By G. Thordir. Pomona College.

Activated platelets secrete cytokines that perpetuate this process and increase the potential for thrombus (clot) In patients such as Ann Jeina and formation locally cheap 20mg erectafil otc pump for erectile dysfunction. As the evolving plaque matures discount erectafil 20 mg with amex drugs for treating erectile dysfunction, a fibrous cap forms over its Ivan Applebod, who have elevated expanding “roof,” which now bulges into the vascular lumen, thereby partially levels of VLDL or LDL, HDL levels occluding it. Vascular smooth muscle cells now migrate from the tunica media to are often low. These patients are predisposed the subintimal space and secrete additional plaque matrix material. The smooth to atherosclerosis and suffer from a high inci- muscle cells also secrete metalloproteinases that thin the fibrous cap near its dence of heart attacks and strokes. Exercise and estrogen administration both “elbow” at the periphery of the plaque. This thinning progresses until the fibrous increase HDL levels. This is one of the reasons cap ruptures, allowing the plaque contents to physically contact the procoagulant exercise is often recommended to aid in the elements present within the circulation. If prevention or treatment of heart disease, and this thrombus completely occludes the remaining lumen of the vessel, an infarction estrogen replacement therapy (ERT) is often of tissues distal to the occlusion (i. Most plaques that rupture also contain focal areas of calcification, menopause, the incidence of heart attacks is which appears to result from the induction of the same cluster of genes as those that relatively low in women, but it rises after promote the formation of bone. The inducers for this process include oxidized menopause and increases to the level found in sterols as well as transforming growth factor beta (TGF- ) derived from certain men by the age of 65 or 70 years. Recent studies suggest that the beneficial amount of of the plaque’s fibrous cap, inducing macrophages to secrete additional metallopro- ethanol may be quite low, about two small teinases that further degrade the arterial-fibrous cap matrix. This contributes further glasses of wine a day, and that beneficial effects to plaque rupture and thrombus formation (see Fig. The consequence is a ascribed to ethanol may result from other com- macrovascular ischemic event such as an acute myocardial infarction (AMI) or an ponents of wine and alcoholic beverages. It is called “lipoprotein little a” to avoid confusion with the apoprotein A increase the rate of atherosclerotic vascular dis- found in HDL. The structure of apoprotein(a) is very similar to that of plasmino- ease in these women. As a result, the accepted gen, a precursor of the protease plasmin that degrades fibrin, a major component of blood indications for ERT are now limited to intoler- clots. Lipoprotein(a), however, cannot be converted to active plasmin. There are reports that able “hot flashes” or vaginal dryness. CHAPTER 34 / CHOLESTEROL ABSORPTION, SYNTHESIS, METABOLISM, AND FATE 643 B Healed Buried fissure thrombus A Atherosclerotic vessel C Plaque Atherosclerotic Mural Intraintimal fissure plaque intraluminal thrombus with small thrombus thrombus (non-occlusive) D Occlusive intraluminal thrombus Fig. Plaque capsule eroded near the “elbow” of plaque creating an early plaque fissure (A), which may heal as plaque increases in size (B) or may grow as thrombus expands, having an intraluminal portion and an intraintimal por- tion (C). If the fissure is not properly sealed, the thrombus may grow and completely occlude the vessel lumen (D), causing an acute infarction of tissues downstream of the vessel occlu- sion. STEROID HORMONES Cholesterol is the precursor of all five classes of steroid hormones: glucocorticoids, mineralcorticoids, androgens, estrogens, and progestins. These hormones are syn- thesized in the adrenal cortex, ovaries, testes, and ovarian corpus luteum. Steroid hormones are transported through the blood from their sites of synthesis to their tar- get organs, where, because of their hydrophobicity, they cross the cell membrane and bind to specific receptors in either the cytoplasm or nucleus. The bound recep- tors then bind to DNA to regulate gene transcription (see Chapter 16, section III. Because of their hydrophobicity, steroid hormones must be complexed with a serum protein. Serum albumin can act as a nonspecific carrier for the steroid hormones, but there are specific carriers as well. The cholesterol used for steroid hormone synthesis is either synthesized in the tissues from acetyl CoA, extracted from intracellular cholesterol ester pools, or taken up by the cell in the form of cholesterol-containing lipoproteins (either internalized by the LDL-recep- tor, or absorbed by the SR-B1 receptor). In general, glucocorticoids and progestins contain 21 carbons, androgens contain 19 carbons, and estrogens contain 18 car- bons. The specific complement of enzymes present in the cells of an organ deter- mines which hormones the organ can synthesize. The oxidative reactions that lead to the synthesis and secretion of glucocorticoids such as cortisol are stimulated by adrenal corticotrophic hormone (ACTH).

Differences between Eukaryotes and Prokaryotes in the Initia- Insulin purchase erectafil 20mg without a prescription erectile dysfunction drugs viagra, an anabolic hormone purchase 20mg erectafil with visa erectile dysfunction treatment in uae, stim- tion of Protein Synthesis ulates general protein synthesis by Eukaryotes Prokaryotes activating the initiation factor Binding of mRNA Cap at 5’ end of mRNA binds eIFs and Shine-Dalgarno sequence eIF4E. Normally, eIF4E is bound to an to small ribosomal 40S ribosomal subunit containing upstream of initiating AUG inhibitor protein, 4E binding protein (4E-BP). Ribosomes 80S 70S Phosphorylated 4E-BP no longer binds to (40S and 60S subunits) (30S and 50S subunits) eIF4E, and eIF4E is now free to participate in the initiation of protein synthesis. GTP is hydrolyzed, the initiation factors are released, and the large ribo- eIF2 is a regulator of the initiation somal (60S) subunit binds. It contains one small and step in protein synthesis. When it is one large subunit, and has two binding sites for tRNA, known as the P (peptidyl) phosphorylated, it is inactive, and Met and A (aminoacyl) sites. During initiation, Met-tRNAi binds to the ribosome at protein synthesis cannot begin. In bac- infection result in phosphorylation of eIF2 by teria, the initiating methionyl-tRNA is formylated, producing a formyl-methionyl- a specific kinase. Met The regulation of globin synthesis by tRNAf that participates in formation of the initiation complex (Fig. Only heme in reticulocytes illustrates the role of three initiation factors (IFs) are required to generate this complex in prokaryotes, eIF2 in regulation of translation. Reticulo- compared with the dozen or more required by eukaryotes. The ribosomes also differ cytes, which are the precursors of red blood in size. Prokaryotes have 70S ribosomes, composed of 30S and 50S subunits, and cells, synthesize the oxygen-carrying hemo- eukaryotes have 80S ribosomes, composed of 40S and 60S subunits. Unlike eukary- globin molecules from the globin polypep- otic mRNA, bacterial mRNA is not capped. Identification of the initiating AUG tide chains and the Fe-binding pigment, triplet in prokaryotes occurs when a sequence in the mRNA (known as the heme. In the absence of heme, the rate of Shine–Dalgarno sequence) binds to a complementary sequence near the 3 -end of initiation of globin synthesis decreases. Heme acts by inhibiting the phosphorylation of the initiation factor eIF2. Elongation of Polypeptide Chains active in the presence of heme and globin synthesis is initiated. After the initiation complex is formed, addition of each amino acid to the growing polypeptide chain involves binding of an aminoacyl-tRNA to the A site on the ribo- Many antibiotics that are used to some, formation of a peptide bond, and translocation of the peptidyl-tRNA to the P combat bacterial infections in site (Fig. The peptidyl-tRNA contains the growing polypeptide chain. BINDING OF AMINOACYL-tRNA TO THE A SITE tein synthesis in prokaryotes and eukary- otes. For example, streptomycin binds to the When Met-tRNAi (or a peptidyl-tRNA) is bound to the P site, the mRNA codon in 30S ribosomal subunit of prokaryotes. It the A site determines which aminoacyl-tRNA will bind to that site. An aminoacyl- interferes with initiation of protein synthesis tRNA binds when its anticodon is antiparallel and complementary to the mRNA and causes misreading of mRNA. In eukaryotes, the incoming aminoacyl-tRNA first combines with elongation Although the bacterium causing his infection was sensitive to streptomycin, this drug was not used to treat Neu Moania CH3 because it can cause permanent hearing S loss. Its use is, therefore, confined mainly to the treatment of tuberculosis or other infec- CH2 tions that do not respond adequately to CH2 other antibiotics. O Formyl H C N C H group H C O The antibiotic tetracycline binds to the 30S ribosomal subunit of O prokaryotes and inhibits binding of met aminoacyl-tRNA to the A site of the ribo- tRNAf some. The initial methionine is not infection was found to be sensitive to tetra- formylated in eukaryotic protein synthesis. After step 3, step 1 is repeated using the aminoacyl-tRNA for the new codon in the A site.

Several differ- ent proteins are produced during translation of the polycistronic transcript purchase erectafil 20mg without prescription impotence with diabetes, one from each cistron (see Fig buy discount erectafil 20 mg on line impotence forum. In prokaryotes, rRNA is produced as a single, long transcript that is cleaved to produce the 16S, 23S, and 5S ribosomal RNAs. One of the cleavage enzymes, RNase P, is a protein contain- ing an RNA molecule. TRANSCRIPTION OF EUKARYOTIC GENES The process of transcription in eukaryotes is similar to that in prokaryotes. RNA polymerase binds to the transcription factor complex in the promoter region and to the DNA, the helix unwinds within a region near the startpoint of transcription, DNA strand separation occurs, synthesis of the RNA transcript is initiated, and the RNA transcript is elongated, copying the DNA template. The DNA strands separate Although each eukaryotic mRNA as the polymerase approaches and rejoin as the polymerase passes. Eukaryotes also have three polymerases, rather catalyze more than one reaction. Other differences include the facts that eukaryotic mRNA usually contains the coding information for only one polypeptide chain and that eukaryotic RNA is transcribed in the nucleus and migrates to the The terms hnRNA (heterogeneous cytoplasm where translation occurs. Synthesis of Eukaryotic mRNA to a pool of RNA molecules in the nucleus In eukaryotes, extensive processing of the primary transcript occurs before the that were rapidly synthesized and varied mature mRNA is formed and can migrate to the cytosol, where it is translated into greatly in size. These RNA molecules are now known to be the mRNA precursors that a protein product. RNA polymerase II synthesizes a large primary transcript from vary greatly in size because they contain the template strand that is capped at the 5 end as it is transcribed (Fig. The exons that encode different sizes of polypep- transcript also rapidly acquires a poly(A) tail at the 3 end. Pre-mRNAs thus con- tide chains and introns that vary in amount tain untranslated regions at both the 5 and 3’ ends (the leader and trailing and size. The product, mRNA, migrates to the cytoplasm, where it will ine) donates its methyl group, it direct protein synthesis. The coding region of the pre-mRNA, which begins with the start codon processes affected by a deficiency of these for protein synthesis and ends with the stop codon, contains both exons and vitamins. Exons consist of the nucleotide codons that dictate the amino acid sequence of the eventual protein product. Between the exons, interspersing There are three different types of regions called introns contain nucleotide sequences that are removed by splicing methyl caps, shown in blue: CAP0 reactions to form the mature RNA. The mature RNA thus contains a leader refers to the methylated guanosine (on the nitrogen at the seven position, N7) sequence (that includes the cap), a coding region comprising exons, and a tailing added in the 5 to 5 linkage to the mRNA; sequence that includes the poly(A) tail. CAP1 refers to CAP0 with the addition of a This mature mRNA complexes with the poly(A) binding protein and other methyl to the 22 carbon of ribose on the proteins. It travels through pores in the nuclear envelope into the cytoplasm. TRANSCRIPTION AND CAPPING OF mRNA donated by S-adenosylmethionine (SAM). CH (n7) CAP 0 “Capping” of the primary transcript synthesized by RNA polymerase II occurs at 3 its 5 -end as it is being transcribed (Fig. To form the cap, the terminal triphosphate loses one phosphate, forming a 5 -diphosphate. The -phosphate of the diphosphate CAP 1 then attacks the -phosphate of GTP, 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.

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