�• The Role of Dopamine in Parkinson's Disease and Schizophrenia :o

&>chide

rcephrnt

e

hal

nof lu

ia

c

is the

a debpopulatio

ilitating n

mental worldwide.

disorder Its

that symptoms

affects

rmenrr i edisorde

mationsrs,

, and social

delusions, withdra

disordered wal. The

thinking,disease

causiy st

e k s during late adolescence to early adulthood.

tof he

schizneurotr

ophreniansmitter

a is still dopamine

unknown, appears

although to

anbe

lvedof.

Parkinson's disease is somewhat better understood and is believed to arise from decreased dopamine activity in another part of the brain. Parkinson's disease is a chronic neurodegenerative disease characterized by a loss of coor­dination and movement. The disease tends to strike after the age of 60. Symptoms of Parkinson's disease include tremor (shaking), bradykinesia (slow movement), rigidity (stiffness of limbs), and impaired balance. About 60,000

278 CHAPTER EIGHT Carbohydrate Metabolism

Glucose

FIGURE 8.10

.. ---..... . Glycogen _::;;.glucoseH"'okoaso � Glucose-1-pho.,.,,1e ·

\ -------� 't ---� ADP ") 1' f , UTP) �PPGlucose-6-phosphate

\ ,,'\J7 _,r' ♦ t CP � � Fructose-6-phosphate

)

Glucose-6-phosphatase

�-

ATP I Fructose� -bisphosphate

PFK 1 � phosphatase-��

Fructose-1,6-blsphosphate

p

+

ATP

:t ) f A. Dlhydn,x""'°"" .. !::,

Glycera/dehyde-3-phosphate ◄ phosphate

11 -+�� :.-----� ��+(H+Glycerate-1,3-blsphosphate

• �,rcATF

•

Glycerate-3-phosphate

lt Giycerate-2-phosphate

�ll-----=:-- Phosphoenolpyruvate

ATP ,P,

�_/

◄ +

Certainamino aclda

Carbohydrate Metabolism: Gluconeogenesls and Glycolysls In gluconeogenesis, which occurs when blood sugar levels are low and liver glycogen is deplered, 7 of rhe 10 reactionsof glycolysis are reversed. Three irreversible glycolytic reacrions are bypassed by alternative reactions. The major substrates for gluconeogenesis are certain amino acids {derived from muscle), lactate (formed in muscle and red blood cells), and glycerol {produced from the degradation of triacylglycerofs). In concrnst to the reactions of glycolysis, whichoccur only in cytoplasm. the gluconeogenesis reactions catalyzed by pyruvate carboxylase and, in some species. PEP carboxykinase occur within rhe mitochondria. The reaction catalyzed by glucose-6-phosphatase takes place in the endo­plasmic reticulum. Note that gluconeogenesis and glycolysis do nor occur simultaneously. In glycolysis, pyruvare isconverted either to acetyl-CoA {not shown) or to lactate.

330

. ·erve j, impulse Axon

7 • ORGANIC CHEMISTRY AND BIOMOLECULES

terminal

�

Synaptic deft

Figure 7-60 Communication between neurons.

new cases of Parkinson's disease arc diagnosed in the

United States every year. Schizophrenia and Parkinson's disease are two very

different diseases, but both involve an imbalance of dopa·

mine in the brain. Dopamine, a neurotransmitter essential

for normal brain function, is involved in the brain's

reward and pleasure centers. Dopamine is also involved in

regulating movement and emotional responses. Dopamine is

an amine, as suggested by the ending in its name.

II

HO

I anunc

�N,1-1

HOA/

Dop�rmnc

Although there is no cure for schizophrenia or Parkin•

son's disease, prescription drugs are available to treat

some of the more debilitating symptoms. In order to

understand the biochemistry of schizophrenia and Parkin­

son's disease, we must first understand how nerve cells

communicate with one another on a molecular level.

The human brain has about 100 billion (1 X 1011 )

nerve cells, known as neurons. Most neurons communicate

through chemical messengers known as neurotransmitters:

organic molecules characterized by an amine functional

group. Communication between neurons begins with an

electrical impulse that travels along the axon, the long

shaft of a nerve cell. When the electrical impulse reaches

the end of the axon, neurotransmitters are released from

the neuron into the synaptic cleft , the gap between two

neurons, shown in the inset in Figure 7-60. Neurotransmit•

ters diffuse to the next neuron, where they bind to specific

receptors on the cell membrane of the receiving neuron. In

this way electrical impulses travel from one neuron to the

Receiving neuron

next, creating what is known as a neuronal pathway. The

transmission of electrical impulses through a neuronal

pathway ultimately leads to a physiological response. The

two neuronal pathways in the brain that use dopamine as a

neurotransmitter are highlighted in Figure 7-61.

The impaired movement associated with Parkinson's

disease is believed to result from the loss of dopamine­

producing neurons along one of the two neuronal path­

ways in the brain that rely on dopamine, highlighted in red

in Figure 7-61. Neurons differ from most other cells in the

body in that they do not regenerate themselves, so the loss

of these cells is permanent. Patients with Parkinson's dis­

ease show 80 percent less dopamine activity in this neuro

nal pathway. Effective prescription drugs are available to treat man�

of the symptoms of Parkinson's disease. Dopamine 1tsdl

Frontal -f cortex

• Dopamine pathway 1(in Parkinson's)

• Dopamine pathway 2(in schizophrenia}

Figure 7-61 Neuronal pathways that Involve dopamine.·

pathway shown in red controls movement and is iovolved

Parkinson's disease. The pathway shown in greeo affeclS

memory, and motivation and is involved in schizophref1il-

SUMMARY 331

cannot be administered as a drug because it can't cross the blood-brain barrier. Instead, the drug L-dopa is adminis• tered. The only difference between the chemical structure of L-dopa and dopamine is the carboxylic acid functional group in L-dopa. The carboxylic acid is removed in a biochemical reaction in the neuron that converts t-dopainto dopamine:

.... , II

HO

D'):

· �:

HO Oil -

l.•OOl'A

HO��'n

HO

J>op.t11:111k:

The prolonged use of L-dopa eventually reduces its ability to activate the dopamine receptor. At that point other drugs arc usually prescribed. Unfortunately, dopamine receptors eventually become less sensitive to these drugstoo and symptoms of the disease return.

Figure 7-61. Stimulation of this particular neuronal path­way is associated with feelings of reward and desire, memory, and motivation. By binding to the dopamine receptor in this neuronal pathway, antipsychotic medica• tions prevent dopamine from binding to its receptor. The first generation of antipsychotic drugs bound to all dopa­mine receptors in the brain, including those in the neuro• nal pathway that control movement (shown in red in Figure 7-61 ). Consequently, some of the side effects of these drugs were tremors and other symptoms like those from Parkinson's disease. The newest class of anripsychotic medications, known as atypical atttipsychotics, block dopamine receptors but specifically target a type of dopa• mine receptor that is found only in the neuronal pathway associated with schizophrenia (shown in green). Therefore, atypical antipsychotic drugs have fewer movemenNelatedside effects.

The thought disorders associated with schizophrenia are believed to result from the opposite effect: an excessof qopamine activity in another neuronal pathway in the brain that involves dopamine, highlighted in green in

Summary .\lcohols and Ethers

There have been significant advances in the treatment of these two diseases as scientists have unraveled the chemistry behind each of these diseases. Further research should eventually lead to even better treatment optionsfor these patients in the future .

594 13 • PROTEINS: STRUCTURE AND Fl.IN

lungs

Liver Ltt \

1 \.)

1 \J r<ocoast,i<tioo

A. . , ACE . Aog,ot'"''" I -----> Aog,o .

og,ot,osmog'"

T\

l

Low blood volume and

Aldosterone

drop in blood �sodium levels leads to Remn

release

.,,, Kidney

' Adrenal cortex

Signals kidneys to stop producing Renin

Water and salt retention

Figure 13-32 The reactions, enzymes, and organs involved in the regulation of blood pressure by the renin-angiotensin-aldosterone system. Blood pressure depends on water and salt retention as well as blood volume.

Once again we sec how understanding a biochemical process has led to the development of treatments for life-threatening conditions. As scientists commue to gain a better understanding of the biochemical reactions thar

occur in our cells, you will continue to see advances in the

field of medicine, and yet another reason for you to learn your chemistry basics!

zinc arom, zn2+, a cofactor at the active site of ACE, ro form a strong electrostatic interaction.

Since the introduction of captopril, many new and improved ACE inhibitors have been developed for the treatment of hypertension. These ACE inhibitors have fewer side effects than captopril today ACE inhibitors are some of the most widely prescribed drugs on the market.

0

H'-sYN CH1

0

Cap1npril 'OH

Figure 13-33 The structure of Captopril, the first effective ACE inhibitor produced in the laboratory for the treatment of hypertension, was designed to resemble the structure of the peptides found in the venom of the poisonous Brazilian pit viper.[© blickwinkel/Alamy)

liiEnzyme inhibitor

t:i,Jl-1j®¢t§1tfAA1 ACE Inhibitors as a Treatment for Hypertensis wide

have rangbeen used as pharmaceuticals inthe treatment of a e of diseases including cancer,AIDS, diabetes, and heart disease. Some of the earliestenzyme inhibitors were used before their mechanism ofaction was even understood. Aspirin, for example, wasused ro treat pain and inflammation long before it wasdiscovered in the l 970s to be an inhibitor of C)1c/ooxy­ge11ase, a key enzyme involved in several biochemicalpathways leading to inflammation.

In this section we consider a class of enzyme inhibitorsused ro treat chronically elevated blood pressure, a condi­tion known as hypertension. Hypertension is a major riskfactor in stroke, heart attack, heart failure, and kidneyfailure. More than half of Americans over age 65 sufferfrom hypertension.

How the Body Raises Blood PressureThe body

carefully

nor controls

rblood pressure so that it

blood neither falls

pressure too

is low

a compises too high. Regulation of

biological the

factors. blood plays

The lex process

concentration of involving

sodium several

ions+(Na ) in an important sure,

because sodium

ions thro

cause water role to be

in blood retained

pres­inthe

blood circulatory

pressure. system

Indeed, pugh osmosis, which increases

to eat a loweople with hypertension areadvised sodium

+

diet. When the kidneys detecta enzyme called

drop in sodiumre11i11.

ion, Na , concentration they releRe11i,, acts on a single substrate:

ase ansinogen, a angioten polypepti

the peptideproduced by the liver

between. Re11i11

bond le

de with 452 catalyzes the

amino hydrolysis

acids,of

sinogen to produce the hucine and valine in angioten­

tide with 10 amino acids e (sormone angiotensin I, a polypep­

t The

conv next

erts step in

e Figure 13- this biochemical pathway

31 ). is a reaction

by Angiotetrsi11 C

angiotensin I into angitha

otensin II, catalyzedproduced in the lun

onverting Enzyme (ACE), an enzymethe peptide bond between

gs. ACE phenylalanine

catalyzes theand

hydrolysis histidine in

of

Angiot

on angiorensin octapeptide,

I,and to

the produce

dipeptidthe hormone angiotensin II, an

e His-Leu.ensin II signals a nu

that raise blood pressure: (1)mber

Irof

causes the physiological

muscles events

sur•rounding blood vessels to

constrict-a

process

known

asvasoconstriction, and (2) it triggers the release of the ste­roid signals

hormone aldosterone reab

from the adrenal cortex, whichexcreting

the kidneys to

sorb sodium ions rather thanthemsummaaldosterone system,

through the urine. The renin-angiorensin­ri

thethe central

physiological role of the

events peptide

that

zed in hormone

Figure l 3-32, showsangiotension II in

pressure. lead to an increase in blood

Developing a Treatment for HypertensionOnce scientists discovered how the renin-angiotensin­aldosterone pathway is involved in blood pressure, it washypothesized that a competitive inhibitor of ACE-a keyenzyme in the second step of the pathway shown in Fig­ure 13-32-might offer a viable treatment for high bloodpressure. An ACE inhibitor is a molecule that binds toACE and prevents angiotensin I, the natural substrate,from binding to ACE, thus blocking the formation ofangiotensin II. In

the absence of angiotensin II, bloodpressure decreases.

Inste

One of the first substances shown to be a competitiveinhibitor of ACE was a polypeptide isolated from the venomof the poisonous pit viper (Figure 13-33 ). Snake venom iswell known for containing polypeptides that interfere withblood coagulation and other blood regulation mecha­nisms. polypeptides,

However, peptide

since analoenzymes in rhe stomach hydrolyze

effective as orally administgs of snake venom are not

ered drugs.ad, compounds that

asnake venom but that are not

are peptides

structurally were

similar synthesized

tond tested. The first effective

synthetic

ACE

inhibitor tobe used as a drug was capropril, whose structure is shownin Figure 13.33_ The sulfur atom in captopril binds to the

Asp-Arg-Val-Tyr-Ile-His-Pro-Phc His-Lcu-Val-Tyr-Ser{Pi-�(Angiotcnsinogcn)

J 1k,,in

Asp-Arg-Val-Tyr-Ile-His-Pro-Phc•His-l�u + Val-Tyr-Ser�rotefnl( Angio1cnsin I)

1 A"GJ'c,lmsi11 Coi1vcl1it1g E11.:,•mc (ACI:.)

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe + His-Leu(Angiorcnsin II)

biochemical 13-31 The

pathway key

that reactions

controls and

blood enzymes

pressure in t

Figure he renln-angiotensin.

Energy Drinks: Are They Really Harmless as a Source of Energy?

Energy for use in the human body is provided by consuming and me­tabolizing carbohydrates, proteins, and fat. The energy content of such consumed materials is usually given in units of calories. The primary "energy-providing" active ingredients in energy drinks are caffeine (1,3,7-trimethylxanthine, C8H 10N402) and sugar. Caffeine is an al­kaloid with no caloric value while sugar provides large amounts of calories but no other nutrients. For this reason, energy provided by sugar is often called "empty calories." In nature, caffeine is produced by plants such as Coffea arabica (coffee), Camellia sinensis (tea), and Theobroma cacao (cocoa). The plants produce caffeine to pre­vent insects and fungi from feeding on them. When animals, includ­ing humans, consume caffeine, it doesn't provide energy, but acts as a stimulant which increases the heart rate and produces a temporary boost in alertness. Sugar does provide energy, but it is in a short-lived temporary form commonly referred to as a "sugar high."

Caffeine has been consumed in many cultures for centuries in the form of tea and coffee, but something has changed. If you shop at gro­cery or convenience stores, you cannot help noticing the large num­ber of energy drinks being promoted. These drinks come in brightly colored and even fluorescent cans displaying intense graphics to draw attention. Whose attention are they trying to get? If you analyze the marketing strategies, the target audience consists of teenagers and young adults.

So what is the big deal'! Although there is still plenty of debate about caffeine and its effects on the body, empirical evidence has

A number of energy drinks are widely available in grocery and convenience stores.

510 Chapter 16

shown that large quantities can cause s1gmficanthealth and behavioral problems. For instance. too muccan result in nervousness and insomnia. The tnsofatigue, leading to more caffeine consumption, mo�•more lack _of sleep, irritability, etc. Ad�itionuJly, incr�consumption appears to correlate with an increase in boand occasionally, abnormal heart rhythms. Add 1ctton tis possible, with unpleasant symptoms resulting upon °cof use.

Other implications associated with the consumpl.lun ofdrinks are often indirect. Life is full of tradeoffs and energ) d no exception. When u person reaches for an energy drink. thq healthful beverages such us water, milk, or juice. Instead oring water, calcium, vitamin D, or nutrients from the above-lhC beverages, they are drinking an "energy" drink consisting water and large quantities of caffeine and sugar. The excessne consumption will have adverse long-term effects upon heal example, high sugar diets are known to increase the risk of osteoporosis, and type 2 diabetes.

So. the next time you feel fatigued, drink a cool, refre�hing water and rest for a few minutes. If you feel you must drink som to awaken the senses, try a cup of green tea without sugar. Tea

tains no empty calories and provides antioxidants. Most im remember that the best way to stay healthy and energized 1� to nutritious diet while getting plenty of rest and exercise.

i 0-------�-------'

Some sports drinks are formulated to replenish fluids as well as provide carbohydrates for energy.

-

II eal'ti ,,, /

"·' AMINES -

tvo te Alkaloids: Amines in PlantsAlkaloids are phypounds produced by psiologically active nitrogen-containing com­like alkaloidor s basic are used in characteristics lants.

anesthetics, The we in

term have tidepresseen alkaloid for refers amines. lo the alkalCertaini•lantAs s, a although stimulantmany are habit forming.an sants, and as stimu­, nicknobloown d, that which smoking increases otine the cigarettes heart can increases rate damage and the level

the blood of pressure. adrenaline ft is in wellthelung sure to cancer. lars and However, other carcinogens in cigarette lungs smoke and can that lead expoto­smoking. Coniine, which is nicotine oblained is from responsible hemlocfor k, the is an addiction extremelyoftoxic alkaloid.

�n g L3

Nicollr.c

QCH,-CH,-CH,

Cooiinc I I coffee, Caffeine tea, is soft a drinks, stimulant of chocolate, the central and cocoanervous system. Present inI used alertness, in certain but may pain cause relievers to

nervousness counteract and the dinsomnia. , caffeine Caffeine is increasesalso rowsiness caused byI an antihistamine.I

!:t: -� :..

� � �.. ·• ..: " ;,�

� -

.

...... ' �;.,

-:,,_�•-I . ..� ·.•.� ,,_ ;,,_ -=r�7

/'

.

. . • . •,,.--1 . '

_ �-- ·� '

.. s

,\

., - • ··\r-

_\-.,,

• I - •. 0 • , ' '•<'-,:

••�

--i ,

;-, .... . ;/ ... .• • ,, ·, ·.::· � ,?_ ·-. '- ..... , _.,-".. , .... ,t"t-z:.... �_.;.•_ '.�,t.5 "9,-. :J . ' �- .. - - .... : ....

�-�•- «:· �-;. -�:� :.. -,. . .,-

O C H3 H3c, J

IN N)

0 A N I

NJ CH3

Culleia.:

Ill

' ' ..

HO

bark Several of the alkaloids cinchona are used tree in has been medicine. used Quinine obtained fromthe malaria concentrations since the to a1600s. Atropine healthy from slow hbelladonna in the is used treatment in lowof eart rates and as ananesthetic for eye ccelera1e examinations.un

CH3 CH,=CH I HO

�

�111-CH, ;:b J� O -OH CHCH,-w

0-C6

Qvi□inc A1ropinc For oriental many poppy centuries, planl, have morphine been and used codeine, as alkaloids found inthe Codeine, which is structurally similar to morphieffective is

painkillers.chemical prescription modification painkillers of and morphine, cough is syrups. strongly Heroin, ne, used obtained in by someaused medically. addicting and is not

HO Mi1rpl'u11C

Codc:J11c