Introduction to Nitrogen Metabolism

8/6/2019 Introduction to Nitrogen Metabolism

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Introduction to Nitrogen MetabolismGlutamate DehydrogenaseGlutamine SynthaseDigestive Tract NitrogenEssential vs. Nonessential Amino AcidsRemoval of Nitrogen from Amino AcidsThe Urea CycleRegulation of the Urea CycleUrea Cycle Disorders (UCDs)Table of Urea Cycle DefectsNeurotoxicity of Ammonia

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Introduction

Humans are totally dependent on other organisms for converting atmosphericnitrogen into forms available to the body. Nitrogen fixation is carried out by bacterialnitrogenases forming reduced nitrogen, NH4

+ which can then be used by allorganisms to form amino acids.
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Overview of the flow of nitrogen in the biosphere. Nitrogen, nitrites and nitratesare acted upon by bacteria (nitrogen fixation) and plants and we assimilate thesecompounds as protein in our diets. Ammonia incorporation in animals occursthrough the actions of glutamate dehydrogenase and glutamine synthase.Glutamate plays the central role in mammalian nitrogen flow, serving as both anitrogen donor and nitrogen acceptor.

Reduced nitrogen enters the human body as dietary free amino acids, protein,and the ammonia produced by intestinal tract bacteria. A pair of principal enzymes,glutamate dehydrogenase and glutamine synthatase, are found in all organisms andeffect the conversion of ammonia into the amino acids glutamate and glutamine,respectively. Amino and amide groups from these 2 substances are freelytransferred to other carbon skeletons by transamination and transamidationreactions.


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Representative aminotransferase catalyzed reaction.

Aminotransferases exist for all amino acids except threonine and lysine. Themost common compounds involved as a donor/acceptor pair in transaminationreactions are glutamate and -KG, which participate in reactions with many different

aminotransferases. Serum aminotransferases such as aspartate aminotransferase,AST (also called serum glutamate-oxaloacetate-aminotransferase, SGOT) andalanine transaminase, ALT (also called serum glutamate-pyruvate aminotransferase(SGPT) have been used as clinical markers of tissue damage, with increasingserum levels indicating an increased extent of damage (see the Enzyme Kineticspage for description of the use of enzyme levels in diagnosis). Alanine transaminasehas an important function in the delivery of skeletal muscle carbon and nitrogen (inthe form of alanine) to the liver. In skeletal muscle, pyruvate is transaminated toalanine, thus affording an additional route of nitrogen transport from muscle to liver.In the liver, alanine transaminase transfers the ammonia to -KG and regeneratespyruvate. The pyruvate can then be diverted into gluconeogenesis. This process is

referred to as the glucose-alanine cycle (see above).


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The glucose-alanine cycle is used primarily as a mechanism for skeletal muscleto eliminate nitrogen while replenishing its energy supply. Glucose oxidationproduces pyruvate which can undergo transamination to alanine. This reaction iscatalyzed by alanine transaminase, ALT. Additionally, during periods of fasting,skeletal muscle protein is degraded for the energy value of the amino acid carbonsand alanine is a major amino acid in protein. The alanine then enters the bloodstream and is transported to the liver. Within the liver alanine is converted back topyruvate which is then a source of carbon atoms for gluconeogenesis. The newlyformed glucose can then enter the blood for delivery back to the muscle. The amino

group transported from the muscle to the liver in the form of alanine is converted tourea in the urea cycle and excreted.

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The Glutamate Dehydrogenase Reaction


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The reaction catalyzed by glutamate dehydrogenase is:

The glutamate dehydrogenase utilizes both nicotinamide nucleotide cofactors;NAD+ in the direction of nitrogen liberation and NADP+ for nitrogen incorporation. Inthe forward reaction as shown above glutamate dehydrogenase is important inconverting free ammonia and -KG to glutamate, forming one of the 20 amino acidsrequired for protein synthesis. However, it should be recognized that the reversereaction is a key anapleurotic process linking amino acid metabolism with TCA cycleactivity. In the reverse reaction, glutamate dehydrogenase provides an oxidizablecarbon source used for the production of energy as well as a reduced electroncarrier, NADH. As expected for a branch point enzyme with an important link toenergy metabolism, glutamate dehydrogenase is regulated by the cell energycharge. ATP and GTP are positive allosteric effectors of the formation of glutamate,whereas ADP and GDP are positive allosteric effectors of the reverse reaction.Thus, when the level of ATP is high, conversion of glutamate to -KG and otherTCA cycle intermediates is limited; when the cellular energy charge is low,glutamate is converted to ammonia and oxidizable TCA cycle intermediates.Glutamate is also a principal amino donor to other amino acids in subsequenttransamination reactions. The multiple roles of glutamate in nitrogen balance make it

a gateway between free ammonia and the amino groups of most amino acids.

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The Glutamine Synthetase Reaction

The reaction catalyzed by glutamine synthetase is:
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The glutamine synthetase reaction is also important in several respects. First itproduces glutamine, one of the 20 major amino acids. Second, in animals,glutamine is the major amino acid found in the circulatory system. Its role there is tocarry ammonia to and from various tissues but principally from peripheral tissues tothe kidney, where the amide nitrogen is hydrolyzed by the enzyme glutaminase(reaction below); this process regenerates glutamate and free ammonium ion, whichis excreted in the urine.

Note that, in this function, ammonia arising in peripheral tissue is carried in anon-ionizable form which has none of the neurotoxic or alkalosis-generatingproperties of free ammonia.

Liver contains both glutamine synthetase and glutaminase but the enzymes arelocalized in different cellular segments. This ensures that the liver is neither a netproducer nor consumer of glutamine. The differences in cellular location of thesetwo enzymes allows the liver to scavenge ammonia that has not been incorporated

into urea. The enzymes of the urea cycle are located in the same cells as those thatcontain glutaminase. The result of the differential distribution of these two hepaticenzymes makes it possible to control ammonia incorporation into either urea orglutamine, the latter leads to excretion of ammonia by the kidney.

When acidosis occurs the body will divert more glutamine from the liver to thekidney. This allows for the conservation of bicarbonate ion since the incorporation ofammonia into urea requires bicarbonate (see below). When glutamine enters the


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kidney, glutaminase releases one mole of ammonia generating glutamate and thenglutamate dehydrogenase releases another mole of ammonia generating -KG. Theammonia will ionizes to ammonium ion (NH4

+) which is excreted. The net effect is areduction in the concentration of hydrogen ion, [H+], and thus an increase in the pH(see also Kidneys and Acid-Base Balance).

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Digestive Tract Nitrogen

While glutamine, glutamate, and the remaining nonessential amino acids can bemade by animals, the majority of the amino acids found in human tissuesnecessarily come from dietary sources (about 400g of protein per day). Proteindigestion begins in the stomach, where a proenzyme called pepsinogen is secreted,autocatalytically converted to Pepsin A, and used for the first step of proteolysis.However, most proteolysis takes place in the duodenum as a consequence ofenzyme activities secreted by the pancreas. All of the serine proteases and the zinc

peptidases of pancreatic secretions are produced in the form of their respectiveproenzymes. These proteases are both endopeptidase and exopeptidase, and theircombined action in the intestine leads to the production of amino acids, dipeptides,and tripeptides, all of which are taken up by enterocytes of the mucosal wall.

A circuitous regulatory pathway leading to the secretion of proenzymes into theintestine is triggered by the appearance of food in the intestinal lumen. Specialmucosal endocrine cells secret the peptide hormones cholecystokinin (CCK) andsecretin into the circulatory system. Together, CCK and secretin cause contractionof the gall bladder and the exocrine secretion of a bicarbonate-rich, alkaline fluid,containing protease proenzymes from the pancreas into the intestine. A second,paracrine role of CCK is to stimulate adjacent intestinal cells to secrete

enteropeptidase, a protease that cleaves trypsinogen to produce trypsin. Trypsinalso activates trypsinogen as well as all the other proenzymes in the pancreaticsecretion, producing the active proteases and peptidases that hydrolyze dietarypolypeptides.

Subsequent to luminal hydrolysis, small peptides and amino acids aretransferred through enterocytes to the portal circulation by diffusion, facilitateddiffusion, or active transport. A number of Na+-dependent amino acid transportsystems with overlapping amino acid specificity have been described. In thesetransport systems, Na+ and amino acids at high luminal concentrations are co-transported down their concentration gradient to the interior of the cell. The ATP-dependent Na+/K+ pump exchanges the accumulated Na+ for extracellular K+,

reducing intracellular Na+ levels and maintaining the high extracellular Na+

concentration (high in the intestinal lumen, low in enterocytes) required to drive thistransport process.

Transport mechanisms of this nature are ubiquitous in the body. Small peptidesare accumulated by a proton (H+) driven transport process and hydrolyzed byintracellular peptidases. Amino acids in the circulatory system and in extracellular


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fluids are transported into cells of the body by at least 7 different ATP-requiringactive transport systems with overlapping amino acid specificities.

Hartnup disorder is an autosomal recessive impairment of neutral amino acidtransport affecting the kidney tubules and small intestine. It is believed that thedefect lies in a specific transport system responsible for neutral amino acid transport

across the brush-border membrane of renal and intestinal epithelium. Deficiencies inthe solute carrier family 6 (neurotransmitter transporter), member 19 gene (symbolSLC6A19) are associated with Hartnup disorder. The encoded protein is alsoreferred to as the system B(0) neutral amino acid transporter 1 [B(0)AT1] proteinThe characteristic diagnostic feature of Hartnup disorder is a dramatic neutralhyperaminoaciduria. Additionally, individuals excrete indolic compounds thatoriginate from the bacterial degradation of unabsorbed tryptophan. The reducedintestinal absorption and increased renal loss of tryptophan lead to a reducedavailability of tryptophan for niacin and nicotinamide nucleotide biosynthesis. As aconsequence affected individuals frequently exhibit pellegra-like rashes

Many other nitrogenous compounds are found in the intestine. Most are

bacterial products of protein degradation. Some have powerful pharmacological(vasopressor) effects.

Products of Intestinal Bacterial Activity

Substrates Products

Vasopressor Amines Other

Lysine Cadaverene

Arginine Agmatine

Tyrosine Tyramine

Ornithine Putrescine

Histidine Histamine

Tryptophan Indole and skatole

All amino acids NH4+

Prokaryotes such as E. coli can make the carbon skeletons of all 20 aminoacids and transaminate those carbon skeletons with nitrogen from glutamine orglutamate to complete the amino acid structures. Humans cannot synthesize thebranched carbon chains found in branched chain amino acids or the ring systemsfound in phenylalanine and the aromatic amino acids; nor can we incorporate sulfurinto covalently bonded structures. Therefore, the 10 so-called essential amino
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acids (see Table below) must be supplied from the diet. Nevertheless, it should berecognized that, depending on the composition of the diet and physiological state ofan individual, one or another of the non-essential amino acids may also become arequired dietary component. For example, arginine is only normally considered to beessential amino acid during early childhood development because enough for adultneeds is made by the urea cycle.

To take a different type of example, cysteine and tyrosine are considered non-essential but are formed from the essential amino acids methionine andphenylalanine, respectively. If sufficient cysteine and tyrosine are present in the diet,the requirements for methionine and phenylalanine are markedly reduced;conversely, if methionine and phenylalanine are present in only limited quantities,cysteine and tyrosine can become essential dietary components. Finally, it shouldbe recognized that if the -keto acids corresponding to the carbon skeletons of theessential amino acids are supplied in the diet, aminotransferases in the body willconvert the keto acids to their respective amino acids, largely supplying the basicneeds.

Unlike fats and carbohydrates, nitrogen has no designated storage depots in thebody. Since the half-life of many proteins is short (on the order of hours), insufficientdietary quantities of even one amino acid can quickly limit the synthesis and lowerthe body levels of many essential proteins. The result of limited synthesis andnormal rates of protein degradation is that the balance of nitrogen intake andnitrogen excretion is rapidly and significantly altered. Normal, healthy adults aregenerally in nitrogen balance, with intake and excretion being very well matched.Young growing children, adults recovering from major illness, and pregnant womenare often in positive nitrogen balance. Their intake of nitrogen exceeds their loss asnet protein synthesis proceeds. When more nitrogen is excreted than is incorporatedinto the body, an individual is in negative nitrogen balance. Insufficient quantities of

even one essential amino acid is adequate to turn an otherwise normal individualinto one with a negative nitrogen balance.

The biological value of dietary proteins is related to the extent to which theyprovide all the necessary amino acids. Proteins of animal origin generally have ahigh biological value; plant proteins have a wide range of values from almost noneto quite high. In general, plant proteins are deficient in lysine, methionine, andtryptophan and are much less concentrated and less digestible than animal proteins.The absence of lysine in low-grade cereal proteins, used as a dietary mainstay inmany underdeveloped countries, leads to an inability to synthesize protein (becauseof missing essential amino acids) and ultimately to a syndrome known askwashiorkor, common among children in these countries.

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Essential vs. Nonessential Amino Acids

Nonessential Essential


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Alanine Arginine*

Asparagine Histidine

Aspartate Isoleucine

Cysteine Leucine

Glutamate Lysine

Glutamine Methionine*

Glycine Phenylalanine*

Proline Threonine

Serine Tyrptophan

Tyrosine Valine

*The amino acids arginine, methionine and phenylalanine are consideredessential for reasons not directly related to lack of synthesis. Arginine issynthesized by mammalian cells but at a rate that is insufficient to meet thegrowth needs of the body and the majority that is synthesized is cleaved toform urea. Methionine is required in large amounts to produce cysteine if thelatter amino acid is not adequately supplied in the diet. Similarly, phenyalanine

is needed in large amounts to form tyrosine if the latter is not adequatelysupplied in the diet.

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Removal of Nitrogen from Amino Acids

The dominant reactions involved in removing amino acid nitrogen from the bodyare known as transaminations (see general reaction above). This class of reactionsfunnels nitrogen from all free amino acids into a small number of compounds; then,either they are oxidatively deaminated, producing ammonia, or their amine groupsare converted to urea by the urea cycle. Transaminations involve moving an -amino group from a donor -amino acid to the keto carbon of an acceptor -ketoacid. These reversible reactions are catalyzed by a group of intracellular enzymesknown as aminotransferases, which generally employ covalently bound pyridoxalphosphate as a cofactor. However, some aminotransferases employ pyruvate as acofactor.

Aminotransferases exist for all amino acids except threonine and lysine. Themost common compounds involved as a donor/acceptor pair in transamination


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reactions are glutamate and -KG, which participate in reactions with many differentaminotransferases. Serum aminotransferases such as aspartate aminotransferase,AST (also called serum glutamate-oxaloacetate-aminotransferase, SGOT) andalanine transaminase, ALT (also called serum glutamate-pyruvate aminotransferase(SGPT) have been used as clinical markers of tissue damage, with increasingserum levels indicating an increased extent of damage (see the Enzyme Kineticspage for description of the use of enzyme levels in diagnosis). Alanine transaminasehas an important function in the delivery of skeletal muscle carbon and nitrogen (inthe form of alanine) to the liver. In skeletal muscle, pyruvate is transaminated toalanine, thus affording an additional route of nitrogen transport from muscle to liver.In the liver, alanine transaminase transfers the ammonia to -KG and regeneratespyruvate. The pyruvate can then be diverted into gluconeogenesis. This process isreferred to as the glucose-alanine cycle (see above).

Because of the participation of -KG in numerous transaminations, glutamate isa prominent intermediate in nitrogen elimination as well as in anabolic pathways.Glutamate, formed in the course of nitrogen elimination, is either oxidatively

deaminated by liver glutamate dehydrogenase forming ammonia, or converted toglutamine by glutamine synthase and transported to kidney tubule cells. There theglutamine is sequentially deamidated by glutaminase and deaminated by kidneyglutamate dehydrogenase.

The ammonia produced in the latter two reactions is excreted as NH4+ in the

urine, where it helps maintain urine pH in the normal range of pH4 to pH8. Theextensive production of ammonia by peripheral tissue or hepatic glutamatedehydrogenase is not feasible because of the highly toxic effects of circulatingammonia. Normal serum ammonium concentrations are in the range of 2040M,and an increase in circulating ammonia to about 400M causes alkalosis andneurotoxicity.

A final, therapeutically useful amino acid-related reaction is the amidation ofaspartic acid to produce asparagine. The enzyme asparagine synthase catalyzesthe ATP-requiring transamidation reaction shown below:


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Most cells perform this reaction well enough to produce all the asparagine theyneed. However, some leukemia cells require exogenous asparagine, which theyobtain from the plasma. Chemotherapy using the enzyme asparaginase takesadvantage of this property of leukemic cells by hydrolyzing serum asparagine toammonia and aspartic acid, thus depriving the neoplastic cells of the asparaginethat is essential for their characteristic rapid growth.

In the peroxisomes of mammalian tissues, especially liver, there exists a minorenzymatic pathway for the removal of amino groups from amino acids. L-amino acidoxidase is FMN-linked and has broad specificity for the L-amino acids.

A number of substances, including oxygen, can act as electron acceptors fromthe flavoproteins. If oxygen is the acceptor the product is hydrogen peroxide, whichis then rapidly degraded by the catalases found in liver and other tissues.

Missing or defective biogenesis of peroxisomes or L-amino acid oxidase causesgeneralized hyperaminoacidemia and hyperaminoaciduria, generally leading toneurotoxicity and early death.

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The Urea Cycle

Earlier it was noted that kidney glutaminase was responsible for convertingexcess glutamine from the liver to urine ammonium. However, about 80% of theexcreted nitrogen is in the form of urea which is also largely made in the liver, in aseries of reactions that are distributed between the mitochondrial matrix and thecytosol. The series of reactions that form urea is known as the Urea Cycle or theKrebs-Henseleit Cycle.


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Diagram of the urea cycle. The reactions of the urea cycle which occur in themitochondrion are contained in the red rectangle. All enzymes are in red, CPS-I iscarbamoyl phosphate synthetase-I, OTC is ornithine transcarbamoylase. Click onthe enzyme names to go to a descriptive page of the urea cycle disorder caused bydeficiency in the particular enzyme.

The essential features of the urea cycle reactions and their metabolic regulationare as follows: Arginine from the diet or from protein breakdown is cleaved by thecytosolic enzyme arginase, generating urea and ornithine. In subsequent reactionsof the urea cycle a new urea residue is built on the ornithine, regenerating arginineand perpetuating the cycle.


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Ornithine arising in the cytosol is transported to the mitochondrial matrix, whereornithine transcabamoylase catalyzes the condensation of ornithine with carbamoylphosphate, producing citrulline. The energy for the reaction is provided by the high-energy anhydride of carbamoyl phosphate. The product, citrulline, is thentransported to the cytosol, where the remaining reactions of the cycle take place.

The synthesis of citrulline requires a prior activation of carbon and nitrogen ascarbamoyl phosphate (CP). The activation step requires 2 equivalents of ATP andthe mitochondrial matrix enzyme carbamoyl phosphate synthetase-I (CPS-I). Thereare two CP synthetases: a mitochondrial enzyme, CPS-I, which forms CP destinedfor inclusion in the urea cycle, and a cytosolic CP synthatase (CPS-II), which isinvolved in pyrimidine nucleotide biosynthesis. CPS-I is positively regulated by theallosteric effectorN-acetylglutamate, while the cytosolic enzyme is acetylglutamateindependent.

In a 2-step reaction, catalyzed by cytosolic argininosuccinate synthetase,citrulline and aspartate are condensed to form argininosuccinate. The reactioninvolves the addition of AMP (from ATP) to the amido carbonyl of citrulline, forming

an activated intermediate on the enzyme surface (AMP-citrulline), and thesubsequent addition of aspartate to form argininosuccinate.

Arginine and fumarate are produced from argininosuccinate by the cytosolicenzyme argininosuccinate lyase (also called argininosuccinase). In the final step ofthe cycle arginase cleaves urea from arginine, regenerating cytosolic ornithine,which can be transported to the mitochondrial matrix for another round of ureasynthesis. The fumarate, generated via the action of arginiosuccinate lyase, isreconverted to aspartate for use in the argininosuccinate synthetase reaction. Thisoccurs through the actions of cytosolic versions of the TCA cycle enzymes,fumarase (which yields malate) and malate dehydrogenase (which yieldsoxaloacetate). The oxaloacetate is then transaminated to aspartate by AST.

Beginning and ending with ornithine, the reactions of the cycle consumes 3equivalents of ATP and a total of 4 high-energy nucleotide phosphates. Urea is theonly new compound generated by the cycle; all other intermediates and reactantsare recycled. The energy consumed in the production of urea is more thanrecovered by the release of energy formed during the synthesis of the urea cycleintermediates. Ammonia released during the glutamate dehydrogenase reaction iscoupled to the formation of NADH. In addition, when fumarate is converted back toaspartate, the malate dehydrogenase reaction used to convert malate tooxaloacetate generates a mole of NADH. These two moles of NADH, thus, areoxidized in the mitochondria yielding 6 moles of ATP.

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Regulation of the Urea Cycle

The urea cycle operates only to eliminate excess nitrogen. On high-protein dietsthe carbon skeletons of the amino acids are oxidized for energy or stored as fat andglycogen, but the amino nitrogen must be excreted. To facilitate this process,enzymes of the urea cycle are controlled at the gene level. With long-term changes
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in the quantity of dietary protein, changes of 20-fold or greater in the concentrationof cycle enzymes are observed. When dietary proteins increase significantly,enzyme concentrations rise. On return to a balanced diet, enzyme levels decline.Under conditions of starvation, enzyme levels rise as proteins are degraded andamino acid carbon skeletons are used to provide energy, thus increasing thequantity of nitrogen that must be excreted.

Short-term regulation of the cycle occurs principally at CPS-I, which is relativelyinactive in the absence of its allosteric activatorN-acetylglutamate. The steady-stateconcentration of N-acetylglutamate is set by the concentration of its componentsacetyl-CoA and glutamate and by arginine, which is a positive allosteric effector ofN-acetylglutamate synthetase.

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Urea Cycle Disorders (UCDs)

A complete lack of any one of the enzymes of the urea cycle will result in deathshortly after birth. However, deficiencies in each of the enzymes of the urea cycle,including N-acetylglutamate synthase, have been identified. These disorders arereferred to as urea cycle disorders or UCDs. More information on the individualUCDs can be found in the Inborn Errors in Metabolism pages. A common thread tomost UCDs is hyperammonemia leading to ammonia intoxication with the

consequences described below. Blood chemistry will also show elevations inglutamine. In addition to hyperammonemia, UCDs all present with encephalopathyand respiratory alkalosis. The most dramatic presentation of UCD symptoms occursin neonates between 24 and 48 hours after birth. Afflicted infants exhibitprogressively deteriorating symptoms due to the elevated ammonium levels.Deficiencies in arginase do not lead to symptomatic hyperammonemia as severe oras commonly as in the other UCDs. Deficiencies in carbamoylphosphate synthetaseI (CPS I), ornithine transcarbamoylase, argininosuccinate synthetase andargininosuccinate lyase comprise the common neonatal UCDs. When making a
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diagnosis of neonatal UCD based upon presenting symptoms and observedhyperammonemia, it is possible to make a differential diagnosis as to which of thefour enzyme deficiencies is the cause as shown in the Figure below.

Schema for the differential diagnosis (DDx) of neonatal UCDs. The presentationof hyperammonemia between 24 and 48hrs after birth (but not before 24hrs afterbirth) would likely indicate a UCD. This diagnosis can be confirmed by the absenceof acidosis or ketosis. The first diagnostic test is to assay for plasma levels ofcitrulline. Moderately high levels are indicative of argininosuccinate lyase deficiency(ALD) and extremely high levels indicative of argininosuccinate synthetasedeficiency (ASD). If no, or trace, citrulline is detected then analysis of urine oroticacid can be used to distinguish between CPS I deficiency (CPSD) and OTCdeficiency (OTCD).

Clinical symptoms are most severe when the UCD is at the level of carbamoylphosphate synthetase I (CPSI). Symptoms of UCDs usually arise at birth andencompass, ataxia, convulsions, lethargy, poor feeding and eventually coma anddeath if not recognized and treated properly. In fact, the mortality rate is 100% for


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UCDs that are left undiagnosed. Several UCDs manifest with late-onset such as inadulthood. In these cases the symptoms are hyperactivity, hepatomegaly and anavoidance of high protein foods.

In general, the treatment of UCDs has as common elements the reduction ofprotein in the diet, removal of excess ammonia and replacement of intermediates

missing from the urea cycle. Administration of levulose reduces ammonia through itsaction of acidifying the colon. Bacteria metabolize levulose to acidic byproductswhich then promotes excretion of ammonia in the feces as ammonium ions, NH4

+.Antibiotics can be administered to kill intestinal ammonia producing bacteria.Sodium benzoate and sodium phenylacetate can be administered to covalently bindglycine (forming hippurate) and glutamine (forming phenylacetylglutamine),respectively. These latter compounds, which contain the ammonia nitrogen, areexcreted in the feces. Ammunol is an FDA-approved intravenous solution of 10%sodium benzoate and 10% sodium phenylacetate used in the treatment of the acutehyperammonemia in UCD patients. However, hemodialysis is the only effectivemeans to rapidly reduce the level of circulating ammonia in UCD patients.

Buphenyl is an FDA-approved oral medication for chronic adjunctive therapy ofhyperammonemia in UCD patients. Dietary supplementation with arginine orcitrulline can increase the rate of urea production in certain UCDs.

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Table of UCDs

UCDEnzyme

DeficiencySymptoms/Comments

Type IHyperammonemia,CPSD

Carbamoylphosphatesynthetase I

with 24h72h after birth infant becomeslethargic, needs stimulation to feed,vomiting, increasing lethargy,hypothermia and hyperventilation;without measurement of serum ammonialevels and appropriate intervention infantwill die: treatment with arginine whichactivates N-acetylglutamate synthetase

N-acetylglutamate

synthetaseDeficiency

N-acetylglutamatesynthetase

severe hyperammonemia, mildhyperammonemia associated with deep

coma, acidosis, recurrent diarrhea,ataxia, hypoglycemia, hyperornithinemia:treatment includes administration ofcarbamoyl glutamate to activate CPS I

Type 2Hyperammonemia,OTCD

Ornithinetranscarbamoylase

most commonly occurring UCD, only X-linked UCD, ammonia and amino acidselevated in serum, increased serum
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orotic acid due to mitochondrialcarbamoylphosphate entering cytosoland being incorporated into pyrimidinenucleotides which leads to excessproduction and consequently excess

catabolic products: treat with highcarbohydrate, low protein diet, ammoniadetoxification with sodium phenylacetateor sodium benzoate

ClassicCitrullinemia, ASD

Argininosuccinatesynthetase

episodic hyperammonemia, vomiting,lethargy, ataxia, siezures, eventualcoma: treat with arginine administrationto enhance citrulline excretion, also withsodium benzoate for ammoniadetoxification

Argininosuccinicaciduria, ALD

Argininosuccinatelyase(argininosuccinase)

episodic symptoms similar to classiccitrullinemia, elevated plasma andcerebral spinal fluid argininosuccinate:treat with arginine and sodium benzoate

Hyperargininemia,AD

Arginase

rare UCD, progressive spasticquadriplegia and mental retardation,ammonia and arginine high in cerebralspinal fluid and serum, arginine, lysineand ornithine high in urine: treatment

includes diet of essential amino acidsexcluding arginine, low protein diet

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Neurotoxicity Associated with Ammonia

Earlier it was noted that ammonia was neurotoxic. Marked brain damage isseen in cases of failure to make urea via the urea cycle or to eliminate urea throughthe kidneys. The result of either of these events is a buildup of circulating levels ofammonium ion. Aside from its effect on blood pH, ammonia readily traverses the

brain blood barrier and in the brain is converted to glutamate via glutamatedehydrogenase, depleting the brain of -KG. As the -KG is depleted, oxaloacetatefalls correspondingly, and ultimately TCA cycle activity comes to a halt. In theabsence of aerobic oxidative phosphorylation and TCA cycle activity, irreparable celldamage and neural cell death ensue.

In addition, the increased glutamate leads to glutamine formation. This depletesglutamate stores which are needed in neural tissue since glutamate is both a
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neurotransmitter and a precursor for the synthesis of -aminobutyrate: GABA,another neurotransmitter. Therefore, reductions in brain glutamate affect energyproduction as well as neurotransmission.

Additional untoward consequences are the result of elevations in neuralglutamine concentration. Glial cell (astrocytes) volume is controlled by intracellular

organic osmolyte metabolism. The organic osmolyte is glutamine. As glutaminelevels rise in the brain the volume of fluid within glial cells increases resulting in thecerebral edema seen in infants with hyperammonemia caused by urea cycledefects.

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Return to The Medical Biochemistry Page

Michael W. King, Ph.D / IU School Medicine / miking at iupui.edu / 19962011

Last modified: February 16, 2011

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Omega 3 fish oilsupplements

www.lef.org/Omega-3
http://www.lef.org/Vitamins-Supplements/Top10/Omega-3-Fish-Oil.htmhttp://www.lef.org/Vitamins-Supplements/Top10/Omega-3-Fish-Oil.htm

Introduction to Nitrogen Metabolism

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Transcript of Introduction to Nitrogen Metabolism