DENTAL BIOCHEMISTRY BCH 812
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INTEGRATION OF METABOLISM Chapter 30 301 Metabolism consists of highly interconnected pathways N4 00 U P ATP is the universal currency of energy ATP is generated by the oxidation of fuels including glucose fatty acids and amino acids The common intermediate in most of the oxidations is acetyICoA NADPH is the major electron donor in reductive biosyntheses In most biosynthetic reactions the products are more reduced than precursors and so reductive power is needed as well as ATP Biomolecules are constructed from a relatively small set of building blocks Biosynthetic and degradative pathways are almost always distinct 3011 Recurring motif in metabolic regulation N Alosteric interactions The first irreversible reaction in a pathway the committed step is nearly always tightly controlled Enzymes catalyzing committed steps are allosterically regulated as exemplified by phosphofructokinase in glycolysis and acetyl CoA carboxylase in fatty acid synthesis Covalent modi cation Ser OH Tyr OH ADP pp Ser07i70 1 iTyr O A M P A B Guc007 Examples of reversible R 0 covalent modifications of N proteins A phosphorylation o B adenylylation and C Gluic carboxymethylation OCH C 3 Enzyme level The amount of an enzyme is controlled in addition to its activity The rates of synthesis and degradation of many regulatory enzymes are altered by hormones 4 Compartmentation Cyrosol ll Glycolysis l Pentose phosphate pathway l Fatty acid synthesis l Mimchondrialmatrix l y Citric acid cycle Oxidatlve phosphorylation H iOxidation of fattyacids l l Ketone body formation L i 1 K a In rerpia y ofborh compartments Gluconeogenesis Urea synthesis 5 Metabolic specialization of organs See below 3012 Major metabolic pathways and control sites 1 Glycolysis Main purposes are generation of ATP and carbon skeletons for biosynthesis Fructose 6 phosphate Phosphofructokinase catalyzes the committed step in glycolysis ATP Phosphofrumkinase and is the most important control point In quotvi the level of F26 BP is the important regulator When blood glucose is low ADP minimal w ATP an I imam glucagon down reQUIateS the level of F26BP to slow down glycolysis and thereby conserve glucose see section 1622 Activated by PIPIer Amlvalecl by AMP Fructose 16bisphosphate o The muscle phosphofructokinase is regulated differently so that F 26 BP increases and stimulates enzyme activity in response to epinephrine Thus glycolysis increases to provide ATP for muscle contraction o In the liver epinephrine causes glucose to be released into the blood stream by lowering the rate of glycolysis and increasing the rate of glycogen breakdown 2 Citric acid cycle Oxidation of fuel molecules carbohydrates amino acids and fatty acids in the mitochondrion Acetyl CoA 3 NAD FAD GDP Pi 2 H20 gt 2 C02 3 NADH FADH2 GTP 2 H Co A 3 NADH FADH2 gt 9 ATP 3 X 25 ATPNADH 15 ATPFADHZ Note that oxidation of NADH and FADH2 and generation of ATP only occurs if ADP is available This coupling is called respiratog control and it ensures that the rate of the citric acid cycle matches the need for ATP An abundance of ATP also diminishes the activity of two enzymes in the citric acid cycle isocitrate dehydrogenase and oc ketoglutarate dehydrogenase 3 Pentose phosphate pathway Glucose 6 phosphate o Generates two NADPH per glucose 6 NADP D G39ugg edfg zfte phosphate for reductive biosyntheses and NADPH y the formation of ribose 5 phosphate for the 6Phosphoglucon05lactone synthesis of nucleotides 0 Committed step is the dehydrogenation of H20 Lactonase glucose 6 phosphate a reaction that is controlled by the level of NADP the 6Phosphogluconate electron acceptor P I U1 9 Gluconeogenesis Liver and kidneys use noncarbohydrate precursors such as lactate glycerol and amino acids to make glucose The major entry point is pyruvate which is carboxylated to oxaloacetate in mitochondria Gluconeogenesis and glycolysis are usually P reciprocally regulated so that one pathway is quiescent while the other is highly active The box at the right shows the main Fructose 16bisphosphate H20 Fructose 16bisphosphatase Activated by citrate Inhibited by AMP Inhibited by F26BP Fructose 6phosphate components that act reciprocally Glycogen synthesis and degradation Rapidly utilized fuel store Glycogen synthase transfers glucose from UDPglucose to the terminal hydroxyl residue of a growing glycogen polymer Glycogen is degraded by a separate enzymatic pathway in which glycogen phosphorylase catalyzes the cleavage of one glucose from the polymer using orthophosphate to yield glucose 1phosphate Synthesis and degradation are coordinately controlled by a hormone triggered amplifying cascade so that the synthase is inactive when phosphorylase is active and vice versa The enzymes are regulated by phosphorylation and by noncovalent allosteric interactions 0 CoA HEAS Acetyl cm Fatty acid synthesis and degradation Synthesized In the cytosol on an acyl carrIer MONA Mm protein arbnxylase Acetyl groups are carried from the mitochondrion Aciwatedbvciuate to the cytosol by the citratemalate shuttle m db mm H r I v Citrate in the cytosol stimulates acetyl CoA Pa39m mll carboxylase the enzyme catalyzing the o committed step When ATP and acetyl CoA are 700C k W abundant the level of crtrate Increases which x 5 accelerates the rate of fatty acid synthesis Malnnvlm Carnitine transports fatty acids into mitochondria where there are degraded to acetyl CoA via the betaoxidation pathway Acetyl CoA enters the citric acid cycle ifthe supply of oxaloacetate is sufficient Alternatively acetyl CoA can give rise to ketone bodies The FADH2 and NADH formed in the beta oxidation pathway transfer their electron to 02 through the electron transport chain Like the citric acid cycle betaoxidation can continue only if NAD and FAD are regenerated Thus the rate of fatty acid degradation is also coupled to the need for ATP 3013 KEYjunctions Glucose 6phosphate pyruvate and acetyl CoA Carnitine Acyl CoA Carnitine ymanskrasel Inhibited by malonyl CoA COASH Acyl carnitine Glucose lephosphate Glycogen V Glucose 6Phospho gluconate l Ribose 5 phosphate 4 uctose 6phosphate 7 Pyruvate Made when glucose 6phosphate and ATP are abundant Made when ATP or carbon for biosynthesis are required Made when NADPH is needed for reductive biosynthesis and when ribose 5phosphate is needed to make nucleotides PYRUVATE and ACETYL CoA The oxidative decarboxylation of pyruvate inside mitochondria is a key reaction in metabolism because it moves carbon atoms of carbohydrates and amino acids to oxidation by the citric acid cycle or to the synthesis of lipids The pyruvate dehydrogenase complex which catalyzes this irreversible reaction is highly regulated by allosteric interactions and covalent modi cations Glucose 6phosphate l Alanine Oxaloacetate l V ever a Fatty 3 Hydroxy 393 Ethyl lt D39Acety GoiA acids Lactate glutary C Cholesterol Ketone CO2 bodies Note adain that mammals cannot convert acetvl CoA into pvruvate which means that lipids cannot be converted into carbohvdrates 302 Metabolic profiles of the major organs I TABLE 30 Fuel reserves in a typical 70kg man Available energy in kcal Organ Glucose or glycogen Triacylglycerols Mobilizable proteins Blood 60 250 45 200 0 0 Liver 4 1700 450 2000 400 1700 Brain 8 30 0 0 O IVluscle 1200 5000 450 2000 24000 100000 Adipose tissue 80 330 135000 560000 40 170 Source After G F Cahill Ir 31in Eridum inal Metal 51976398 1 Brain Glucose is the only source of fuel except during prolonged starvation An adult human brain consumes about 120 g glucoseday H r w W Ketone bodies acetoacetate and 3 Acemscemm hydroxyacetate see figure are generated in the liver during starvation and replace glucose as fuel forthe brain Ketone bodies are transportable equivalents of fatty acids that cannot traverse the blood brain barrier because they are bound to albumin in blood 50cc CoA CcA quotanagram Succmalc u u ch c CHz C SC0A Acemaceryl CoA rmmas Fm Cl 2 Ht r F Cm AcerICoA 2 Muscle The major fuels are glucose fatty acids and ketone bodies The large store of glucoseglycogen is the preferred fuel for bursts of activity Muscle and brain lack glucose 6 phosphatase and cannot export glucose Pyruvate gt lactate gt pyruvate gt glucose liver gt glucose muscle the Cori cycle This cycle shifts part ofthe metabolic burden of muscle to the liver Resting muscle uses fatty acids instead of glucose and heart muscle prefers ketone bodies to glucose L39VER MUSCLE GWTT 639Ph05Phate gtGucose mucosa Glycogen Gluconeogenesis ClYCOlysrs Pyruvate Pyruvate Lactate Lactate M 39 Alanine f Protein degradation 3 Adipose tissue Glucose VLDL from the liver from the liver Glucose Fatty acids 0 Fatty 3ph05phale acyl CoA Triarylglycemls Glycerol iymml to the liver Fatty at itlrallmmin Luinplkxes u the iver 4 Kidneys The major purpose of the kidney is to produce urine which serves as a vehicle for excreting metabolic waste products and for maintaining the osmolarity of body fluids The blood plasma is filtered nearly 60 times per day in the renal tubules Most ofthe material filtered out ofthe blood is reabsorbed so only 1 to 2 liters of urine is produced The kidneys require large amounts of energy to accomplish the reabsorption 5 Liver The metabolic activities of the liver are essential for providing fuel to the brain muscle and other peripheral organs To meet these demands the liver tries not to use glucose or fatty acids as fuel but instead uses keto acids derived from breakdown of amino acids Acyl CoA 7 CoA Carmtma Acvl carnitine Cvlosclic side N Acvl carnitine AcleoA CoA Camitine ll Food ll malonyl CoA low transport The liver also plays an central role in the regulation of lipid metabolism When fuel is abundant fatty acids are transferred from the liver to adipose tissue in VLDL particles But when fuels are scarce the fatty acids are converted to ketone bodies in the liver by a process that uses carnitine as a carrier How is the transport of acyl carnitine into the mitochondrial matrix controlled fatty acids go to adipose tissue Malonyl CoA inhibits the enzyme that attaches a fatty acid to carnitine ll Food ll malonyl CoA high transport fatty acids degraded in liver 303 Food intake and starvation induce metabolic changes Most of us experience a starvedfed cycle on a daily basis It is composed of three parts 1 N The wellfed or postabsorptive state This occurs after we consume and digest an evening meal Insulin is secreted from the pancreas in response to increased glucose in the blood stream t signals muscle and liverto synthesize glycogen and it accelerates glycolysis in the liver which in turn increases the synthesis of fatty acids Insulin and glucagon are the major regulators of energy metabolism The early fasting state The bloodglucose level begins to drop several hours after a meal leading to a decrease in insulin secretion and a rise in glucagon secretion from the alpha cells of the pancreas into the blood stream Just as insulin signals the fed state glucagon signals the starved state Glucagon signals the liverto breakdown glycogen and inhibit glycogen synthesis It does this via the cyclic AMP cascade leading to the phosphorylation and activation of phosphorylase and the inhibition of glycogen synthase Section 215 Glucagon also inhibits fatty acid synthesis by diminishing the production of pyruvate and by lowering the activity of acetyl CoA carboxylase Glucagon also stimulates gluconeogenesis in the liver and blocks glycolysis by lowering the level of F26BP Both muscle and liver use fatty acids as fuel when the bloodglucose level drops The blood glucose level is kept at about 80 mgdl by three factors 1the mobilization of glycogen and the release of glucose by the liver 2 the release of fatty acids by adipose tissue and 3 the shift in the fuel used from glucose to fatty acids by muscle and the liver 3031 Metabolic adaptations in prolonged starvation minimize protein degradation 1 N F b The refed state Assuming that you have a hearty breakfast the following things happen Fat is processed exactly as it is processed in the normal fed state However glucose is not The liver does not initially absorb glucose from the blood but rather leaves it for the peripheral tissues In addition the liver continues in a gluconeogenic mode so that it can replenish its glycogen stores As the bloodglucose level rises the liver completes the replenishment of glycogen and begins to process the remaining excess glucose for fatty acid synthesis The first priority of metabolism in starvation is to provide glucose to the brain and other tissues such as red blood cells that are absolutely dependent on this fuel The second priority of metabolism in starvation is to preserve protein This is accomplished by shifting the fuel being used from glucose to fatty acids and ketone bodies see box at the Plasma level lli 2 A 6 Days of starvation right 1 st day liver The dominant metabolic processes are mobilization of triacylglycerols in adipose tissue and gluconeogenesis in the liver The liver obtains energy for its own needs by oxidizing fatty acids released from adipose tissue The concentration of acetyl CoA and citrate consequently increase which turn off glycolysis 1 st day muscle The uptake of glucose by muscle is markedly diminished because of the low insulin level whereas fatty acids enter freely Consequently muscle shifts almost entirely from glucose to fatty acids for fuel In addition betaoxidation of fatty acids halts the conversion of pyruvate into acetyl CoA because acetyl CoA stimulates the phosphorylation of the pyruvate dehydrogenase complex which renders it inactive Hence pyruvate lactate and alanine are exported to the liver for conversion into glucose 5 During the first 3 days of 9 starvation some muscle protein is degraded but this slows down so that the animal can still move rapidly in order to survive This halt in protein breakdown and loss of muscle mass occurs because large amounts of acetoacetate and 3 hydroxybutyrate ketone bodies are formed by the liver This change in metabolism occurs because the citric acid cycle is unable to oxidize all the acetyl units generated by degradation of fatty acids Gluconeogenesis Synthesis Breakdown 2 mm m i Wm M i i s a fquot can Br ydroxyrsrmekhytgluuryl CoA Amouem e WW H4 mn mzrnyurnxybulyrm o 200 H Acetoaceme Succi vl DA CDA Kranslerase Succinale o o k k CoA m c 5 H mmmyl con cm males 0 r Call 2 H15 5 AKEM EDA depletes the supply of oxaloacetate which is essential forthe entry of acetyl CoA into the citric acid cycle Ketone bodies begin to supply about 13rd ofthe fuel forthe brain and also become a major fuel for the heart Several weeks of starvation Ketone bodies become the major fuel of the brain 3032 Metabolic derangements in Diabetes result from relative insulin insufficiency and glucagon excess 9 P About 1 of the population in industrialized countries have this disease Glucose is overproduced by the liver and underutilized by other organs Normally insulin acts mainly on muscle liver and adipose tissue cells to stimulate the synthesis of glycogen fats and proteins while inhibiting the breakdown ofthese fuels lnsulin also stimulates the uptake of glucose by most cells except by brain and liver cells Glucagon does pretty much the opposite of insulin There are two types of diabetes mellitus Insulindependent orjuvenileonset type I Little or no insulin is produced by the betapancreatic cells because of a genetic defect that causes the immune system to attack the pancreatic beta cells Corrected by giving patents insulin Noninsulindependent type II Accounts for over 90 of all cases of diabetes and accounts for 18 of all cases diagnosed after age 65 These patents have normal or even elevated blood insulin At least in some patients their symptoms appearto result from a lack of insulin receptors on insulinresponsive cells The exact causes of type II are not known but consuming too many calories for long periods of time is highly associated with this disease 3033 Caloric homeostasis a means of regulating body weight Obesity has become an epidemic in the United States with nearly 20 of adults classified as obese Obesity is a risk factor in diabetes mellitus hypertension and cardiovascular disease Obesity is caused by consuming more calories than are burned with excess being stored as fat in adipocytes The biochemical means by which caloric homeostasis and appetite are usually maintained is very complex and not totally understood But two important signal molecules are insulin and leptin a hormone of 146 amino acids secreted by adipocytes in direct proportion to fat mass Leptin exerts it effect by binding to a membrane receptor in the hypothalamus to generate satiation signals During periods when more energy is expended that ingested the starved state adipose tissue loses mass Under these conditions the secretion of both leptin and insulin declines fuel utilization is increased and energy stores are used The converse is true when calories are consumed in excess 304 Fuel choice during exercise is determined by intensity and duration of activity Very different fuels power sprinting and marathon running Skeletal muscle uses ATP to drive contraction but there are many sources of ATP and some can be used quickly while others cannot The table shown below indicates how rapidly the muscle can use a fuel and how much total highenergy phosphate is available During a 100meter sprint stored ATP creatine phosphate and anaerobic glycolysis of muscle glycogen are the sources of energy During a marathon run energy is produced from breakdown of glycogen and fatty acids Since breakdown of fatty acids and transformation into ATP are very slow they would limit the speed of a runner Elite marathon runners have trained their body to consume equal amounts of glycogen and fatty acids so that maximum pace can be obtained This combination of fuel consumption allows them to have just enougy glycogen to finish a race I TABLE 30 Fuel sources for muscle contraction Maximal rate of ATP Total P available 01 Fuel source production mmols mm Muscle ATP 223 lreatine phosphate 733 446 Conversion of muscle 391 7700 glycogen into lactate Conversion of muscle 167 84000 glycogen into CUT Conversion oflivcr 62 19000 glycogen into X Conversion of adipose 77 4000000 tissue fatty acids into X Note Fuels stored are estimated for a 70kg person having a muscle mass OHS kg Nnurcr After l i Hultman and R 1 Harris In Principles nf Iixcrriw e liuulienush y J R l nm39tn1ansEd Karger mm pp 7871 305 Ethanol alters energy metabolism in the liver Excess consumption of ethanol can result in a number of health problems most notably liver damage Ethanol cannot be excreted and must be metabolized There are two metabolic pathways 1 In the first pathway ethanol is converted to acetate Alcohol dehydrogenase cytosol CHscHZOH NAD gt CHsCHO NADH H Aldehyde dehydrogenase mitochondria CHsCHO NAD H20 gt CHsCOO39 NADH H Ethanol consumption thus leads to an accumulation of NADH which inhibits gluconeogenesis by preventing the oxidation of lactate to pyruvate In fact the high concentration of NADH causes the opposite reaction to predominate and lactate accumulates This may lead to hypoglycemia and lactic acidosis The high level of NADH also inhibits fatty acid oxidation and in fact signals the liver to make fatty acids Hence triacylglycerols accumulate in the liver leading to a condition known as fatty liver l The second pathway for ethanol metabolism is called the ethanolinducible microsoma ethanoloxidizing system MEOS and uses the cytochrome P450 system Section 2642 This system generates acetaldehyde which is then converted to acetate Because this system uses oxygen it generates free radicals that damage tissues and because NADPH is consumed the antioxidant glutathione cannot be regenerated exacerbating the oxidative stress EtOH 02 NADPH H gt CH30HO H20 NADP Accumulation of acetyl CoA has several consequences First ketone bodies will form and be released into the blood exacerbating the acidic conditions already resulting from the high lactate concentration The processing of the acetate in the liver becomes inefficient leading to build up of acetaldehyde This very reactive compound forms covalent bonds with 14 many important functional groups of proteins impairing protein function and damaging the liver in ways that lead to cell death In summary damage to the liver occurs in three stages Fatty liver Alcoholic hepatitis in which groups of cells die and inflammation results This stage can be fatal Cirrhosis in which fibrous structure and scar tissue are produced around dead cells The cirrhotic liver is unable to convert ammonia into urea and blood levels of ammonia rise to a point where the nervous system is toxified and coma and death can follow N4 9 The metabolic interrelationships among organs and tissues mane homes 30 co gt Glueass Um gt Kenna bodies Rum m Adlpou mm Fatty acids 2 TrilcyllJmmls Z 1 Proteins The major energy metabolism pathways summary Glucose Glycogen Triacylglycerols glucose6 mm glycogen glycogen triacylglycernl Ilium vhosphamse synlhase phnsphnrylase synthesis fggilytllgleyml lipase Fany acids Glucvswphosphate fructose16 phosphofrucmkinase bisphasphauaae glumnw Fatty acid I oxidalicn genesis glycolysis synthesis ATP 1 ATP quot059mmquot NAFDH gt NADH F pyruvate NADFH m kinase Lactate lactate dehydmgenase pyruvat carbnxyiase acetyl CuA carboxylase unosnhuenoi ruvale g camoxykinase g were bodies Kemgenic amino acids G Eequoti Z xaioacetate amino acids