Regulation of Energy Metabolism PDF

REGULATION OF ENERGY METABOLISM CREATININE CREATININE PHOSPHATE GLYCOGEN  SUB-TOPICS The brain and energy metabolism* Glucagon and insulin Creatinine phosphate Creatinine Glycogen Gluconeogenesis Fructose Fatty acids The Krebs cycles* Fermentative and aer...

REGULATION OF ENERGY METABOLISM CREATININE CREATININE PHOSPHATE GLYCOGEN  SUB-TOPICS The brain and energy metabolism* Glucagon and insulin Creatinine phosphate Creatinine Glycogen Gluconeogenesis Fructose Fatty acids The Krebs cycles* Fermentative and aerobic metabolism* *Doctor’s lessons  INTRODUCTION Creatine phosphate (CP) or PCr (Pcr) also known as phosphocreatine. It is a phosphorylated creatine molecule that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle and the brain to recycle adenosine triphosphate (ATP), the energy currency of the cell.  LEARNING OUTCOMES On successful completion of the lesson, the student will be able to: describe the chemistry of creatine phosphate; identify the function of creatine phosphate.  CHEMISTRY In the kidneys, the enzyme AGAT (Arginine:glycine amidinotransferase) catalyzes the conversion of two amino acids - arginine and glycine - into guanidinoacetate (also called glycocyamine or GAA) which is then transported in the blood to the liver. a methyl group is added to GAA from the amino acid methionine by the enzyme GAMT, forming non- phosphorylated creatine. This is then released into the blood by the liver where it travels mainly to the muscle cells (95% of the body's creatine is in muscles) and to a lesser extent the brain, heart and pancreas.  CHEMISTRY Once inside the cells it is transformed into phosphocreatine by the enzyme complex creatine kinase, which makes it able to donate its phosphate group to convert adenosine diphosphate (ADP) into adenosine triphosphate (ATP). This process is an important component of all vertebrates' bioenergetic systems. For instance, while the human body only produces 250 gm of ATP daily, it recycles its entire body weight in ATP each day through creatine phosphate.  CHEMISTRY Creatine phosphate can be broken down into creatinine, which is then excreted in the urine. A 70 kg man contains around 120 gm of creatine, with 40% being the unphosphorylated form and 60% as creatine phosphate. Of that amount, 1–2% is broken down and excreted each day as creatinine. Phosphocreatine is used intravenously in hospitals for cardiovascular problems under the name Neoton and also used by some professional athletes, as it is not a controlled substance.  FUNCTIONS Phosphocreatine can anaerobically donate a phosphate group to ADP to form ATP during the first 2 to 7 seconds following an intense muscular or neuronal effort. Conversely, excess ATP can be used during a period of low effort to convert creatine to phosphocreatine. The reversible phosphorylation of creatine (i.e., both the forward and backward reaction) is catalyzed by several creatine kinases.  FUNCTIONS The presence of creatine kinase (CK-MB, MB for muscle/brain) in blood plasma is indicative of tissue damage and is used in the diagnosis of myocardial infarction. The cell's ability to generate phosphocreatine from excess ATP during rest, as well as its use of phosphocreatine for quick regeneration of ATP during intense activity, provides a spatial and temporal buffer of ATP concentration. FUNCTIONS  SUMMARY Phosphocreatine acts as high-energy reserve in a coupled reaction. The energy given off from donating the phosphate group is used to regenerate the other compound - in this case, ATP. Phosphocreatine plays a particularly important role in tissues that have high, fluctuating energy demands such as muscle and brain.  INTRODUCTION Creatinine (Cr) is a breakdown product or waste product of creatine phosphate in muscle that is cleared from the body through the urine. It is usually produced at a fairly constant rate by the body (depending on muscle mass).  LEARNING OUTCOMES On successful completion of the lesson, the student will be able to: describe the physiology of creatinine; identify the diagnostic use of creatinine.  PHYSIOLOGY Creatinine is produced via a biological system involving creatine, creatine phosphate and adenosine triphosphate (ATP). Creatine is synthesized primarily in the liver from the methylation of glycocyamine by S-Adenosyl methionine. It is then transported through blood to the other organs, muscle, and brain, where, through phosphorylation, it becomes the high-energy compound creatine phosphate. Creatinine is a breakdown product of creatine phosphate in muscle. PHYSIOLOGY  PHYSIOLOGY Creatinine is removed from the blood chiefly by the kidneys, primarily by glomerular filtration. Little or no tubular reabsorption of creatinine occurs. If the filtration in the kidney is deficient, blood creatinine concentrations rise.  PHYSIOLOGY Therefore, creatinine concentrations in blood and urine may be used to calculate the creatinine clearance (CrCl), which correlates approximately with the glomerular filtration rate (GFR). Blood creatinine concentrations may also be used alone to calculate the estimated GFR (eGFR). The GFR is clinically important because it is a measurement of renal function.  PHYSIOLOGY Each day, 1% to 2% of muscle creatine is converted to creatinine. The conversion is nonenzymatic and irreversible. Men tend to have higher concentrations of creatinine than women because, in general, they have a greater mass of skeletal muscle. Increased dietary intake of creatine or eating a lot of protein (like meat) can increase daily creatinine excretion.  DIAGNOSTIC USE Serum creatinine is the most commonly used indicator (but not direct measure) of renal function. Elevated creatinine is not always representative of a true reduction in GFR. A high reading may be due to increased production of creatinine not due to decreased kidney function, to interference with the assay, or to decreased tubular secretion of creatinine.  DIAGNOSTIC USE Urine creatinine In normal circumstances, all this daily creatinine production is excreted in the urine. Creatinine concentration is checked during standard urine drug tests. SUMMARY  INTRODUCTION Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one of two forms of long-term energy reserves, with the other form being triglyceride stores in adipose tissue (i.e., body fat).  LEARNING OUTCOMES On successful completion of the lesson, the student will be able to: describe the structure of glycogen; identify the function of glycogen; explain the metabolism of glycogen.  STRUCTURE Glycogen is a branched biopolymer consisting of linear chains of glucose residues with an average chain length of approximately 8–12 glucose units. Glucose units are linked together linearly by α(1→4) glycosidic bonds from one glucose to the next. Branches are linked to the chains from which they are branching off by α(1→6) glycosidic bonds between the first glucose of the new branch and a glucose on the stem chain. Due to the way glycogen is synthesized, every glycogen granule has at its core a glycogenin protein. STRUCTURE (CONT.)  STRUCTURE (CONT.) Glycogen in muscle, liver and fat cells is stored in a hydrated form, composed of three or four parts of water per part of glycogen associated with 0.45 millimoles (18 mg) of potassium per gram of glycogen. Glucose is an osmotic molecule and can have profound effects on osmotic pressure in high concentrations possibly leading to cell damage or death if stored in the cell without being modified. Glycogen is a non-osmotic molecule, so it can be used as a solution to storing glucose in the cell without disrupting osmotic pressure. STRUCTURE  FUNCTIONS Liver As a meal containing carbohydrates or protein is eaten and digested, blood glucose levels rise and the pancreas secretes insulin. Blood glucose from the portal vein enters liver cells (hepatocytes). Insulin acts on the hepatocytes to stimulate the action of several enzymes, including glycogen synthase. Glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases.  FUNCTIONS Liver (cont.) After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced and glycogen synthesis stops. When it is needed for energy, glycogen is broken down and converted again to glucose. Glycogen phosphorylase is the primary enzyme of glycogen breakdown. For the next 8–12 hours, glucose derived from liver glycogen is the primary source of blood glucose used by the rest of the body for fuel.  FUNCTIONS Liver (cont.) Glucagon, another hormone produced by the pancreas, serves as a countersignal to insulin. In response to insulin levels being below normal (when blood levels of glucose begin to fall below the normal range), glucagon is secreted in increasing amounts and stimulates both glycogenolysis (the breakdown of glycogen) and gluconeogenesis (the production of glucose from other sources).  FUNCTIONS Muscle Muscle cell glycogen appears to function as an immediate reserve source of available glucose for muscle cells. As muscle cells lack glucose-6-phosphatase, which is required to pass glucose into the blood, the glycogen they store is available solely for internal use and is not shared with other cells. This is in contrast to liver cells, which, on demand, readily do break down their stored glycogen into glucose and send it through the blood stream as fuel for other organs.  METABOLISM Glycogen degradation consists of three steps: 1) the release of glucose 1-phosphate from glycogen 2) the remodeling of the glycogen substrate to permit further degradation 3) the conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism The glucose 6-phosphate derived from the breakdown of glycogen has three fates: 1) it is the initial substrate for glycolysis 2) it can be processed by the pentose phosphate pathway to yield NADPH and ribose derivatives 3) it can be converted into free glucose for release into the bloodstream (This conversion takes place mainly in the liver and to a lesser extent in the intestines and kidneys.) METABOLISM Glucose 6-phosphate derived from glycogen can 1) be used as a fuel for anaerobic or aerobic metabolism as in, for instance, muscle 2) be converted into free glucose in the liver and subsequently released into the blood 3) be processed by the pentose phosphate pathway to generate NADPH or ribose in a variety of tissues. NADPH is a cofactor, used to donate electrons and a hydrogens to reactions catalyzed by some enzymes.  METABOLISM Glycogen synthesis requires an activated form of glucose, uridine diphosphate glucose (UDP-glucose), which is formed by the reaction of UTP and glucose 1-phosphate. UDP-glucose is added to the nonreducing end of glycogen molecules. As is the case for glycogen degradation, the glycogen molecule must be remodeled for continued synthesis.  METABOLISM The regulation of these processes is quite complex. Several enzymes taking part in glycogen metabolism allosterically respond to metabolites that signal the energy needs of the cell. These allosteric responses allow the adjustment of enzyme activity to meet the needs of the cell in which the enzymes are expressed.  METABOLISM Glycogen metabolism is also regulated by hormonally stimulated cascades that lead to the reversible phosphorylation of enzymes, which alters their kinetic properties. Regulation by hormones allows glygogen metabolism to adjust to the needs of the entire organism. By both these mechanisms, glycogen degradation is integrated with glycogen synthesis. METABOLISM  SUMMARY Approximately 4 grams of glucose are present in the blood of humans at all times. In fasted individuals, blood glucose is maintained constant at this level at the expense of glycogen stores in the liver and skeletal muscle. Liver glycogen stores serve as a store of glucose for use throughout the body, particularly the central nervous system. Glycogen stores in skeletal muscle serve as a form of energy storage for the muscle itself; however, the breakdown of muscle glycogen impedes muscle glucose uptake, thereby increasing the amount of blood glucose available for use in other tissues.