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If the enzyme that cat- alyzes this reaction is defective order viagra extra dosage 200 mg on line, or if vitamin B12 or FH4 levels are insufficient discount 130 mg viagra extra dosage with mastercard, homocysteine will accumulate. Elevated homocysteine levels have been linked to cardiovascular and neurologic disease. A vitamin B12 deficiency can be brought about by the lack of intrinsic factor, a gastric protein required for the absorption of dietary B12. A consequence of vitamin B12 deficiency is the accumulation of methyl-FH4 and a decrease in other folate derivatives. This is known as the 732 CHAPTER 40 / TETRAHYDROFOLATE, VITAMIN B12, AND S-ADENOSYLMETHIONINE 733 methyl-trap hypothesis, in which, because of the B12 deficiency, most of the The Schilling test involves the patient ingesting radioactive (Co60) carbons in the FH4 pool are trapped in the methyl-FH4 form, which is the most stable. The carbons cannot be released from the folate, because the one reaction in crystalline vitamin B12 after which a 24-hour urine sample is collected. The which they participate cannot occur because of the B12 deficiency. This will therefore radioactivity in the urine sample is com- lead to a functional folate deficiency, even though total levels of folate are nor- pared with the input radioactivity, and the mal. A folate deficiency (whether functional or actual) will lead to megaloblastic difference represents the amount of B12 anemia caused by an inability of blood cell precursors to synthesize DNA and absorbed through the digestive tract. This leads to large, partially replicated cells being released into the blood to attempt to replenish the cells that have died. Folate deficiencies Folate deficiencies frequently also have been linked to an increased incidence of neural-tube defects, such as occur in individuals with chronic spina bifida, in mothers who become pregnant while folate deficient. A number of factors are involved: inadequate dietary intake of folate; direct damage to intestinal cells and brush border enzymes, which interferes with absorption of dietary folate; a defect in the enterohepatic circulation, which reduces the absorption of folate; liver damage causing THE WAITING ROOM decreased hepatic production of plasma pro- teins; and interference with kidney resorp- After resection of the cancer in his large intestine and completion of a tion of folate. His colon was completely normal, with excellent healing at the site of Jean Ann Tonich, a bone marrow aspirate was performed. His physician expressed great optimism about a cure of Colin’s greater than normal number of red and previous malignancy but cautioned him about the need for regular colonoscopic white blood cell precursors, most of which examinations over the next few years. Bea Twelvlow, a 75-year-old woman, went to see her physician because These hematopoietic precursor cells of a numbness and tingling in her arms. A diet history indicated a normal when exposed to too little folate and/or vita- and healthy diet, but Bea was not taking any supplemental vitamin pills. Hence, the megaloblastic cells tend to B12 levels did indicate a deficiency, but the results of a Schilling test were normal. Megaloblastic erythroid progenitors are usually destroyed in the bone marrow The initial laboratory profile, determined when Jean Ann Tonich first pre- (although some reach the circulation). Thus, sented to her physician with evidence of early alcohol-induced hepatitis, marrow cellularity is often increased but pro- included a hematologic analysis that showed that Jean Ann was anemic. The average volume of her red blood cells (mean cor- anemia, characteristic of a folate or B12 defi- puscular volume, or MCV) was 108 fL (reference range 80–100), and the hema- ciency. The nuclei of the circu- ng/mL (reference range 6–15), and her lating granulocytic leukocytes had increased nuclear segmentation (polysegmented serum B12 level was 154 pg/mL (reference neutrophils). Because these findings are suggestive of a macrocytic anemia (in range 150–750). It was clear, therefore, that Jean which blood cells are larger than normal), measurements of serum folate and vita- Ann’s megaloblastic anemia was caused by min B12 (cobalamin) levels were ordered. The man- agement of a pure folate deficiency in an I. TETRAHYDROFOLATE (FH4) alcoholic patient includes cessation of alco- A. Structure and Forms of FH hol intake and a diet rich in folate. The coenzyme form that functions in accept- The abbreviation fL stands for fem- ing one-carbon groups is tetrahydrofolate polyglutamate (Fig. One fL is 10 12 milliliters referred to as tetrahydrofolate or FH4.

Long-chain fatty acids that are unsaturated fatty acids generally require addi- tional isomerization and oxidation–reduction reactions to rearrange their double bonds during -oxidation cheap viagra extra dosage 200 mg without prescription. Metabolism of water-soluble medium-chain-length fatty acids does not require carnitine and occurs only in liver discount viagra extra dosage 200mg. Odd-chain-length fatty acids undergo -oxidation to the terminal three-carbon propionyl CoA, which enters the TCA cycle as succinyl CoA. Fatty acids that do not readily undergo mitochondrial -oxidation are oxidized first by alternate routes that convert them to more suitable substrates or to urinary excretion products. Excess fatty acids may undergo microsomal -oxidation, which converts them to dicarboxylic acids that appear in urine. Very-long-chain fatty acids (both straight chain and branched fatty acids such as phytanic acid) are whittled down to size in peroxisomes. Peroxisomal - and -oxidiation generates hydrogen peroxide (H2O2), NADH, acetyl CoA, or propionyl CoA and a short- to medium-chain-length acyl CoA. The acyl CoA products are transferred to mitochondria to complete their metabolism. In the liver, much of the acetyl CoA generated from fatty acid oxidation is con- verted to the ketone bodies, acetoacetate and -hydroxybutyrate, which enter the blood (see Fig. In other tissues, these ketone bodies are converted to acetyl 418 CHAPTER 23 / OXIDATION OF FATTY ACIDS AND KETONE BODIES 419 Long-chain Fatty acid-albumin 1 Plasma Fatty acid membrane ATP binding proteins CoA 2 Fatty acyl CoA Carnatine Outer mitochondrial 3 membrane CoA Fatty acyl carnitine Inner Carnatine mitochondrial membrane CoA Fatty acyl CoA β-oxidation FAD (2H) spiral 4 NADH 5 Acetyl CoA (Liver) TCA Ketone cycle bodies 2CO2 NADH, FAD (2H), GTP Fig. Overview of mitochondrial long-chain fatty acid metabolism. The liver synthesizes ketone bodies but cannot use them as a fuel. The rate of fatty acid oxidation is linked to the rate of NADH, FAD(2H), and acetyl CoA oxidation, and, thus, to the rate of oxidative phosphorylation and ATP utilization. Additional regulation occurs through malonyl CoA, which inhibits for- mation of the fatty acyl carnitine derivatives. Fatty acids and ketone bodies are used as a fuel when their level increases in the blood, which is determined by hormonal regulation of adipose tissue lipolysis. THE WAITING ROOM Otto Shape was disappointed that he did not place in his 5-km race and has decided that short-distance running is probably not right for him. After careful consideration, he decides to train for the marathon by running 12 miles three times per week. He is now 13 pounds over his ideal weight, and he plans on losing this weight while studying for his Pharmacology finals. He considers a variety of dietary supplements to increase his endurance and selects one containing carnitine, CoQ, pantothenate, riboflavin, and creatine. Since age 14 months she has experi- enced recurrent episodes of profound fatigue associated with vomiting and increased perspiration, which required hospitalization. These episodes occurred only if she fasted for more than 8 hours. Because her mother gave her food late at night and woke her early in the morning for breakfast, Lofata’s physical and mental development had progressed normally. On the day of admission for this episode, Lofata had missed breakfast, and by noon she was extremely fatigued, nauseated, sweaty, and limp. She was unable to hold any food in her stomach and was rushed to the hospital, where an infusion of The liver transaminases measured glucose was started intravenously. Her symptoms responded dramatically to this in the blood are aspartate amino- therapy. Her blood urea nitrogen (BUN) level was slightly transaminase (SGOT), and alanine amino- transferase (ALT), which was formerly called elevated at 26 mg/dL (reference range 8–25) as a result of vomiting, which led serum glutamate pyruvate transaminase to a degree of dehydration. Her blood levels of liver transaminases were slightly ele- (SGPT). Elevation of liver enzymes reflects vated, although her liver was not palpably enlarged. Despite elevated levels of free damage of the liver plasma membrane. Di Abietes, a 27-year-old woman with type 1 diabetes mellitus, had been admitted to the hospital in a ketoacidotic coma a year ago (see Chapter 4). She had been feeling drowsy and had been vomiting for 24 hours before that admission.

The function of these cell wall exterior to the membrane order 130 mg viagra extra dosage with amex. They are prokaryotes purchase 120mg viagra extra dosage free shipping, which do not contain membranes is to collect or concentrate enzymes and other molecules serving a com- nuclei or other organelles (i. The transporters and surrounded subcellular structures) found in receptors in each membrane system control this localized environment and commu- eukaryotic cells. Nonetheless, bacteria carry nication of the cell or organelle with the surrounding milieu. Each organelle has different enzymes and carries out different gen- The Vibrio cholerae responsible for Dennis eral functions. For example, the nucleus contains the enzymes for DNA and Veere’s cholera are gram-negative bacteria. Their plasma membrane is surrounded by a Not all cells in the human are alike. Different cell types differ quantitatively thin cell wall composed of a protein–polysac- in their organelle content, or their organelles may contain vastly different charide structure called peptidoglycan and an outer membrane. In contrast, gram-positive amounts of a particular enzyme, consistent with the function of the cell. For bacteria have a plasma membrane and a thick example, liver mitochondria contain a key enzyme for synthesizing ketone bod- peptidoglycan cell wall that retains the Gram ies, but they lack a key enzyme for their use. Thus, the enzymic content of the organelles varies somewhat from cell tions, but also can grow under low oxygen type to cell type. They possess enzymes similar to those in human cells for glycolysis, the TCA cycle, and oxidative phosphorylation. PLASMA MEMBRANE have a low tolerance for acid, which partially A. Structure of the Plasma Membrane accounts for their presence in slightly basic seawater and shellfish. All mammalian cells are enclosed by a plasma membrane composed of a lipid bilayer (two layers) containing embedded proteins (Fig. The membranes The variable carbohydrate compo- are continuous and sealed so that the hydrophobic lipid bilayer selectively nents of the glycolipids on the cell restricts the exchange of polar compounds between the external fluid and the surface function as cell recognition intracellular compartment. The membrane is referred to as a fluid mosaic markers. For example, the A, B, or O blood because it consists of a mosaic of proteins and lipid molecules that can, for the groups are determined by the carbohydrate most part, move laterally in the plane of the membrane. The proteins are classi- composition of the glycolipids. Cell surface fied as integral proteins, which span the cell membrane, or peripheral proteins, glycolipids may also serve as binding sites which are attached to the membrane surface through electrostatic bonds to lipids for viruses and bacterial toxins before pene- or integral proteins. Many of the proteins and lipids on the external leaflet con- trating the cell. For example, the cholera AB tain covalently bound carbohydrate chains and therefore are glycoproteins and toxin binds to GM1-gangliosides on the sur- glycolipids. This layer of carbohydrate on the outer surface of the cell is called face of the intestinal epithelial cells. The toxin is then endocytosed in caveolae the glycocalyx. LIPIDS IN THE PLASMA MEMBRANE Each layer of the plasma membrane lipid bilayer is formed primarily by phos- One of the bacterial toxins secreted pholipids, which are arranged with their hydrophilic head groups facing the aque- by Clostridium perefringens, the ous medium and their fatty acyl tails forming a hydrophobic membrane core (see bacteria that cause gas gangrene, Fig. The principle phospholipids in the membrane are the glycerol lipids is a lipase that hydrolyzes phosphocholine phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine and the from phosphatidylcholine and from sphin- sphingolipid sphingomyelin (Fig. The resulting lysis of the cell ferent cell types, with phosphatidylcholine being the major plasma membrane lipid membrane releases intracellular contents in most cell types and sphingolipids the most variable. These bacteria are strict anaer- The lipid composition of the bilayer is asymmetric, with a higher content of phos- obes and grow only in the absence of oxy- phatidylcholine and sphingomyelin in the outer leaflet and a higher content of phos- gen. As their toxins lyse membranes in the phatidylserine and phosphatidylethanolamine in the inner leaflet. Phosphatidylserine endothelial cells of blood vessels, the capil- contains a net negative charge that contributes to the membrane potential and might be laries are destroyed, and the bacteria are important for binding positively charged molecules within the cell. Phosphatidylinosi- protected from oxygen transported by the tol, which is found only in the inner membrane, functions in the transfer of informa- red blood cells.

However 120mg viagra extra dosage otc, the effects of epinephrine-stimulated phosphorylation by pro- tein kinase A on skeletal muscle glycogen degradation and glycogen synthesis are similar to those occurring in liver (see Fig viagra extra dosage 200 mg visa. Muscle glycogen phosphorylase is a genetically distinct isoenzyme of liver glyco- gen phosphorylase and contains an amino acid sequence that has a purine nucleotide Epinephrine Nerve impulse Sarcoplasmic cAMP Ca2+ 3 reticulum 2 Ca2+ protein kinase A + ATP myosin 2+ ATPase Ca –calmodulin ADP phosphorylase adenylate kinase P Muscle kinase contraction AMP + 1 + P glycogen glycogen phosphorylase b phosphorylase a Pi Fig. Activation of muscle glycogen phosphorylase during exercise. Glycogenolysis in skeletal muscle is initiated by muscle contraction, neural impulses, and epinephrine. AMP produced from the degradation of ATP during muscular contraction allosterically activates glycogen phosphorylase b. The neural impulses that initiate contraction release Ca2 from the sarcoplasmic reticulum. The Ca2 binds to calmodulin, which is a modifier protein that activates phosphorylase kinase. Phosphorylase kinase is also activated through phospho- rylation by protein kinase A. The formation of cAMP and the resultant activation of protein kinase A are initiated by the binding of epinephrine to plasma membrane receptors. When AMP binds to this site, it changes the conformation at the cat- alytic site to a structure very similar to that in the phosphorylated enzyme (see Fig. Thus, hydrolysis of ATP to ADP and the consequent increase of AMP gen- erated by adenylate kinase during muscular contraction can directly stimulate glycogenolysis to provide fuel for the glycolytic pathway. AMP also stimulates gly- colysis by activating phosphofructokinase-1, so this one effector activates both glycogenolysis and glycolysis. The activation of the calcium/calmodulin subunit of phosphorylase kinase by the Ca2 released from the sarcoplasmic reticulum during muscle contraction also provides a direct and rapid means of stimulating glycogen degradation. CLINICAL COMMENTS Getta Carbo’s hypoglycemia illustrates the importance of glycogen stores in the neonate. At birth, the fetus must make two major adjustments in the way fuels are used: it must adapt to using a greater variety of fuels than were available in utero, and it must adjust to intermittent feeding. In utero, the fetus receives a relatively constant supply of glucose from the maternal circulation through the placenta, producing a level of glucose in the fetus that approximates 75% of maternal blood levels. With regard to the hormonal regulation of fuel uti- lization in utero, fetal tissues function in an environment dominated by insulin, which promotes growth. During the last 10 weeks of gestation, this hormonal milieu leads to glycogen formation and storage. At birth, the infant’s diet changes to one containing greater amounts of fat and lactose (galactose and glucose in equal ratio), presented at intervals rather than in a constant fashion. At the same time, the neonate’s need for glucose will be relatively larger than that of the adult because the newborn’s ratio of brain to liver weight is greater. Thus, the infant has even greater difficulty in maintaining glucose homeostasis than the adult. At the moment that the umbilical cord is clamped, the normal neonate is faced with a metabolic problem: the high insulin levels of late fetal existence must be quickly reversed to prevent hypoglycemia. This reversal is accomplished through the secretion of the counterregulatory hormones epinephrine and glucagon. Glucagon release is triggered by the normal decline of blood glucose after birth. The neural response that stimulates the release of both glucagon and epinephrine is activated by the anoxia, cord clamping, and tactile stimulation that are part of a normal delivery. These responses have been referred to as the “normal sensor function” of the neonate. Within 3 to 4 hours of birth, these counterregulatory hormones reestablish nor- mal serum glucose levels in the newborn’s blood through their glycogenolytic and gluconeogenic actions. The failure of Getta’s normal “sensor function” was partly the result of maternal malnutrition, which resulted in an inadequate deposition of glycogen in Getta’s liver before birth. The consequence was a serious degree of postnatal hypoglycemia. The ability to maintain glucose homeostasis during the first few days of life also depends on the activation of gluconeogenesis and the mobilization of fatty acids.