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Urea is pro- duced from the guanidinium group on the side chain of arginine order albenza 400 mg with visa medicine 831. The portion of arginine originally derived from ornithine is reconverted to ornithine. The reactions by which citrulline is converted to arginine and arginine is cleaved to produce urea occur in the cytosol. Ornithine, the other product of the arginase 706 SECTION SEVEN / NITROGEN METABOLISM NH + O H O Fumarate Arginine 3 2 Urea CH C O– 2 CH2 CH2 Malate Ornithine NAD+ Argininosuccinate CH2 CH2 + NADH H 3 Carbamoyl Oxaloacetate phosphate C C O – – Glutamate Ornithine α-Ketoglutarate Aspartate Citrulline α-Ketoglutarate PLP ornithine aminotransferase Fig. The Krebs bicycle, indicating the common steps between the TCA and urea O O cycles. All reactions shown occur in the cytoplasm except for the synthesis of citrulline, C H C O– which occurs within the mitochondria. CH2 CH2 CH2 CH2 + + reaction, is transported into the mitochondrion in exchange for citrulline, where it H 3 H 3 can react with carbamoyl phosphate, initiating another round of the cycle. Origin of Ornithine Glutamate Glutamate semi-aldehyde Ornithine is an amino acid. However, it is not incorporated into proteins during the Fig. The ornithine aminotransferase process of protein synthesis because no genetic codon exists for this amino acid. This is a reversible reaction depend- Although ornithine is normally regenerated by the urea cycle (one of the products ent on pyridoxal phosphate, which normally of the arginase reaction), ornithine also can be synthesized de novo if needed. The usual direction of this reaction is the formation of glutamate semialdehyde, which is the first step of the degradation pathway for ornithine. Regulation of the Urea Cycle The human liver has a vast capacity to convert amino acid nitrogen to urea, thereby preventing toxic effects from ammonia, which would otherwise accumulate. In gen- eral, the urea cycle is regulated by substrate availability; the higher the rate of ammonia production, the higher the rate of urea formation. Regulation by substrate availability is a general characteristic of disposal pathways, such as the urea cycle, which remove toxic compounds from the body. This is a type of “feed-forward” reg- ulation, in contrast to the “feedback” regulation characteristic of pathways that pro- The precise pathogenesis of the duce functional endproducts. NAG is formed specifically to activate CPSI; it has no other known func- pletely understood. The synthesis of NAG from acetyl CoA and glutamate is stimu- however, attributable in part to toxic materi- lated by arginine (Fig. Thus, as arginine levels increase within the liver, two als that are derived from the metabolism of important reactions are stimulated. The first is the synthesis of NAG, which will nitrogenous substrates by bacteria in the gut increase the rate at which carbamoyl phosphate is produced. The second is to pro- that circulate to the liver in the portal vein. In both of these physiologic states, as amino acid carbon is converted to liver cells to degrade these compounds to glucose, amino acid nitrogen is converted to urea. The induction of the synthesis harmless metabolites. As a result, these tox- ins are “shunted” into the hepatic veins of urea cycle enzymes under these conditions occurs even though the uninduced unaltered and eventually reach the brain enzyme levels are far in excess of the capacity required. The ability of a high-pro- through the systemic circulation (“portal- tein diet to increase urea cycle enzyme levels is another type of “feed-forward” systemic encephalopathy”). CHAPTER 38 / FATE OF AMINO ACID NITROGEN: UREA CYCLE 707 NH is one of the toxins that results Arginine 4 from the degradation of urea or pro- CO + NH+ teins by intestinal bacteria and is not 2 4 – – metabolized by the infected liver. The subse- COO CH3 COO 2 ATP carbamoyl quent elevation of ammonia concentrations in (CH2)2 + (CH2)2 O phosphate + + the fluid bathing the brain causes depletion of + synthetase CH NH3 S CH NH C CH3 tricarboxylic acid (TCA) cycle intermediates (CPSI) – – and ATP in the central nervous system. Glutamate subsequently reacts with – ammonia to form glutamine. H2N C O P O The absolute level of ammonia and its O– metabolites, such as glutamine, in the blood Carbamoyl or cerebrospinal fluid in patients with hepatic phosphate encephalopathy correlates only roughly with the presence or severity of the neurologic Fig. Activation of carbamoyl phosphate synthetase I (CPSI). Function of the Urea Cycle during Fasting hepatic failure.
The -phosphate of the diphosphate CAP 1 then attacks the -phosphate of GTP buy 400 mg albenza amex schedule 9 medications, liberating pyrophosphate, and forming an CH (n7) CH unusual 5 to 5 triphosphate linkage. Methylation also occurs on the ribose 2 -hydroxyl group in the ter- (CH3)-SAM minal nucleotide to which the cap is attached, and sometimes the 2 -hydroxyl group of the adjacent nucleotide ribose. This cap “seals” the 5 end of the pri- CAP 2 mary transcript and decreases the rate of degradation. The phosphates in blue originated from the original RNA transcript; the phosphate in black comes from GTP. ADDITION OF A POLY(A) TAIL After the RNA polymerase transcribes the stop codon for protein translation, it passes a sequence called the polyadenylation signal (AAUAAA) (Fig. It continues past the polyadenylation signal until it reaches an unknown, and possibly unspecific, termination signal many nucleotides later. However, as the primary tran- script is released from the RNA polymerase elongation complex, an enzyme com- plex binds to the polyadenylation signal and cleaves the primary transcript approx- imately 10 to 20 nucleotides downstream, thereby forming the 3 end. After this Polyadenylation Cleavage cleavage, a poly(A) tail that can be over 200 nucleotides in length is added to the signal site 3 -end. ATP serves as the precursor for the sequential addition of the adenine nucleotides. They are added one at a time, with poly(A) polymerase catalyzing each addition. The poly(A) tail is a protein binding site that protects the mRNA from degradation. Therefore, the multidrug therapy, which included the antibiotic rifampin, was continued. Rifampin binds to the RNA polymerases of several Repeat of ATP addition bacteria. As RNA polymerase continues to transcribe the The presence of a poly (A) tail on eukaryotic mRNA allows this form of RNA to DNA, enzymes cleave the transcript (hnRNA) be easily separated from the more abundant rRNA. After extracting all of the at a point 10–20 nucleotides beyond an RNA from a cell, the total RNA is applied to a column of beads to which oligo- AAUAAA sequence, just before a run of Us dT has been covalently attached. As the mRNA flows through the column, its poly (A) tail (or Gs). Approximately 250 adenine will base pair with the oligo-dT, and the mRNA will become bound to the column. All nucleotides are then added to the 3 -end of the other types of RNA will flow through the column and not bind to the beads. The bound hnRNA, one at a time, by poly(A) polymerase. REMOVAL OF INTRONS Exon Intron Exon Eukaryotic pre-mRNA transcripts contain regions known as exons and introns. Introns, therefore, do not contribute intron sequences shown in blue dashed boxes to the amino acid sequence of the protein. They always appear at this posi- These introns are carefully removed from the pre-mRNA transcript and the exons tion in introns. The sequences on the exon side spliced together, so that the appropriate protein is produced from the gene. The consensus sequences at the intron/exon boundaries of the pre-mRNA are AGGU (AGGT in the DNA). The sequences vary to some extent on the exon side of the boundaries, but almost all introns begin with a 5 GU and end with a 3 AG Anne Niemick has -thalassemia (Fig. These intron sequences at the left splice site and the right splice site (enough of the -chain is produced are, therefore, invariant. Because every 5 GU and 3 AG combination does not to maintain blood hemoglobin lev- result in a functional splice site, clearly other features within the exon or intron help els above 6. One mutation resulting to define the appropriate splice sites.
Production of a membrane-bound antibody (IgM) and a smaller secreted antibody (IgD) from the same gene best albenza 400 mg symptoms hiatal hernia. Initially, the lympho- cytes produce a long transcript that is cleaved and polyadenylated after the second stop codon. The intron that contains the first stop codon is removed by splicing between the 5 - and 3 -splice sites. Therefore, translation ends at the second stop codon, and the protein contains a hydrophobic exon at its C-terminal end that becomes embedded in the cell membrane. After antigen stimulation, the cells produce a shorter tran- script by using a different cleavage and polyadenylation site. This transcript lacks the 3 -splice site for the intron, so the intron is not removed. In this case, translation ends at the first stop codon. The IgD antibody does not contain the hydrophobic region at its C-terminus, so it is secreted from the cell. Apoprotein B gene CAA Transcription CAA Transcript heme Intestine kinase Liver (inactive) RNA editing Heme mRNA CAA UAA mRNA kinase (active) (stop) eIF2 eIF2 P Translation active inactive Liver Intestinal ApoB ApoB Initiation 4563 2152 of translation Amino acids Amino acids Fig. In liver, the apoprotein B (ApoB) gene produces a protein that con- eIF2. When eIF2 is phosphorylated by heme tains 4,563 amino acids. In intestinal cells, the same gene produces a protein that contains kinase, it is inactive, and protein synthesis can- only 2,152 amino acids. Conversion of a C to a U (through deamination) in the RNA tran- not be initiated. Heme inactivates heme kinase, script generates a stop codon in the intestinal mRNA. Thus, the protein produced in the intes- thereby preventing phosphorylation of eIF2 tine (B-48) is only 48% of the length of the protein produced in the liver (B-100). The mRNA for ferritin has an iron mRNA for the transferrin receptor. When the iron response element binding protein, IRE-BP does not tion of the mRNA is prevented by binding of contain bound iron, it binds to IRE, preventing translation. When IRE-BP binds iron, it dis- the iron response element binding protein sociates, and the mRNA is translated. When iron lev- els are high, IRE-BP binds iron and is not protein located in cell membranes that permits cells to take up transferrin, the pro- bound to the mRNA. The mRNA is rapidly tein that transports iron in the blood. The rate of synthesis of the transferrin recep- degraded, preventing synthesis of the transfer- tor increases when intracellular iron levels are low, enabling cells to take up more rin receptor. Synthesis of the transferrin receptor, like that of the ferritin receptor, is regu- lated by the binding of the iron response element binding protein (IRE-BP) to the iron response elements (IRE). However, in the case of the transferrin receptor mRNA, the IREs are hairpin loops located at the 3 -end of the mRNA, and not at the 5 end where translation is initiated. When the IRE-BP does not contain bound iron, it has a high affinity for the IRE hairpin loops. Consequently, IRE-BP prevents degradation of the mRNA when iron levels are low, thus permitting synthesis of more transferrin receptor so that the cell can take up more iron. Conversely, when iron levels are elevated, IRE-BP binds iron and has a low affinity for the IRE hair- pin loops of the mRNA. Without bound IRE-BP at its 3 end, the mRNA is rapidly degraded and the transferrin receptor is not synthesized. Follicular lymphomas are the most common subset of non-Hodgkin’s lymphomas (25–40% of cases). Patients with a more aggressive course, as seen in Arlyn Foma, die within 3 to 5 years after diag- nosis if left untreated. In patients pretreated with multidrug chemotherapy (in this case AV/CM), a response rate of 50% has been reported when interferon- is added to this regimen. In addition, a significantly longer event-free survival has been reported when using this approach.
The major clinical disturbances in Parkinson’s disease are a result of dopamine •OH O – 2 depletion in the neostriatum generic albenza 400 mg overnight delivery medicine knowledge, resulting from degeneration of dopaminergic neurons NO whose cell bodies reside in the substantia nigra pars compacta. The decrease in dopamine production is the result of severe degeneration of these nigrostriatal neu- RNOS rons. Although the agent that initiates the disease is unknown, a variety of studies 3 support a role for free radicals in Parkinson’s disease. Within these neurons, Lipid peroxidation dopamine turnover is increased, dopamine levels are lower, glutathione is Protein oxidation DNA strand breaks decreased, and lipofuscin (Lewy bodies) is increased. Iron levels are higher, and fer- ritin, the storage form of iron, is lower. Furthermore, the disease is mimicked by the 4 Lipofuscin compound 1-methyl-4-phenylpyridinium (MPP ), an inhibitor of NADH dehydro- Neuronal genase that increases superoxide production in these neurons. Even so, it is not degeneration known whether oxidative stress makes a primary or secondary contribution to the disease process. Drug therapy is based on the severity of the disease. In the early phases of the Reduced dopamine release disease, a monoamine oxidase B-inhibitor is used that inhibits dopamine degrada- tion and decreases hydrogen peroxide formation. A model for the role of ROS and patients are treated with levodopa (L-dopa), a precursor of dopamine. RNOS in neuronal degradation in Parkinson’s disease. Dopamine levels are reduced by Cora Nari experienced angina caused by severe ischemia in the ventric- monoamine oxidase, which generates H2O2. Superoxide also can be produced by mito- the site of atherosclerotic plaques within the lumen of the coronary arter- chondria, which SOD will convert to H2O2. When TPA was infused to dissolve the clots, the ischemic area of her heart was reaction to proceed, generating hydroxyl radi- reperfused with oxygenated blood, resulting in ischemic–reperfusion injury. NO, produced by inducible nitric oxide case, the reperfusion injury resulted in ventricular fibrillation. The RNOS and hydroxyl radical decreased O2 supply results in decreased ATP generation from mitochondrial oxida- lead to radical chain reactions that result in tive phosphorylation and inhibition of cardiac muscle contraction. As a conse- lipid peroxidation, protein oxidation, the for- quence, cytosolic AMP concentration increases, activating anaerobic glycolysis and mation of lipofuscin, and neuronal degenera- lactic acid production. If ATP levels are inadequate to maintain Na ,K -ATPase tion. The end result is a reduced production activity, intracellular Na increases, resulting in cellular swelling, a further increase and release of dopamine, which leads to the in H concentration, and increases of cytosolic and subsequently mitochondrial clinical symptoms observed. The decrease in ATP and increase in Ca may open the mitochondrial permeability transition pore, resulting in permanent inhibition of oxidative phos- phorylation. Damage to lipid membranes is further enhanced by Ca2 activation of phospholipases. Reperfusion with O2 allows recovery of oxidative phosphorylation, provided that the mitochondrial membrane has maintained some integrity and the mitochondrial transition pore can close. However, it also increases generation of free radicals. The transfer of electrons from CoQ• to O2 to generate superoxide is increased. Endothe- lial production of superoxide by xanthine oxidase also may increase. These radicals may go on to form the hydroxyl radical, which can enhance the damage to compo- nents of the electron transport chain and mitochondrial lipids, as well as activate the Currently, an intense study of ischemic insults to a variety of animal organs is underway, in an effort to discover ways of pre- venting reperfusion injury. These include methods designed to increase endogenous antioxidant activity, to reduce the genera- tion of free radicals, and, finally, to develop exogenous antioxidants that, when administered before reperfusion, would prevent its injurious effects. Each of these approaches has met with some success, but their clinical application awaits further refinement. With the growing number of invasive procedures aimed at restoring arterial blood flow through partially obstructed coronary vessels, such as clot lysis, balloon or laser angioplasty, and coronary artery bypass grafting, development of methods to prevent ischemia–reperfusion injury will become increasingly urgent. CHAPTER 24 / OXYGEN TOXICITY AND FREE RADICAL INJURY 455 mitochondrial permeability transition. As macrophages move into the area to clean up cellular debris, they may generate NO and superoxide, thus introducing perox- ynitrite and other free radicals into the area.
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