What is McArdle disease can be caused by a problem with the metabolism of which particular compound. and explain in detail?
We will illustrate, in addition, how biochemical measurements can pinpoint a disorder and allow one to determine which enzyme is functioning improperly.a. Mouth(1). Salivary glands produce a-amylase, which cleaves a-1,4 bonds between glucose residues in dietary starch. (Pancreatic a-amylase catalyzes the same reaction.)b. Stomach(1). Chief cells produce the proteolytic enzyme pepsin, as its inactive precursor pepsinogen. Pepsin digests proteins.(2). Parietal cells produce hydrochloric acid (HCl) and intrinsic factor.(a). HCl causes pepsinogen (the precursor of pepsin) to cleave itself (autocatalysis), producing pepsin.(b). Intrinsic factor binds dietary vitamin B12 and aids in its absorption.(c). Vitamin B12 is the cofactor for the conversion of homocysteine to methionine and methyl malonyl-CoA to succinyl-CoAc. Gallbladder(1). Bile salts, synthesized in the liver from cholesterol, pass through the gallbladder into the intestine, where they aid in lipid digestion.(2). Bilirubin diglucuronide, produced in the liver from bilirubin (the excretory product of heme degradation), passes through the gallbladder into the intestine.d. Pancreas(1). The pancreas produces bicarbonate (HCO3- ), which neutralizes stomach acid as it enters the intestinal lumen. The subsequent increase in pH in the lumen allows more extensive ionization of bile salts (so they serve as better detergents) and increases the activity of digestive enzymes.(2). The pancreas produces digestive enzymes (e.g., trypsin, chymotrypsin, the carboxypeptidases, elastase, a-amylase, lipase).(3). The B (or b) cells of the endocrine pancreas produce insulin (the hormone that stimulates the storage of fuels in the fed state) and the A (or a) cells produce glucagon (the hormone that stimulates the release of stored fuels during fasting).e. Intestine(1). The enzymes from the exocrine pancreas digest food in the intestinal lumen.(2). The intestinal digestive enzymes are bound to the brush borders of intestinal epithelial cells (aminopeptidases, dipeptidases and tripeptidases, lactase, sucrase, maltases, and isomaltases).(3). The absorption of digestive products occurs through the intestinal epithelial cells.(4). The intestinal epithelial cells produce chylomicrons from the digestive products of dietary fat (fatty acids and 2-monoacylglycerols) and secrete the chylomicrons into the lymph.(5). Most bile salts are resorbed in the ileum and recycled by the liver. Only 5% are excreted in the feces. This excretion of bile salts, along with cholesterol secreted by the liver into the gut via the gallbladder, is the major means by which the body disposes of the cholesterol ring structure (sterol nucleus).f. Liver (the enzymic regulation of liver function is summarized in Tables below)(1). Functions of the liver include:(a). Storage of glycogen produced from dietary carbohydrate.(b). Synthesis of very low-density lipoprotein (VLDL), mainly from dietary carbohydrate.(c). Production of high-density lipoprotein, which transfers CII and E apolipoproteins to chylomicrons and VLDL, converts cholesterol to cholesterol esters (via the lecithin-cholesterol acyltransferase reaction), and reduces blood by which cholesterol and cholesterol esters are transported from tissues to the liver (reverse cholesterol transport).(d). Maintenance of blood glucose levels during fasting via glycogenolysis and gluconeogenesis.(e). Production of urea from nitrogen derived, in part, from amino acids because they are being converted to glucose (via gluconeogenesis) during fasting.(f). Production of ketone bodies from fatty acids derived from lipolysis of adipose triacylglycerols during fasting.(g). Synthesis of cholesterol (which is also made in other tissues).(h). Conversion of cholesterol to bile salts.(i). Production of many blood proteins (e.g., albumin, blood-clotting proteins).(j). Production of purines and pyrimidines, which are transported to other tissues via red blood cells.(k). Degradation of purines (to uric acid) and pyrimidines (to CO2 , H2 O, and ammonia).(l). Oxidation of drugs and other toxic compounds via the cytochrome P450 system.(m). Conjugation of bilirubin and excretion of bilirubin diglucuronide into the bile.(n). Oxidation of alcohol via alcohol and acetaldehyde dehydrogenases and the microsomal ethanol-oxidizing system (MEOS).(o). Synthesis of creatine (from guanidinoacetate), which is used to produce creatine phosphate, mainly in the muscle and brain.(p). Conversion of dietary fructose to glycolytic intermediates.(2). If liver cell function is compromised (e.g., in viral hepatitis or alcoholic cirrhosis):(a). NH4+ , which is toxic (particularly to the central nervous system), increases in the blood.(b). The BUN level decreases because the liver has a decreased capacity to produce urea.(c). Blood glucose decreases because of decreased glycogenolysis and gluconeogenesis.(d). Blood cholesterol levels decrease owing to an inability to produce and secrete VLDL.(e). The production of bile salts decreases.(f). Bilirubin levels increase in the body (causing jaundice) because of reduced conjugation with glucuronic acid.(g). Lysis of damaged liver cells allows enzymes to leak into the blood.1. Lactate dehydrogenase increases.2. Alanine aminotransferase increases.3. Aspartate aminotransferase increases.4. Alkaline phosphatase increases.(h). Chronic liver problems result in decreased protein synthesis.1. Serum proteins (e.g., albumin) decrease.2. VLDL production decreases because of decreased apolipoprotein B-100 and triacylglycerols accumulate in the liver. A fatty liver results.g. Brain(1). Glucose is the major fuel for the brain.(2). The brain can use ketone bodies, but only after 3 to 5 days of fasting when blood ketone body levels are elevated.(3). The brain needs energy to think (i.e., memory involves RNA synthesis), conduct nerve impulses, synthesize neurotransmitters, and so on.h. Red blood cells(1). Red blood cells lack mitochondria, so they have no TCA cycle, b-oxidation of fatty acids, electron transport chain, and other pathways that occur in the mitochondria.(2). Glucose is the major fuel for red blood cells.(a). Glucose is converted to pyruvate and lactate.(3). Red blood cells carry bases and nucleosides from the liver to other tissues.(4). The major function of red blood cells is to carry O2 from the lungs to the tissues and to aid in the return of CO2 from the tissues to the lungs.i. Adipose tissue(1). The major fuel of adipose tissue is glucose.(2). Insulin stimulates the transport of glucose into adipose cells.(3). The function of adipose tissue is to store triacylglycerol in the fed state and release it (via lipolysis) during fasting.(a). In the fed state, insulin stimulates the synthesis and secretion of lipoprotein lipase (LPL), which degrades the triacylglycerols of chylomicrons and VLDL in the capillaries. Fatty acids from these lipoproteins enter adipose cells and are converted to triacylglycerols and stored. Glucose provides the glycerol moiety. (Glycerol is not used because adipose cells lack glycerol kinase.)(b). During fasting, adipocyte triglyceride lipase and hormone-sensitive lipase (phosphorylated and activated via a cAMP-mediated mechanism) initiate lipolysis in adipose cells.j. Muscle(1). Muscle uses all fuels that are available (glycogen stores, and fatty acids, glucose, ketone bodies, lactate, and amino acids from the blood) to obtain energy for contraction.(2). During fasting, muscle protein is degraded to provide amino acids (particularly alanine) for gluconeogenesis.(3). Creatine phosphate transports high-energy phosphate from the mitochondria to actinomyosin fibers and provides ATP for muscle contraction.(4). Creatinine is produced nonenzymatically from creatine phosphate, and a constant amount (dependent on the body muscle mass) is released into the blood each day and excreted by the kidneys.(5). Muscle glycogen phosphorylase differs from liver phosphorylase but catalyzes the same reaction (glycogen+Pi-glucose-1-phosphate).(6). Insulin stimulates the transport of glucose into muscle cells.k. Heart(1). The heart is a specialized muscle that uses all fuels from the blood.(2). The muscle-brain (MB) isozyme of CK is found in heart muscle. Its release can be used to monitor a heart attackl. Kidney(1). The kidney excretes substances from the body via the urine, including urea (produced by the urea cycle in the liver), uric acid (from purine degradation), creatinine (from creatine phosphate), NH4+ (from glutamine via glutaminase), H2SO4 (produced from the sulfur of cysteine and methionine), and phosphoric acid.(2). Daily creatinine excretion is constant and depends on the body muscle mass. It is used as a measure of kidney function (the creatinine-clearance rate).(3). Glutaminase action increases during acidosis and produces NH3 , which enters the urine and reacts with H+ to form NH4+ . NH4+ buffers the urine and removes acid (H+) from the body.(4). Uric acid excretion is inhibited by lead (Pb) and metabolic acids (ketone bodies and lactic acid). High blood uric acid can result in gout. Gout can be caused either by increased production or by decreased excretion of uric acid. Deficiency of the base salvage enzyme hypoxanthine guanine phosphoribosyl transferase in Lesch-Nyhan syndrome results in increased production of uric acid.(5). Kidney dysfunction can lead to increased BUN, creatinine, and uric acid in the blood and decreased levels of these compounds in the urine.(6). During ketoacidosis, ketone bodies are excreted by the kidney, and during lactic acidosis, lactic acid is excreted.(7). Elevated blood glucose levels (over 180 mg/dL) in DM results in the excretion of glucose in the urine.McArdle disease is caused by a defective muscle glycogen phosphorylase, such that the muscle cannot generate glucose from glycogen, leading to exercise intolerance. Glycogen accumulates in the muscle because of this enzyme deficiency (McArdle disease is one of the glycogen storage disease). A defect in the synthesis or processing of collagen will lead to a variety of diseases, of which Ehlers-Danlos syndrome is one (osteogenesis imperfecta is another). Parkinson disease is caused by low levels of dopamine in the nervous system. In the initial stages of Parkinson disease, giving DOPA can reduce the severity of the symptoms because DOPA can be decarboxylated to form dopamine. DOPA can easily enter the brain, whereas dopamine cannot. Tay-Sachs disease results from an inability to degrade GM2, a ganglioside (it is also a sphingolipid). The enzyme missing is b-hexosaminidase. Maple syrup urine disease is caused by the lack of branched-chain a-keto acid dehydrogenase activity, a necessary step in the metabolism of the branched-chain amino acids (leucine, isoleucine, and valine).When Blood Sugar Increases:When Blood Sugar Decreases:Insulin is released, which leads to the dephosphorylation of:Glucagon is released, which leads to the phosphorylation of:PFK-2 (kinase activity now active)PFK-2 (phosphatase activity now active)Pyruvate kinase (now active)Pyruvate kinase (now inactive)Glycogen synthase (now active)Glycogen synthase (now inactive)Phosphorylase kinase (now inactive)Phosphorylase kinase (now active)Glycogen phosphorylase (now inactive)Glycogen phosphorylase (now active)Pyruvate dehydrogenase (now active)Pyruvate dehydrogenase (now inactive)Acetyl-CoA carboxylase (now active)Acetyl-CoA carboxylase (now inactive)Which leads to activeGlycolysis GlycogenolysisFatty acid synthesisFatty acid oxidationGlycogen synthesisGluconeogenesis Liver Enzymes Regulated by Activation/InhibitionEnzymeActivated byState in Which ActivePhosphofructokinase 1Fructose 2,6-bisP, AMPFedPyruvate carboxylaseAcetyl-CoAFed and fastingAcetyl-CoA carboxylaseCitrateFedCarnitine palmitoyltransferase ILoss of inhibitor (malonyl-CoA)FastingLiver Enzymes Regulated by Phosphorylation/DephosphorylationEnzymeActive formState in Which ActiveGlycogen synthaseDephosphorylatedFedPhosphorylase kinasePhosphorylatedFastingGlycogen phosphorylasePhosphorylatedFastingPhosphofructokinase- 2/fructose 2,6-bisphosphatase (acts as a kinase, increasing fructose2,6-bisP levels)DephosphorylatedFedPhosphofructokinase-2/fructose 2,6-bisphosphatase (acts as aphosphatase, decreasing fructose 2,6-bisP levels)PhosphorylatedFastingPyruvate kinaseDephosphorylatedFedPyruvate dehydrogenaseDephosphorylatedFed