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Because of its impor- pyruvate levels cheap coreg 25mg on-line, PDC kinase is inhibited coreg 25 mg for sale, and PDC remains in an active buy coreg 12.5 mg cheap, nonphos- 2 tance in central nervous system metabolism buy discount coreg 6.25 mg online, phorylated form discount 12.5 mg coreg free shipping. In the heart generic 6.25mg coreg amex, 2 pyruvate dehydrogenase deficiency is a increased intramitochondrial Ca during rapid contraction activates the phos- problem in both males and females, even if phatase, thereby increasing the amount of active, nonphosphorylated PDC. For this reason, it is PDC is also regulated through inhibition by its products, acetyl CoA and NADH. This inhibition is stronger than regular product inhibition because their binding to Pi PDC inactive ADP ADP – Pyruvate – kinase phosphatase + Ca2+ Acetyl CoA + NADH + ATP Pi PDC active + – Pyruvate Acetyl CoA CoASH CO2 NAD+ NADH + – Fig. PDC kinase, a subunit of the enzyme, phosphorylates PDC at a specific serine residue, thereby converting PDC to an inactive form. PDC phosphatase, another sub- unit of the enzyme, removes the phosphate, thereby activating PDC. When the substrates, pyruvate and CoASH, are bound to PDC, the kinase activity is inhibited and PDC is active. When the products acetyl CoA and NADH bind to PDC, the kinase activity is stimulated, and the enzyme is phosphorylated to the inactive form. E1 and the kinase exist as tissue-specific isozymes with overlapping tissue specificity, and somewhat different regulatory properties. The substrates of the enzyme, CoASH and NAD , antagonize this product inhibition. Thus, when an ample supply of acetyl CoA for the TCA cycle is already available from fatty acid oxidation, acetyl CoA and NADH build up and dramatically decrease their own fur- ther synthesis by PDC. PDC can also be rapidly activated through a mechanism involving insulin, which plays a prominent role in adipocytes. In many tissues, insulin may, slowly over time, increase the amount of pyruvate dehydrogenase complex present. The rate of other fuel oxidation pathways that feed into the TCA cycle is also increased when ATP utilization increases. Insulin, other hormones and diet control the availability of fuels for these oxidative pathways. TCA CYCLE INTERMEDIATES AND ANAPLEROTIC REACTIONS A. TCA Cycle Intermediates are Precursors for Biosynthetic Pathways Pyruvate, citrate, -ketoglutarate The intermediates of the TCA cycle serve as precursors for a variety of different path- and malate, ADP, ATP, and phos- ways present in different cell types (Fig. This is particularly important in the phate (as well as many other com- central metabolic role of the liver. The TCA cycle in the liver is often called an “open pounds) have specific transporters in the cycle” because there is such a high efflux of intermediates. After a high carbohydrate inner mitochondrial membrane that trans- meal, citrate efflux and cleavage to acetyl CoA provides acetyl units for cytosolic fatty port compounds between the mitochondrial acid synthesis. During fasting, gluconeogenic precursors are converted to malate, matrix and cytosol in exchange for a com- which leaves the mitochondria for cytosolic gluconeogenesis. In contrast, CoASH, cycle intermediates to synthesize carbon skeletons of amino acids. Succinyl CoA may acetyl CoA, other CoA derivatives, NAD and NADH, and oxaloacetate, are not trans- be removed from the TCA cycle to form heme in cells of the liver and bone marrow. To In the brain, -ketoglutarate is converted to glutamate and then to -aminobutyric acid obtain cytosolic acetyl CoA, many cells (GABA), a neurotransmitter. In skeletal muscle, -ketoglutarate is converted to gluta- transport citrate to the cytosol, where it is mine, which is transported through the blood to other tissues.
Coli generic coreg 12.5mg line, under high lactose buy 25 mg coreg visa, high glucose conditions buy coreg 25 mg low price, which of the following could lead to maximal transcription activation of the lac operon? A mutation in the I (repressor) gene of a “non-inducible” strain of E generic coreg 12.5 mg on line. Which of the following provides a rational explanation? Which of the following double-stranded DNA sequences shows perfect dyad symmetry (the same sequence of bases on both strands)? Which of the following describes a common theme in the structure of DNA binding proteins? The potential uses of these techniques for the diagnosis and treatment of disease are vast purchase 25mg coreg otc. Polymorphisms coreg 25 mg free shipping, inherited differences in DNA base sequences, are abundant in the human population, and many alterations in DNA sequences are associated with diseases. Tests for DNA sequence variations are more sensitive than many other techniques (such as enzyme assays) and permit recognition of diseases at earlier and therefore potentially more treatable stages. These tests can also identify carriers of inherited diseases so they can receive appropriate counseling. Because genetic variations are so distinctive, DNA “fingerprinting” (analysis of DNA sequence differences) can be used to determine family relationships or to help identify the perpetrators of a crime. Techniques of molecular biology are used in the prevention and treatment of disease. For example, recombinant DNA techniques provide human insulin for the treatment of diabetes, Factor VIII for the treatment of hemophilia, and vaccines for the prevention of hepatitis. Although treatment of disease by gene therapy is in the experimental phase of development, the possibilities are limited only by the human imagination and, of course, by ethical considerations. To recognize normal or pathologic genetic variations, DNA must be isolated from the appropriate source, and adequate amounts must be available for study. Techniques for isolating and amplifying genes and studying and manip- ulating DNA sequences involve the use of restriction enzymes, cloning vectors, polymerase chain reaction (PCR), gel electrophoresis, blotting onto nitrocellu- lose paper, and the preparation of labeled probes that hybridize to the appropri- ate target DNA sequences. Gene therapy involves isolating normal genes and inserting them into diseased cells so that the normal genes are expressed, permit- ting the diseased cells to return to a normal state. Students must have at least a general understanding of recombinant DNA techniques to appreciate their current use and the promise they hold for the future. THE WAITING ROOM Erna Nemdy, a third-year medical student, has started working in the hos- pital blood bank two nights per week (see Chapter 15 for an introduction to Erna Nemdy and her daughter, Beverly). Because she will be handling human blood products, she must have a series of hepatitis B vaccinations. She has reservations about having these vaccinations and inquires about the efficacy and safety of the vaccines currently in use. Her growth rate has been in the lower 30th percentile over the last CFTR (cystic fibrosis transmem- year. Since birth, she has had occasional episodes of spontaneously brane conductance regulator) protein, which reversible and minor small bowel obstruction. These episodes are superimposed on is a chloride channel (see Chapter 10, Fig. In the absence of chloride secretion, as bulky, glistening, foul-smelling stools two or three times per day. She has expe- dried mucus blocks the pancreatic duct, resulting in decreased secretion of digestive rienced recurrent flare-ups of bacterial bronchitis in the last 10 months, each time enzymes into the intestinal lumen. A quantitative sweat test was unequivocally resulting malabsorption of fat and other positive (Excessive sodium and chloride were found in her sweat on two occa- foodstuffs decreases growth and may lead sions. Based on these findings, the pediatrician informed Sissy’s parents that Sissy to varying degrees of small bowel obstruc- probably has cystic fibrosis (CF). A sample of her blood was sent to a DNA testing tion. Liver and gallbladder secretions may laboratory to confirm the diagnosis and to determine specifically which one of the be similarly affected.
Such patients usu- bolic homeostasis because they continuously fluctuate in response to our daily eat- ally have sufficient insulin responsiveness to ing pattern discount coreg 6.25 mg with mastercard. They provide good examples of the basic concepts of hormonal block fatty acid release and ketone body for- regulation coreg 6.25mg generic. Certain features of the release and action of other insulin counterregula- mation 6.25mg coreg with visa, but they are unable to significantly tory hormones discount coreg 25mg on line, such as epinephrine generic coreg 25 mg mastercard, norepinephrine purchase 6.25 mg coreg visa, and cortisol, will be described stimulate glucose entry into peripheral tis- and compared with insulin and glucagon. The severely elevated levels of glucose Insulin is the major anabolic hormone that promotes the storage of nutrients: glu- in the blood compared with inside the cell leads to an osmotic effect that causes water cose storage as glycogen in liver and muscle, conversion of glucose to triacylglyc- to leave the cells and enter the blood. It also increases the synthesis of albumin hyperglycemia, the kidney produces more and other blood proteins by the liver. Insulin promotes the utilization of glucose as urine, leading to dehydration, which in turn a fuel by stimulating its transport into muscle and adipose tissue. At the same time, may lead to even higher levels of blood glu- insulin acts to inhibit fuel mobilization. If dehydration becomes severe, further Glucagon acts to maintain fuel availability in the absence of dietary glucose by cerebral dysfunction occurs and the patient stimulating the release of glucose from liver glycogen (see Chapter 28), by stimulat- may become comatose. Chronic hyper- ing gluconeogenesis from lactate, glycerol, and amino acids (see Chapter 31), and, glycemia also produces pathologic effects in conjunction with decreased insulin, by mobilizing fatty acids from adipose tria- through the nonenzymatic glycosylation of a cylglycerols to provide an alternate source of fuel (see Chapter 23 and Fig. Hemoglobin A (HbA), one of the proteins that becomes glycosy- sites of action are principally the liver and adipose tissue; it has no influence on lated, forms HbA (see Chapter 7). Ann skeletal muscle metabolism because muscle cells lack glucagon receptors. The highest levels of insulin occur approximately 30 4. They return to basal has been significantly elevated over the last levels as the blood glucose concentration falls, approximately 120 minutes after 12 to 14 weeks, the half-life of hemoglobin in the meal. The release of glucagon from the alpha cells of the pancreas, con- the bloodstream. All membrane and serum proteins Therefore, the lowest levels of glucagon occur after a high-carbohydrate meal. This process distorts protein structure and slows protein carbohydrate meal provides an integrated control of carbohydrate, fat, and degradation, which leads to an accumula- protein metabolism. Bea Selmass’s studies confirmed that her fasting serum glucose levels were These events contribute to the long-term below normal. She continued to experience the fatigue, confusion, and blurred microvascular and macrovascular complica- vision she had described on her first office visit. These symptoms are called tions of diabetes mellitus, which include dia- neuroglycopenic (neurologic symptoms resulting from an inadequate supply of glucose betic retinopathy, nephropathy, and neu- to the brain for the generation of ATP). Stimulation of the sympathetic nervous system (because of the low lev- eral artery insufficiency (macrovascular). Elevated epinephrine levels cause tachycardia, palpitations, anxiety, tremulousness, pallor, and sweating. In addition to the symptoms described by Bea Selmass, individuals may experience confusion, lightheadedness, headache, aberrant behavior, blurred vision, loss of con- sciousness, or seizures. Selmass’s doctor explained that the general diagnosis of “fasting” hypoglycemia was now established and that a specific cause for this disorder must be found. CHAPTER 26 / BASIC CONCEPTS IN THE REGULATION OF FUEL METABOLISM BY INSULIN, GLUCAGON, AND OTHER HORMONES 481 Glycogen Liver + – Protein – + Glucose + Fatty acids Amino + acids Protein VLDL + Glucose CO2 Glycogen + Fatty acids Skeletal muscle – + Triacylglycerols Adipocyte Fig 26. Insulin and glucagon are not the only regulators of fuel metabolism. The inter- tissue balance between the utilization and storage of glucose, fat, and protein is also accomplished by the circulating levels of metabolites in the blood, by neuronal sig- The message carried by glucagon nals, and by the other hormones of metabolic homeostasis (epinephrine, norepi- is that “glucose is gone”; i. These hormones oppose the actions of current supply of glucose is inade- insulin by mobilizing fuels.