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    The nucleoside phosphorylase–nucleoside kinase route for synthesis of pyrimidine nucleoside monophosphates is relatively inefficient for salvage of pyrimidine bases because of the very low concentration of the bases in plasma and tissues order wellbutrin 300mg mastercard. Pyrimidine phosphorylase can use all of the pyrimidines but has a preference for uracil and is sometimes called uridine phosphorylase generic wellbutrin 300 mg free shipping. The phosphorylase uses cyto- sine fairly well but has a very cheap 300 mg wellbutrin visa, very low affinity for thymine; therefore, a ribonucle- oside containing thymine is almost never made in vivo. A second phosphorylase, thymine phosphorylase, has a much higher affinity for thymine and adds a deoxyri- bose residue (see Fig. Of the various ribonucleosides and deoxyribonucleoside kinases, one that merits special mention is thymidine kinase (TK). Activity of thymidine kinase in a given cell is closely related to the prolifer- ative state of that cell. During the cell cycle, the activity of TK rises dramatically as cells enter S phase, and in general rapidly dividing cells have high levels of this enzyme. Radiolabeled thymidine is widely used for isotopic labeling of DNA, for example, in radioautographic investigations or to estimate rates of intracellular DNA synthesis. Salvage Reactions for Conversion of Pyrimidine Nucleosides to Nucleotides. Enzyme Reaction Uridine-cytidine kinase Uridine ATP S UMP ADP Cytidine ATP S CMP ADP Deoxythymidine kinase deoxythymidine ATP S dTMP ADP Deoxycytidine kinase Deoxycytidine ATP S dCMP ADP 756 SECTION SEVEN / NITROGEN METABOLISM – Free Bases Nucleoside O O C Uracil Ribose 1-phosphate Uridine CH2 or or CH Cytosine Cytidine + – Pi H3N COO Aspartate Deoxyribose 1-phosphate H2N Thymine Thymidine C O Pi O P Carbamoyl Fig. Salvage reactions for pyrimidine phosphate nucleoside production. Thymine phosphory- lase uses deoxyribose 1-phosphate as a –O O substrate, such that ribothymidine is rarely C formed. Conversion of carbamoyl phosphate and aspartate to UMP. The defective enzymes in hereditary orotic aciduria are indicated ( ). CHAPTER 41 / PURINE AND PYRIMIDINE METABOLISM 757 C. Regulation of De Novo Pyrimidine Synthesis O Base P O P O The regulated step of pyrimidine synthesis in humans is carbamoyl phosphate syn- thetase II. The enzyme is inhibited by UTP and activated by PRPP (see Fig. Thus, as pyrimidines decrease in concentration (as indicated by UTP levels), CPS- NDP HO OH II is activated and pyrimidines are synthesized. As cells approach S-phase, CPS-II becomes more sensitive to PRPP acti- SH NADP+ thioredoxin vation and less sensitive to UTP inhibition. At the end of S-phase, the inhibition by SH UTP is more pronounced, and the activation by PRPP is reduced. These changes in thioredoxin ribonucleotide the allosteric properties of CPS-II are related to its phosphorylation state. Phospho- reductase reductase rylation of the enzyme at a specific site by a MAP kinase leads to a more easily acti- S vated enzyme. Phosphorylation at a second site by the cAMP-dependent protein NADPH thioredoxin S kinase leads to a more easily inhibited enzyme. THE PRODUCTION OF DEOXYRIBONUCLEOTIDES H For DNA synthesis to occur, the ribose moiety must be reduced to deoxyribose (Fig. This reduction occurs at the dinucleotide level and is catalyzed by ribonu- dNDP HO H cleotide reductase, which requires the protein thioredoxin. Reduction of ribose to deoxyri- side diphosphates can be phosphorylated to the triphosphate level and used as pre- bose. Reduction occurs at the nucleoside cursors for DNA synthesis (see Figs. A ribonucleoside diphos- The regulation of ribonucleotide reductase is quite complex. The enzyme con- phate (NDP) is converted to a deoxyribonucle- tains two allosteric sites, one controlling the activity of the enzyme and the other oside diphosphate (dNDP).

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    Guanine nucleotide exchange and activation of Ras Tyrosine P P Ras GDP Ras GTP kinase P P Grb2 domain GDP GTP SOS P P P P (GEF) Raf 2 quality 300mg wellbutrin. Ras binds raf and initiates such as Grb2 MAP kinase pathway Fig proven wellbutrin 300mg. Binding to the receptor causes a conformational change in Grb2 that P activates another binding site called an SH3 domain cheap wellbutrin 300mg on line. These activated SH3 domains 6 bind the protein SOS (SOS is an acronym for “son of sevenless,” a name unrelated 1 2 to the function or structure of the compound). SOS is a guanine nucleotide Phosphatidylinositol exchange factor (GEF) for Ras, a monomeric G protein located in the plasma mem- (PI) brane (see Chapter 9, Section III. Raf is a serine pro- tein kinase that is also called MAPKKK (mitogen activated protein kinase kinase kinase. The MAP kinase cascade termi- + P nates at a gene transcription factor, thereby regulating transcription of certain genes P P involved in cell survival and proliferation. PI 4,5-bisphosphate (PI-4,5-bisP) Many tyrosine kinase receptors (as well as heptahelical receptors) also have P additional signaling pathways involving phosphatidylinositol phosphates. PHOSPHATIDYLINOSITOL PHOSPHATES IN SIGNAL Second messengers TRANSDUCTION Phosphatidylinositol phosphates serve two different functions in signal transduction: (1) Phosphatidylinositol 4 ,5 bisphosphate (PI-4,5-bisP) can be cleaved to generate the P two intracellular second messengers, diacylglycerol (DAG) and inositol trisphosphate P (IP3); and (2) Phosphatidylinositol 3 ,4 ,5 trisphosphate (PI-3,4,5-trisP) can serve as a plasma membrane docking site for signal transduction proteins. P Phosphatidyl inositol, which is present in the inner leaflet of the plasma membrane, P is converted to PI-4,5-bisP by kinases that phosphorylate the inositol ring at the 4 and PI 3,4,5-trisphosphate (PI-3,4,5-trisP) 5 positions (Fig. PI-4,5-bisP, which has three phosphate groups, is cleaved by Docking site for a phospholipase C-isozyme to generate IP3 and DAG. The phospholipase isozyme C pleckstrin homology (PLC ) is activated by tyrosine kinase growth factor receptors, and phospholipase C domains is activated by a heptahelical receptor–G protein signal transduction pathway. Major route for generation of the PI-4,5-bisP can also be phosphorylated at the 3 position of inositol by the enzyme phosphatidyl inositide signal molecules, inosi- phosphatidylinositol 3 kinase (PI 3-kinase) to form PI -3,4,5- trisP (see Fig. PI 3-kinase phosphorylates PI-4,5-bisP 3- kinase contains an SH2 domain and is activated by binding to a specific phosphoty- and PI-4P at the 3 position. Prime symbols are rosine site on a tyrosine kinase receptor or receptor-associated protein. THE INSULIN RECEPTOR The insulin receptor, a member of the tyrosine kinase family of receptors, provides a good example of divergence in the pathway of signal transduction. Unlike other growth factor receptors, the insulin receptor exists in the membrane as a preformed dimer, with each half containing an and a subunit (Fig. The subunits Insulin is a growth factor that is essential for cell viability and growth. It increases general protein synthesis, which strongly affects muscle mass. How- ever, it also regulates immediate nutrient availability and storage, including glucose transport into skeletal muscle and glycogen synthesis. Thus, Di Abietes and other patients with type I diabetes mellitus who lack insulin rapidly develop hyper- glycemia once insulin levels drop too low. CHAPTER 11 / CELL SIGNALING BY CHEMICAL MESSENGERS 195 Insulin α PIP PIP PIP β β PLCγ Grb2 PI3-kinase P P P P IRS IRS P P P P P P P P Fig. The insulin receptor is a dimer of two membrane-spanning – pairs. The tyrosine kinase domains are shown in blue, and arrows indicate auto-crosspho- sphorylation. The activated receptor binds IRS molecules (insulin receptor substrates) and phos- phorylates IRS at multiple sites, thereby forming binding sites for proteins with SH2 domains: Grb2, phospholipase C (PLC ), and PI 3-kinase. These proteins are associated with various phosphatidylinositol phosphates (all designated with PIP) in the plasma membrane. The activated phosphorylated receptor binds a protein called IRS (insulin receptor substrate).

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    CELLS OF THE BLOOD The blood discount wellbutrin 300 mg on line, together with the bone marrow generic 300 mg wellbutrin overnight delivery, makes up the organ system that makes a significant contribution to achieving homeostasis discount wellbutrin 300mg with visa, the maintenance of the normal composition of the body’s internal environment. Blood can be con- sidered a liquid tissue consisting of water, proteins, and specialized cells. The most abundant cell in the blood is the erythrocyte or red blood cell, which trans- ports oxygen to the tissues and contributes to buffering of the blood through the binding of protons by hemoglobin (see section IV of this chapter, and the mate- rial in Chapter 4, section IV. Red blood cells lose all internal organelles during the process of differentiation. The white blood cells (leukocytes) are nucleated cells present in blood that function in the defense against infection. The platelets (thrombocytes), which contain cyto- plasmic organelles but no nucleus, are involved in the control of bleeding by con- tributing to normal thrombus (clot) formation within the lumen of the blood ves- sel. The average concentration of these cells in the blood of normal individuals is presented in Table 44. Normal Values of Blood Cell Concentrations in Adults Cell Type Mean (cells/mm3) Erythrocytes 5. Classification and Functions of Leukocytes and Thrombocytes The leukocytes can be classified either as polymorphonuclear leukocytes (granulo- cytes) or mononuclear leukocytes, depending on the morphology of the nucleus in these cells. The mononuclear leukocyte has a rounded nucleus, whereas the poly- morphonuclear leukocytes have a multilobed nucleus. THE GRANULOCYTES The granulocytes, so named because of the presence of secretory granules visible on staining, are the neutrophils, eosinophils, and basophils. When these cells are activated in response to chemical stimuli, the vesicle membranes fuse with the cell plasma membrane, resulting in the release of the granule contents (degranulation). The granules contain many cell-signaling molecules that mediate inflammatory processes. The granulocytes, in addition to displaying segmented nuclei (are poly- morphonuclear), can be distinguished from each other by their staining properties (caused by different granular contents) in standard hematologic blood smears; neu- trophils stain pink, eosinophils stain red, and basophils stain blue. Neutrophils are phagocytic cells that rapidly migrate to areas of infection or tis- sue damage. As part of the response to acute infection, neutrophils engulf foreign bodies, and destroy them, in part, by initiating the respiratory burst (see Chapter 24). The respiratory burst creates oxygen radicals that rapidly destroy the foreign material found at the site of infection. A primary function of eosinophils is to destroy parasites such as worms. The eosinophilic granules are lysosomes containing hydrolytic enzymes and cationic proteins, which are toxic to parasitic worms. Eosinophils have also been implicated in asthma and allergic responses, although their exact role in the development of these disorders is still unknown, and this is an active area of research. Basophils, the least abundant of the leukocytes, participate in hypersensitivity reactions, such as allergic responses. Histamine, produced by the decarboxylation of histidine, is stored in the secretory granules of basophils. Release of histamine during basophil activation stimulates smooth muscle cell contraction and increases vascular permeability. The granules also contain enzymes such as proteases, -glucuronidase, and lysophospholipase. These enzymes degrade microbial structures and assist in the remodeling of damaged tissue. MONONUCLEAR LEUKOCYTES The mononuclear leukocytes consist of various classes of lymphocytes and the monocytes.

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