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    Chapter(5) :AAs Metabolism Oamnino acids degradation(catabolism) sees ELE ENERCYan METABOLISM enzymes y > Amino acid oxidation and the METABOLISM production of urea iiiienieneaiiadinaie «ln mammals, amino acids undergo oxidative degradation in three different metabolic circumstances: 1. During the normal synthesis and degradation of cellular proteins (protein turnover) some amino acids that are released from protein breakdown and are not needed for new protein synthesis. undergo oxidative degradation 2. When a diet is rich in protein and the ingested amino acids exceed the body's needs for protein synthesis, the surplus is catabolized; amino acids cannot be stored. 3. During starvation or in uncontrolled diabetes mellitus, when carbohydrates are either unavailable or not properly utilized, cellular proteins are used as fuel. ‘Under all these metabolic conditions, amino acids lose their amino groups to form a-keto acids, the “carbon skeletons” of amino acids. The a -keto acids undergo oxidation to CO, and H,0 or, often more importantly, provide three- and four-carbon units that can be converted by gluconeogenesis into glucose, the fuel for brain, skeletal muscle, and other tissues. Imac protein sins ie ea rome," is on Scot cyano ole scoot a Oe® = Oxalate eee METABOLISM NITROGEN METABOLISM * Amino acid catabolism is part of the larger process of the metabolism of nitrogen Containing molecules. Nitrogen enters the body in a variety of compounds present in food, the most important being amino acids contained in dietary protein. Nitrogen leaves the body as urea, ammonia, and other products derived from amino acid metabolism. The role of body proteins in these transformations involves two important concepts: the amino acid pool and protein turnover. Free amino acids are present throughout the body, such as in cells, blood, and the extracellular fluids. ‘Synthesis of new proteins 300-400g/day all of these amino acids as if they belonged to a ores single entity, called the amino acid pool. This pool Syrthesisor en is supplied by three sources: nonessertol thyroid ae pose @ amino acids provided by the degradation of endogenous Perini) (body) proteins, most of which are reutlized Degradation ofl] Gapoismin | _—teatine iii rent | @ amino acids derived from exogenous (dietary) protein; and — @ronessential amino acids synthesized from simple intermediates C= of metabolism G3 *Conversely, the amino pool is depleted by three routes: © synthesis of body protein @consumption of amino acids as precursors of essential nitrogen-containing small molecules @ conversion of amino acids to glucose, glycogen, fatty acids, and ketone bodies, or oxidation to CO, +H,0. Although the amino acid pool is small (comprising about 90-100 g of amino acids) in comparison with the amount of protein in the body (about 12kg in a 70-kg man), it is conceptually at the center of whole-body nitrogen metabolism. NOTE: In healthy, well-fed individuals, the input to the amino acid pool is balanced by the output. That is, the amount of ‘amino acids contained in the pool is constant. The amino acid pool is said to be in a steady state, and the individual is said to be in nitrogen balance. Protein turnover protein ‘Most proteins in the body are constantly being synthesized and then degraded, permitting the removal of abnormal or unneeded proteins.For many proteins, regulation of synthesis determines the / \ concentration of protein in the cell, with protein degradation assuming a minor role. For other proteins, the rate of synthesis is constitutive (that is, essentially constant), and cellular levels of the protein protein protein are controlled by selective degradation, degradation synthesis Removal of nitrogen from METABOLISM amino acids ll ‘The presence of the a-amino group keeps amino acids safely locked away from oxidative breakdown. Removing the a-amino group is essential for producing energy from any amino acid and is an obligatory step in the catabolism of all amino acids. Once removed, this nitrogen can be incorporated into other compounds or excreted as urea, with the carbon skeletons being metabolized. 1.The Transfer of a-Amino Groups to a-Ketoglutarate Sees ee 00" I aie Ha Ha coo" - aKetoglutarate Glutamate '* This transfer of amino groups from one carbon skeleton to another is catalyzed by a family of enzymes called aminotransferases (also called transaminases). These enzymes are found in the cytosol and mitochondria of cells throughout the body. All amino acids, with the exception of lysine and threonine, Participate in transamination at some point in their catabolism. R Rk LAmino acid a-Keto acid [Note: Lys and Thr lose their a-amino groups by deamination | aminotransferases METABOLISM ‘* Each aminotransferase is specific for one or, at most, a few amino group donors. Aminotransferases are named after the specific amino group donor, because the acceptor of the amino group is almost always a ketoglutarate. ‘Two important aminotransferase reactions are catalyzed by .. @ alanine aminotransferase (ALT) formally called glutamate pyruvate transferase. @ aspartate aminotransferase (AST) formally called glutamate oxaloacetate transferase. LY Aianine aminotransferase | |G) Aspartate aminotransferase imi ellogtania Oraloacetate lutamate «All aminotransferases require the coenzyme pyridoxal phosphate pLp (a derivative of vitamin B,). which is covalently linked to the e-amino group of a specific lysine residue at the active site of the enzyme. Aminotransferases act by transferring the ‘amino group of an amino acid to the pyridoxal part of the coenzyme to generate pyridoxamine phosphate. The pyridoxamine form of the coenzyme then reacts with an a-keto acid to form an amino acid, at the same time regenerating the original aldehyde form of the coenzyme. METABOLISM Diagnostic value of plasma aminotransferases ai ‘*Aminotrans-ferases are normally intracellular enzymes, with the low levels found in the plasma representing the release of cellular contents during normal cell turnover. Elevated plasma levels of aminotransferases indicate damage to cells rich in these enzymes. Two aminotransferases, AST and ALT, are of particular diagnostic value when they are found in the plasma. co) oe | Plasma AST and ALT are elevated in nearly all liver diseases but are particularly high in conditions that cause extensive cell necrosis, such as Liver severe viral hepatitis, toxic injury, and prolonged circulatory collapse. ALT Enzymes is more specific than AST for liver disease, but the latter is more sensitive Zy' because the liver contains larger amounts of AST. Serial measurements of t= at AST and ALT(so-called “liver function tests”) are often useful in Kl determining the course of liver damage. * Aminotransferases may be elevated in nonhepatic diseases such as those that cause damage to cardiac or skeletal muscle. these disorders can usually be distinguished clinically from liver disease. Oxidative deamination of amino acids METABOLISM ‘* the amino groups from many of the a-amino acids are collected in the liver in the form of the amino group of 4 te L-glutamate molecules. These amino groups must next “ a be removed from glutamate to prepare them for excretion. — —| ‘In hepatocytes, glutamate is transported from the cytosol as into mitochondria, where it undergoes oxidative a deamination catalyzed by L-glutamate dehydrogenase. ‘* Glutamate is unique in that it is the only amino acid that undergoes rapid oxidative deamination, a reaction catalyzed by glutamate dehydrogenase ae ‘In mammals, this enzyme is present in the mitochondrial matrix. It is the only enzyme that can use either NAD* or NADP? as the acceptor of reducing Equivalents (as a < coenzyme). cytosol “ee ‘The combined action of an aminotransferase and glutamate dehydrogenase is referred to as transdeamination. nespineouc bor [NOTE:Guanosine triphosphate (GTP) is an allosteric inhibitor of glutamate dehydrogenase, whereas adenosine diphosphate (ADP) is an activator. Therefore, when energy levels are low in the cell, amino acid degradation by glutamate dehydrogenase is high, facilitating eneray production from the carbon skeletons derived from amino acids D-Amino acid oxidase ‘* D-Amino acids are found in plants and in the cell walls of microorganisms, but are not used in the synthesis of mammalian proteins. D-Amino acids are, however, present in the diet, and are efficiently metabolized by the liver. D-Amino acid oxidase is an FAD-dependent enzyme that catalyzes the oxidative deamination of these amino acid isomers, The resulting a-ketoacids can enter the general pathways of amino acid metabolism, and be reaminated to Lisomers, or catabalized for energy. INOTE:Camnvores can obiain immediately folowing @ meal) up fo 90% of thor energy requirements from amino acid oxida, whreas herbivores may fll only 2 smal faction oftheir energy needs by his route] VSo2/ese Mirror @ @ L-a-amino acid o D-a-amino acid Transport of ammonia to the liver ‘*Two mechanisms are available in humans for the transport of ammonia from the peripheral tissues to the liver for its ultimate conversion to urea. @The first, found in most tissues, uses Glutamine synthetase to Combine ammonia with glutamate to form glutamine, a nontoxic transport form of ammonia. The glutamine is transported in the blood to the liver where is cleaved by glutaminase to produce glutamate and free ammonia. METABOLISM @ The second transport mechanism, used primarily by muscle and certain other tissues that degrade amino acids for fuel, amino groups are collected in the form of glutamate by transamination . ‘Glutamate can be converted to glutamine for transport to the liver, or it can transfer its -amino group to pyruvate, (the end- product of muscle glyclosysis) ,by the action of alanine — aminotransferase. The alanine so formed passes into the blood and travels to the liver. In the cytosol of hepatocytes, alanine aminotransferase transfers the amino group from alanine to a-ketoglutarate, Forming pyruvate and glutamate. Glutamate In the cytosol of hepatocytes can then enter mitochondria, where the glutamate dehydrogenase reaction releases NH,*, or can undergo transamination with oxaloacetate to form aspartate, another nitrogen donor in urea synthesis (urea cycle). ba Most tissue aaa Sees] i uver Beas Atatanoes 22 muscte ¥ ‘Biante 2s we * 1 ilne Byron oe BAI succingt Gon Bains ae UREA CYCLE METABOLISM ‘*Urea is the major disposal form of amino groups derived from amino acids and accounts for about 90% of the nitrogen-containing components of urine. '* The first two reactions leading to the synthesis of urea occur in the mitochondrial matrix, whereas the remaining cycle enzymes are located in the cytosol. ‘*0ne nitrogen of the urea molecule is supplied by free ammonia and the other nitrogen by aspartate. [Note: Glutamate isthe immediate precursor of both ammonia (through oxidative deamination by glutamate dehydrogenase) and aspartate nitrogen (through transamination of oxaloacetate by ast).] ‘The carbon and oxygen of urea are derived from CO, (as HCO*).Urea is produced by the liver and. then is transported in the blood to the kidneys for excretion in the urine. ‘The arginine formed by this cycle serves as the immediate precursor of urea. '* Arginase hydrolyzes arginine to ornithine and urea and Is virtually exclusive to the liver. Therefore, only the liver can cleave arginine, thereby synthesizing urea, whereas other tissues, such as the kidney, can synthesize arginine by these reactions. ‘*Formation of urea in the liver is quantitatively the most important disposal route for ammonia. Urea travels in the blood from the liver to the kidneys, where it passes into the glomerular filtrate. METABOLISM, ‘*Urea diffuses from the liver, and is transported in the blood to the kidneys, where itis filtered and excreted in the urine eee A portion of the urea diffuses from the blood into the intestine and is eters anaes cleaved to CO, and NH; by bacterial urease. This ammonia is partly lost in the feces and is partly reabsorbed into the blood. In patients with kidney failure, plasma urea levels are elevated, promoting a greater transfer of urea from blood into the gut.The intestinal action of urease on this urea | DIET becomes a clinically important source of ammonia, contributing to the eee hyperammonemia often seen in these patients. Oral administration of antibiotics reduces the number of intestinal bacteria responsible for this | ciutamate + ATP NH; production. ‘e-Amino acid “GeKetogiutarate NADUP)H Sintnerase rea apr +P; The capacity of the hepatic urea cycle exceeds the normal rates of ee ammonia generation, and the levels of serum ammonia are normally low (5-35 pmol/l). However, when liver function is compromised, due either to HO Glutamate genetic defects of the urea cycle or liver disease, blood levels can rise é 1 above 1,000 pmol/|. Such hyperammonemia is a medical emergency, because ammonia as a direct neurotoxic effect on the CNS. For example, x elevated concentrations of ammonia in the blood cause the symptoms of ammonia intoxication, which include tremors, slurring of speech, somnolence (drowsiness), vomiting, cerebral edema, and blurring of vision. At high concentrations, ammonia can cause coma and death. There are two major types of hyperammonemia. Urea Urea cycle carbon skeletons degradation of AAs The catabolism of the amino acids involves the removal of a sees a-amino groups, followed by the degradation of the resulting : carbon skeletons. These pathways converge to form seven intermediate products: oxaloacetate, pyruvate, a-ketoglutarate, fumarate, succinyl coenzyme A (CoA), acetyl CoA, and acetoacetate. These products directly enter the pathways of intermediary metabolism,resulting either in the synthesis of glucose or lipid or in the production of energy through their oxidation to CO, by the tricarboxylic acid (TCA) cycle. * Amino acids can be classified as glucogenic, ketogenic, or both, based on which of the seven intermediates are produced during their catabolism a Glucogenic amino acids Sagas ‘* Amino acids whose catabolism yields pyruvate or one of the intermediates of the Phase a frome TCA cycle are termed glucogenic. These intermediates are substrates for gluconeogenesis and, therefore, can give rise to the net synthesis of glucose in the liver and kidney. ce Ketogenic amino acids 3) cine 3 | cucamne ‘+ Amino acids whose catabolism yields either acetoacetate or one of its precursors |2) meine (acetyl CoA or acetoacetyl CoA) are termed ketogenic. Acetoacetate is one of the ign ketone bodies, which also include 3-hydroxybutyrate and acetone . Leucine and fg lysine are the only exclusively ketogenic amino acids found in proteins. Their ||shcserine |eerge™ | Scie” carbon skeletons are not substrates for gluconeogenesis and, therefore, cannot 8) isa" [inyotcrnn give rise to the net synthesis of glucose. A. Amino acids that form oxaloacetate > '* Asparagine is hydrolyzed by asparaginase, liberating ammonium (NH,*) and aspartate. Aspartate loses its amino group by transamination to form oxaloacetate. [Note: Some rapidly dividing leukemic cells are unable to synthesize sufficient asparagine to support their growth. This makes asparagine an essential amino acid for these cells, which, therefore, require asparagine from the blood. Asparaginase, which hydrolyzes asparagine to aspartate, can be administered systemically to treat leukemic patients. Asparaginase lowers the level of asparagine in the plasma, thereby depriving cancer cells of a required nutrient.) katoahearate B. Amino acids that form a-ketoglutarate via glutamate > amt tutsmate goo" 1, Glutamine: This amino acid is hydrolyzed to glutamate and ammonium by the oe enzyme glutaminase Glutamate is converted to a-ketoglutarate by transamination b00: or through oxidative deamination by glutamate dehydrogenase . oxavoncerare 2. Proline: This amino acid is oxidized to glutamate. Glutamate is transaminated or oxidatively deaminated to form a-ketoglutarate. 3. Arginine: This amino acid is hydrolyzed by arginase to produce ornithine and urea. (Note: This reaction occurs primarily in the liver as part of the urea cycle.] Ornithine is subsequently converted to a-ketoglutarate. 4, Histidine: This amino acid is oxidatively deaminated by histidase to urocanic acid, which subsequently forms /formiminoglutamate [FIGIu] .FIGIu donates its formimino group to tetrahydrofolate (THF), leaving glutamate, which is degraded as described above. [Note: Individuals deficient in folic acid excrete increased amounts of FIG in the urine, particulary after ingestion ofa large dose of histidine. The FiGlu excretion test has been used in diagnosing a deficiency ra ) ae / nyrbt-coon_A’ ——rovwacn-coo _, _, “006-o1- cir circoo~ haart of folic acid.] 7 a vat or WA ‘¢ a “= ene Rac C. Amino acids that form pyruvate > L.Alanine: This amino acid loses its amino group by transamination to form pyruvate. [Note: Alanine is the major gluconeogenic amino acid.] Hs HENHS* oo lammotransforase Glutamate Hs éoo- PYRUVATE 2, Serine: This amino acid can be converted to glycine and N5,N10-methylenetetrahydrofolate Serine can also be converted to pyruvate by serine dehydratase Glycine —> CO, + Nis a EN Mailer serine | tatvahyarofolate tyrone transerace Tetrahydrofolate si Serine detydratase NH H,0 BD evrvvare 3. Glycine: This amino acid can be converted to serine by the reversible addition of a methylene group from N5,N10-methylenetetrahydrofolic acid or oxidized to CO2 and NH,*. [Not 3: Glycine can be deaminated to glyoxylate, which can be oxidized to oxalate or transaminated to glycine. Deficiency of the transaminase in liver peroxisomes causes overproduction of oxalate, the formation of oxalate stones, and kidney damage.] 4.Cystine is reduced to cysteine, using NADH+H" as a reductant. Cysteine undergoes desulfuration to yield pyruvate. 5. Threonine is converted to pyruvate or to a-ketobutyrate, which forms succinyl CoA. D. Amino acids that form fumarate > L-Phenylalanine Tetrahydro- Phenylalanine and tyrosine: Hydroxylation of phenylalanine Phenylalanine blopterin + 0, produces tyrosine.This reaction, catalyzed by tetrahydrobiopterin- _"yerow/ase Dihycro- Requiring phenylalanine hydroxylase, initiates the catabolism of biopterin + HO phenylalanine, Thus, the metabolism of phenylalanine and tyrosine rea merge, leading ultimately to the formation of fumarate and acetoacetate. Phenylalanine and tyrosine are, therefore, both vy glucogenic and ketogenic. FUMARATE ACETOACETATE NOTE:Inherited deficienci 3: Inherited deficiencies in the enzymes of phenylalanine and tyrosine metabolism lead to the diseases phenylketonuria ,tyrosimenia ,and alkaptonuria as well as the condition of albinism E. Amino acids that form succinyl CoA > 1.Methionine ; is one of four amino acids that form succinyl CoA. This sulfur-containing amino acid deserves special attention because it is converted to S-adenosylmethionine (SAM), the major methyl-group donor in one-carbon metabolism .Methionine is also the source of homocysteine, a metabolite associated with atherosclerotic vascular disease and thrombosis 2.Valine and isoleucine: These amino acids are branched-chain amino acids (BCAAs) that generate propionyl CoA, which is converted to methylmalonyl CoA and then succinyl CoA by biotin- and vitamin B12-requiring reactions . 3.Threonine: This amino acid is dehydrated to a-ketobutyrate, which is converted to propionyl CoA and then to succinyl CoA. Propionyl CoA, then, is generated by the catabolism of the amino acids methionine, valine, isoleucine, and threonine. [Note: Propiony| CoA also is generated by the oxidation of odd-numbered fatty acids.] Amino acids that form acetyl coenzyme A or acetoacetyl coenzyme A Lge) Jeoleucine FERRERO Leucine, isoleucine, lysine, and tryptophan form acetyl CoA or acetoacetyl CoA oop directly, without pyruvate serving as an intermediate (through the pyruvate ee dehydrogenase reaction). As noted earlier, phenylalanine and tyrosine also give rise

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