movie
PRAC 2.5
Investigating sucrase
B.7.7
State and explain the effects of heavy-metal ions, temperature changes and pH changes on enzyme activity. © IBO 2007
Each of the enzymes in the body has a function to perform. With so many enzymes, it should come as no surprise that sometimes one or more enzymes are either missing or not performing as they should. When this happens, problems usually result. The signifi cance of the problem varies. One example is Tay–Sachs disease, a fatal inherited disease in which babies are born without the ability to produce hexosaminidase, the enzyme necessary to break down fats in the brain and blood.
Enzymes are also used to catalyse industrial processes. For example, enzymes in yeasts have been used for many hundreds of years in the production of alcohol and bread. Rennet is an enzyme that can be obtained from the
stomachs of young cows. Rennet reacts with casein in milk, causing the milk to curdle. This is the fi rst stage of the cheese-making process. Rennet can now be made from yeast, hence some cheeses can be labelled ‘vegetarian’. Enzymes are added to detergents to catalyse the breakdown of protein stains, such as blood and grass stains in clothes.
Inhibition of enzymes occurs when a substance prevents the enzyme from doing its job. These inhibitors work in one of two ways.
Competitive inhibitors attach to the active site of the enzyme, blocking the substrate from doing so. The inhibitor has a close structural similarity to substrate, so it binds to the active site of the enzyme. If the inhibition is truly competitive, the binding of substrate and inhibitor are mutually exclusive. (The substrate cannot bind if the inhibitor has already bound to the active site.) Non-competitive inhibitors also bind to the enzyme, but not at the active site. A non-competitive inhibitor may bind to a free enzyme or even to an enzyme–substrate complex. The substrate and the inhibitor do not mutually exclude each other, but the presence of the inhibitor will reduce the ability of the enzyme to work effi ciently. Binding elsewhere causes distortion of the enzyme’s three-dimensional shape, reducing or completely removing the enzyme’s catalytic activity when the distortion is transmitted to the active site, or the inhibitor overlaps the active site. Many heavy metals such as lead, mercury and chromium will function as non-competitive inhibitors.
These inhibitors are important in the regulation of enzyme activity within cells and may also be exploited in the production of drugs. For example, tamoxifen is a hormone treatment that lowers the risk of breast cancer recurring. It is an inhibitor molecule that fi ts neatly onto the estrogen receptors of breast cells, preventing estrogen molecules from doing so. Estrogen’s interaction with breast cells is thought to be responsible for the development of breast cancer. If
tamoxifen can inhibit the reaction of estrogen, breast cancer can be prevented.
Enzymes cannot act at a distance; the enzyme and substrate must combine to form the enzyme–substrate complex ES:
E + S kk1
2
ES k3 E + P
Three rate constants are needed to describe the system. The reaction in which an enzyme and its substrate form an enzyme–substrate complex has a rate constant k1, and that in which the enzyme–substrate complex releases the products and a free enzyme has the rate constant k3. The reaction in which the enzyme–substrate complex releases the substrate and leaves the enzyme free has the rate constant k2.
B.7.6
Compare competitive
inhibition and non-competitive inhibition. © IBO 2007
B.7.3
Describe the relationship between substrate
concentration and enzyme activity. © IBO 2007
CHAPTER 2 HUMAN BIOCHEMISTRY enzyme–substrate complex, ES, from free enzyme and substrate is exactly
balanced by the rate of conversion of ES into free enzyme and product—the concentration of ES remains essentially constant. The high concentration of substrate ensures that the enzyme remains constantly active.
The Michaelis–Menten equation for the initial reaction rate of a single substrate with an enzyme is
V = V Km S
max
/ [ ]
1+ = V S
Km S
max[ ] +[ ] where [S] = substrate concentration
Km= the Michaelis constant = (k k ) k
2 3
1
+
V = rate of conversion of substrate to products
Vmax= the maximum rate of conversion of substrate to products (enzyme activity)
This equation provides a relationship between the rate of conversion observed at any particular substrate concentration and the maximum rate of conversion that would be achieved at infi nite substrate concentrations.
Vmax and Km are often referred to as the kinetic parameters of an enzyme, and their determination is an important part of the characterization of any enzyme. The Michaelis constant, Km, is equal to the substrate concentration at which the rate of conversion of substrate to product is half of the maximum rate possible. It indicates the affi nity of the enzyme for a substrate, or the enzyme activity. When Km is small, there is a high affi nity for the substrate (high enzyme activity) and Vmax will be approached quickly. As Km increases, the affi nity of the enzyme for the substrate decreases.
A plot of the rate of conversion, V, against substrate concentration, [S], gives a value of Vmax. The value of V approaches Vmax slowly and asymptotically.
[S] = Km when V = Vmax 2 .
Maximum rate, Vmax
Km
[S], concentration of substrate (mol dm−3)
Enzyme is saturated:
there is far more substrate than it can deal with.
V, reaction rate (mol dm−3 s−1) Vmax 1 2
Figure 2.7.4 The relationship between rate of reaction, V, and substrate concentration, [S].
B.7.4
Determine Vmax and the value of the Michaelis constant (Km) by graphical means and explain its significance. © IBO 2007
The presence of inhibitors has a signifi cant effect on the maximum rate of conversion of substrate to products and the Michaelis constant (Km), which indicates enzyme activity. A competitive inhibitor will allow the enzyme to reach the same maximum rate of conversion; however, it will take much longer for this to be achieved. The slope of the graph is much less than for the
uninhibited reaction. Since Vmax is the same for the uninhibited reaction and that inhibited by a competitive inhibitor, 1
2Vmax will also be equal; however, the gentler slope of the inhibited graph means that its Km will have a greater value. The enzyme affi nity will be reduced. This is shown in fi gure 2.7.5. Km(3) is the value of Km for a reaction infl uenced by a competitive inhibitor.
In comparison, a non-competitive inhibitor will cause a reduction in the maximum rate of conversion, Vmax. The value of 1
2Vmax will consequently be lower, but the slope of the graph will be such that its Km will be equal to Km for the uninhibited reaction. The enzyme activity will be the same for the uninhibited reaction and the reaction inhibited by a non-competitive inhibitor. This is shown in fi gure 2.7.5 where Km(1) and Km(2) are equal, but Vmax(2) is less than Vmax(1).
TABLE 2.7.1 EFFECT OF INHIBITORS ON ENZYME