278 CHAPTER EIGHT Carbohydrate Metabolism Glycogen H"'o . ---..... koaso .. � glucose Gluc _::;;. ose-1-pho.,.,,1e · � \ ------- Gluc ADP") ' ose 1' f t , UTP---)� Glucose-6-phosphate �PP \ ,, '\J7 _,r � ' t � Fructose-6-p♦ CP Glucose- hosphate 6-phosphatase - ATP I PFK �� - Fructose 1 � ) bisphosphate -�� phosphatase Fructo se-1,6-blsphosphate f Glycera/ dehyde-3-phosphate:t A. ) ◄ Dlhydn,x""'°"" .. !::, p phosphate +�� :.----- + � � �+(H+ Glycera te-11,3-b1lsp hosphate- • ATP • �,rcATF Gly cerate-3-phosphate l Giyc t erate-2-phosphate Pho�sphoenoll- ----=:-- lpyruvate Certain ATP ◄ amino ,P, + aclda �_/ FIGURE 8.10 �• The Role of Dopamine in Parkinson's Disease Carbohydrate Metab and Schizophrenia olism: Gluconeogenesls a In nd Glycolysls :ophrenia is a debilitating mental disorder that affects gluconeogenesis, which Parkinson's disease is somewhat better understood and occurs when blood sugar &>crcent of of glycolysis are revers levels arelo w and liver the population worldwide. Its symptoms is believed to arise from decreased dopamine activity in ed. Three irreversible gly glycogen is deplered, 7 of hide substrates forgluc on colytic reacrions arebyp rhe 10 reactions hallucmations, delusions, disordered thinking, another part of the brain. Parkinson's disease is a chronic eogenesis are certain ami assed by alternative reaction cells), and glycer no acids {derived from s. The major rmenr disorders, and social withdrawal. The disease ol {produced from the deg muscle), lactate (formed in neurodegenerative disease characterized by a loss of coor­ occur only in radation of triacylglycero muscle and red blood s ri e d cytoplasm. the gluconeoge fs). In concrnst to the re iy t k s during late adolescence to early adulthoo . dination and movement. The disease tends to strike after carboxykinas nesis reactions catalyzed actions of glycolysis, which cause e occur within rhe mitoch by pyruvate carboxylase of schizophrenia is still unknown, although an the age of 60. Symptoms of Parkinson's disease include plasmic ondria. The reaction catal and, in some species. PEP reticulum. Note that glucon yzed by glucose-6-phos of the neurotransmitter dopamine appears to be conver eogenesis and glycolysis phatase takes place in the endo­ l tremor (shaking), bradykinesia (slow movement), rigidity ted either to acetyl-CoA do nor occur simultaneous ved. {not shown) or to lactate. ly. In glycolysis, pyruvare is (stiffness of limbs), and impaired balance. About 60,000 33 7 • ORGANIC CHEMISTRY AND BIOMOLECUL 0 ES SUMMARY 331 cannot be administered as a drug because blood-brain barrier. it can't cross the Instead, the Figure 7-61. Stimul tered. drug L-dopa is adminis ation of this particular neuronal The only difference • way between the chemical is associated with path­ of L-dopa and structure feelings of reward dopamine is the carboxyl memory, and motivation. and desire, group in ic acid functional By binding L-dopa. The carboxylic receptor in to the dopamine bioche acid is removed this neuronal pathway, mical reaction in the in a tions prevent antipsychotic medica neuron that converts dopamine from • into dopamine: t-dopa first binding to its receptor. generation of antipsychotic The drugs bound mine receptors in the to all dopa­ brain, including those . ·erve j, HO · �: nal pathway that in the neuro• ...., HO� control movement impulse Axon II � Figure 7-61 (shown in red ). Consequently, some in terminal D'): these of the side HO Oil - 'n drugs were effects of tremors a nd other Synaptic l.•OOl'A from Parkinson's symptoms like HO disease. The those deft J>op.t11:111k: newest class medications, known of anripsychotic The prolonged as atypical atttipsychotics, use of L-dopa eventually dopamine receptors block reduc but specifically to activate the dopamine es its ability mine target a type Receiving receptor. At receptor that is of dopa• � drugs arc usually prescribed. that point other found only in the neuronal neuron Unfortunately, associated with schizophrenia pathway receptors eventually dopamine (shown in green). become less sensitive atypical antipsychotic Therefore, to these drugs have Figure 7-60 Communication between neurons. too and symptoms drugs fewer movemenNelat of the disease return. side effects. ed The thought disorders There associated with have been significant are believed schizophrenia advances to result from the of these two in the treatment s opposite effect: diseases as new ca es of Parkinson's disease arc diagnosed in the next, creating what is known as a neuronal pathway. The of qopamine activity an excess chemistry scientists have unraveled in another neuronal behind each the United States every year. transmission of electrical impulses through a neuronal brain that involves pathway in the of these diseases. Further dopamine, highlighted should eventually research Schizophrenia and Parkinson's e i o in lead to even disease are two v ry pathway ult mately leads t a physiological response. The green in for better treatment these patients in the options different diseases, but both involve an imbalance of dopa· two neuronal pathways in the brain that use dopamine as a future. mine in the brain. Dopamine, a neurotransmitter essential neurotransmitter are highlighted in Figure 7-61. for normal brain function, is involved in the brain's The impaired movement associated with Parkinson's Summary reward and pleasure centers. Dopamine is also involved in disease is believed to result from the loss of dopamine­ regulating movement and emotional responses. Dopamine is producing neurons along one of the two neuronal path­ .\lcohols and Ethers an amine, as suggested by the ending in its name. ways in the brain that rely on dopamine, highlighted in red II in Figure 7-61. Neurons differ from most other cells in the I anunc body in that they do not regenerate themselves, so the loss HO N of these cells is permanent. Patients with Parkinson's dis­ � ,1-1 ease show 80 percent less dopamine activity in this neuro nal pathway. A/ HO Effective prescription drugs are available to treat man� Dop� mnc r of the symptoms of Parkinson's disease. Dopamine 1tsdl 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 Frontal -f communicate with one another on a molecular level. cortex 11 The human brain has about 100 billion (1 X 10 ) 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 • Dopamine pathway 1 shaft of a nerve cell. When the electrical impulse reaches (in Parkinson's) the end of the axon, neurotransmitters are released from • Dopamine pathway 2 the neuron into the synaptic cleft, the gap between two (in schizophrenia} neurons, shown in the inset in Figure 7-60. Neurotransmit• ine.· Figure 7-61 Neuronal pathways that Involve dopam ters diffuse to the next neuron, where they bind to specific olved pathway shown in red controls movement and is iov eclS receptors on the cell membrane of the receiving neuron. In Parkinson's disease. The pathway shown in greeo aff href1il- this way electrical impulses travel from one neuron to the memory, and motivation and is involved in schizop 13 • PROTEINS: STRUCTURE AND Fl.IN 594 liit:i,Jl-1j®¢t§1tfAA1ACE Inhibitors as a Treatment for Hypertension lungs Enzyme inhibitors have been used as pharmaceuticals in angiorensin I, to produce the hormone angiotensin II, an the treatment of a wide range of diseases including cancer, octapeptide, and the dipeptide His-Leu. Liver Ltt \ AIDS, diabetes, and heart disease. Some of the earliest Angiotensin II signals a number of physiological events enzyme inhibitors were used before their mechanism of that raise blood pressure: (1) Ir causes the muscles sur• action was even understood. Aspirin, for example, was rounding blood vessels to constrict-a process known as \.) \J used ro treat pain and inflammation long before it was vasoconstriction, and (2) it triggers the release of the ste­ 1 . 1 , ACE r<ocoast,i<tioo discovered in the l 970s to be an inhibitor of C) c/ooxy­ roid hormone aldosterone from the adrenal cortex, which . 1 . A ge11ase, a key enzyme involved in several biochemical signals the kidneys to reabsorb sodium ions rather than pathways leading to inflammation. excreting them through the urine. The renin-angiorensin­ Aog,o l In this section we consider a class of enzyme inhibitors aldosterone system, summa og,ot,osmog'" Aog,ot'"''" I -----> Water rized in Figure l 3-32, shows Aldosterone used ro treat chronically elevated blood pressure, a condi­ the central role of the peptide hormone angiotension II in and salt \ retention tion known as hypertension. Hypertension is a major risk the physiological events that lead to an increase in blood factor in stroke, heart attack, heart failure, and kidney pressur T ' e. Low blood Adrenal failure. More than half of Americans over age 65 suffer volume and cortex from hypertension. Developing a Treatment for Hypertension drop in blood � .,,, Kidney sodium levels Once scientists discovered how the renin-angiotensin­ How the Body Raises Blood Pressure leads to Remn aldosterone pathway is involved in blood pressure, it was release Signals kidneys to stop producing Renin The body carefully controls blood pressure so that it hypothesized that a competitive inhibitor of ACE-a key of blood pressure by neither falls too low nor rises too high. Regulation of enzyme in the second step of the pathway and organs involved in the regulation shown in Fig­ Figure 13-32 The reactions, enzymes, salt retention as blood pressure is a complex Blood pressure depends on water and process involving several ure 13-32-might offer a viable treatment for high blood the renin-angiotensin-aldosterone system.