By H. Folleck. The College of Santa Fe.

During tests for liver damage caused by a variety of degradation buy 100 mg avana overnight delivery erectile dysfunction hormonal causes, four groups of amino acids are converted to the TCA cycle intermedi- conditions 50mg avana erectile dysfunction treatment chicago. CHAPTER 39 / SYNTHESIS AND DEGRADATION OF AMINO ACIDS 719 Methionine SH CH2 CH2 − + OOC CH CH2OH H C NH3 + − NH3 COO Serine Homocysteine PLP cystathionine synthase − H2O − OOC CH CH2 S + NH3 CH2 CH2 Succinyl CoA Homocysteine is oxidized to a + disulfide, homocystine. To indicate H C NH3 that both forms are being consid- COO− L-Methylmalonyl CoA ered, the term homocyst(e)ine is used. Cystathionine H2O D-Methylmalonyl CoA Homocysteine cystathionase PLP COO– COO– NH+ 4 α-Ketobutryate Propionyl CoA + + H3N CH H3N CH − CH2 CH2 OOC CH CH2 SH + CH CH NH3 2 2 Cysteine SH S O2 SH S – − OOC CH CH2 SO2 CH2 CH2 + NH3 CH2 CH2 + + Cysteine sulfinic acid C C 3 3 α-Ketoglutarate – – PLP COO COO Glutamate Homocysteine Homocystine Pyruvate Because a colorimetric screening test for uri- nary homocystine was positive, the doctor 2− SO3 ordered several biochemical studies on Sulfite Homer Sistine’s serum, which included tests for methionine, homocyst(e)ine (both free 2− and protein-bound), cystine, vitamin B12, SO4 ATP Sulfate PAPS and folate. The level of homocystine in a 24- hour urine collection was also measured. The results were as follows: the serum Urine methionine level was 980 M (reference Fig. Cysteine is synthesized from the carbons range, 30); serum homocyst(e)ine (both and nitrogen of serine and the sulfur of homocysteine (which is derived from methionine). Based on these measurements, Homer Sistine’s doctor concluded that he had homocystinuria caused by an enzyme defi- ciency. Amino Acids Related through -Ketoglutarate/ and homocysteine are very ele- Glutamate vated and cystine is low, cystathio- nine -synthase could be defective, 1. GLUTAMATE but a cystathionase deficiency is also a pos- sibility. With a deficiency of either of these The five carbons of glutamate are derived from -ketoglutarate either by transami- enzymes, cysteine could not be synthesized, nation or by the glutamate dehydrogenase reaction (see Chapter 38). When glutamate is degraded, it is likewise methionine by reactions that require B12 converted back to -ketoglutarate either by transamination or by glutamate dehy- and tetrahydrofolate (see Chapter 40). In the liver, -ketoglutarate leads to the formation of malate, which pro- addition, it would be oxidized to homocys- duces glucose via gluconeogenesis. Thus, glutamate can be derived from glucose tine, which would appear in the urine. A measure- ment of serum cystathionine levels would proline, ornithine, and arginine) (see Fig. Glutathione is an important antioxidant, as has been described previ- ously (see Chapter 24). GLUTAMINE Glutamine is produced from glutamate by glutamine synthetase, which adds NH4 to the carboxyl group of the side chain, forming an amide (Fig. This is one of only three human enzymes that can fix free ammonia into an organic mole- cule; the other two are glutamate dehydrogenase and carbamoyl-phosphate syn- thetase I (see Chapter 38). Glutamine is reconverted to glutamate by a different enzyme, glutaminase, which is particularly important in the kidney. The ammonia it produces enters the urine and can be used as an expendable cation to aid in the excretion of metabolic acids (NH H S NH ). PROLINE In the synthesis of proline, glutamate is first phosphorylated and then converted to – COO glutamate 5-semialdehyde by reduction of the side chain carboxyl group to an CH2 CH2 + Glucose H C NH3 Histidine COO– Glutamate NH+ NH+ α-Ketoglutarate Formiminoglutamate (FIGLU) 4 4 ATP glutamine glutaminase synthetase Glutamine Glutamate ADP + Pi H2O Glutamate semialdehyde NH2 C O CH Ornithine 2 Proline CH Urea 2 + arginase H C NH3 (Liver) – COO Glutamine Arginine Fig. Different enzymes catalyze the addition and can be reconverted to glutamate, which can be converted to glucose in the liver. All of these the removal of the amide nitrogen of glutamine. CHAPTER 39 / SYNTHESIS AND DEGRADATION OF AMINO ACIDS 721 aldehyde (Fig. This semialdehyde spontaneously cyclizes (forming an inter- + NH3 nal Schiff base between the aldehyde and the -amino group). Reduction of this – – cyclic compound yields proline. Hydroxyproline is only formed after proline has COO CH2 CH2 CH COO been incorporated into collagen (see Chapter 49) by the prolyl hydroxylase system, Glutamate which uses molecular oxygen, iron, -ketoglutarate, and ascorbic acid (vitamin C). ATP Proline is converted back to glutamate semialdehyde, which is reduced to form ADP + Pi NADH glutamate. The synthesis and degradation of proline use different enzymes even + H+ NADPH though the intermediates are the same.

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Reverse transcriptase has a higher affinity for the dideoxynu- however 200mg avana otc erectile dysfunction mental, he has not yet developed the cleotides than does the cellular DNA polymerase cheap avana 100 mg with mastercard circumcision causes erectile dysfunction, so the use of this drug will affect symptoms of AIDS. CHAPTER 17 / USE OF RECOMBINANT DNA TECHNIQUES IN MEDICINE 303 In the early studies on cystic fibrosis, DNA sequencing was used to determine Southern Northern Western the type of defect in patients. Buccal cells were obtained from washes of the mucous membranes of the mouth, DNA isolated from these cells was amplified Gel electrophoresis by PCR, and DNA sequencing of the CF gene was performed. A sequencing gel for the region in which the normal gene differs from the mutant gene is shown below. DNA RNA Protein Normal Mutant G C 16 15 14 13 Transfer to paper 12 (bands not visible) 11 10 9 8 7 6 5 Add probe to 4 visualize bands 3 2 DNA DNA Antibody 1 G What is the difference between the normal and the mutant CF gene sequence shown on the gel, and what effect would this difference have on the protein produced from this gene? For Southern blots, DNA molecules are To study genes or other DNA sequences, adequate quantities of material must be separated by electrophoresis, denatured, trans- ferred to nitrocellulose paper (by “blotting”), obtained. It is often difficult to isolate significant quantities of DNA from the orig- and hybridized with a DNA probe. For example, an individual cannot usually afford to part with enough Northern blots, RNA is electrophoresed and tissue to provide the amount of DNA required for clinical testing. Therefore, the treated similarly except that alkali is not used. CLONING OF DNA blots, proteins are electrophoresed, transferred to nitrocellulose, and probed with a specific The first technique developed for amplifying the quantity of DNA is known as antibody. The DNA that you want amplified (the “foreign” DNA) is attached to a vector (a carrier DNA), which is introduced into a host cell that makes multiple copies of the DNA. The foreign DNA and the vector DNA are usually cleaved with the same restriction enzyme, which produces complementary sticky ends in both DNAs. Base pairs form between the complementary single-stranded regions, and DNA ligase joins the mol- A genomic “library” in molecular ecules to produce a chimera, or recombinant DNA. As the host cells divide, they biologists’ terms is a set of host replicate their own DNA, and they also replicate the DNA of the vector, which cells that collectively contain all of the DNA sequences from the genome of includes the foreign DNA. A cDNA library is a set of If the host cells are bacteria, commonly used vectors are bacteriophage (viruses host cells that collectively contain all the that infect bacteria), plasmids (extrachromosomal pieces of circular DNA that are DNA sequences produced by reverse tran- taken up by bacteria), or cosmids (plasmids that contain DNA sequences from the scriptase from the mRNA obtained from lambda phage). When eukaryotic cells are used as the host, the vectors are often cells of a particular type. Thus, a cDNA retroviruses, adenoviruses, free DNA, or DNA coated with a lipid layer (liposomes). Therefore, a 3-base deletion ddATP in the mutant gene corresponds to bases 7 through 9 of the normal gene. If synthesis is terminated with: If synthesis is terminated with: ddATP ddGTP ddCTP ddTTP 10 Loss of 3 bp (indicated by the dashes) main- 11 tains the reading frame, so only the single 12 Size of products 13 amino acid phenylalanine (F) is lost. Pheny- (in nucleotides) lalanine would normally appear as residue 14 15 508 in the protein. The rest of the amino 17 acid sequence of the normal and the mutant Polyacrylamide gel proteins is identical. A reaction mixtures contain one of the dideoxynucleotides, such as ddATP, and some of the normal nucleotide, dATP, which compete for incorporation into the growing polypeptide chain. When a T is encountered on the template strand (position 10), some of the molecules will incorporate a ddATP, and the chain will be terminated. Those that incorporate a normal dATP will continue growing until position 15 is reached, where they will incorporate either a ddATP or the normal dATP. Only those that incorporate a dATP will con- tinue growing to position 17. Thus, strands of different length from the 5 end are produced, cor- responding to the position of a T in the template strand. Each one contains DNA polymerase, a DNA template hybridized to a primer, plus dATP, dGTP, dCTP, and dTTP. Either the primer or the nucleotides must have a radioactive label, so bands can be visualized on the gel by autoradiography. Only one of the four dideoxyribonucleotides (ddNTPs) is added to each tube. Termination of synthe- sis occurs where the ddNTP is incorporated into the growing chain. The template is comple- mentary to the sequence of the newly synthesized strand.

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Other factors include basal ganglia dysfunction cheap avana 100mg with amex impotence remedies, which can independently impair selected aspects of attention and mental flexibility 50mg avana with visa erectile dysfunction aids. Iatrogenic factors that can affect cognition in PD include the use of dopaminomimetic therapy to treat motor symptoms. This drug effect is complex and variable, with levodopa being unable to compensate for all the cognitive deficits observed in PD (7). It depends on the duration of illness, the severity of motor signs, the presence of dementia, sleep disturbances, and possibly depression. For instance, in the early stages of PD, levodopa treatment can improve executive functions normally regulated by the prefrontal cortex. However, this improvement is incomplete and task specific. As the disease advances, patients with a stable clinical response to levodopa fail to exhibit a notable improvement in vigilance and executive function, and patients who exhibit motor fluctuations tend to exhibit transient deterioration in these functions (8). Finally, the effect of these drugs in patients with PD and dementia is likely to be more notable and complex. Other negative iatrogenic influences on cognitive function in PD include the use of drugs like anticholinergics and amantadine, often used to treat tremor and dyskinesias, and psychotropics used to treat sleep disturbances and affective symptoms. These drugs can negatively affect different aspects of memory and attention, particularly in already demented patients. Like these drug effects, many intercurrent medical illnesses and Copyright 2003 by Marcel Dekker, Inc. DEMENTIA: THE PD/AD/LBD OVERLAP SYNDROMES Dementia occurs in approximately 20–30% of PD patients. It represents a major risk factor for the development of many behavioral disturbances, including psychotic symptoms. Dementia appears to be associated with the combined effect of age and the severity of extrapyramidal symptoms (9). Pathologically, up to 40% of autopsy cases with a primary diagnosis of PD have comorbid findings consistent with senile dementia of the Alzheimer’s type (SDAT) (10,11). Conversely, up to 30–40% of patients with SDAT have comorbid parkinsonian features and harbor Lewy body pathology that extends beyond the dopamine neurons in the brainstem to involve the frontal cortex, hippocampus, amygdala, and basal forebrain (12). These defects conspire with aminergic deficits to increase disability and the incidence of psychotropic-induced side effects. They also contribute to the progression of parkinsonian motor symptoms by narrowing the therapeutic window of all antiparkinsonian agents. Lewy body dementia (LBD) is an increasingly recognized syndrome in which dementia is accompanied by spontaneous parkinsonian features, depressive features, and apathy (5,13). Unlike SDAT, this form of dementia exhibits significant fluctuations in arousal ranging from ‘‘narcoleptic-like’’ sleep attacks to delirium in advanced cases. Sleep is often disrupted by sleep fragmentation due to rapid eye movement (REM)–related behavioral disorders. Patients have spontaneous features of PD and are extremely sensitive to drug-induced parkinsonism. Although parkinsonism associated with LBD can be indistinguishable from idiopathic PD, several clinical features tend to help differentiate the two. The course of LBD is more rapid than that of idiopathic PD (5–7 vs. Compared to SDAT patients, LBD patients have spontaneous and drug-induced visual hallucinations early in the course of the illness and frequently exhibit fixed delusions. Although memory is clearly impaired in both conditions, visuospatial and frontal neuropsycho- logical functions are more prominently affected in LBD than in SDAT. BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA IN PARKINSONIAN SYNDROMES Disturbances of behavior, mood, and perception are common in patients with dementia. These so-called behavioral psychological symptoms of Copyright 2003 by Marcel Dekker, Inc.

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