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Catabolism of amino acids - Removal of ammonia Several methods exist:

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Transamination Oxidative deamination Nonoxidative deamination Hydrolytic deamination

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Urea Cycle is isolated to what organ and requires what of other tissues

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the liver contains all the urea cycle enzymes; other tissues (extrahepatic tissue) have to come up with other mechanism to handle NH3 output from AA metabolism with later transfer of output (glutamine or alanine) to liver for urea cycle

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I. Transamination Action

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transfer the ?-amino group from an ?-amino acid to a ?-keto acid forming a new different amino acid from the alpha-keto acid transaminase are AA substrate specific

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Transamination Characteristics

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a. Enzymes are transaminases b. Freely reversible c. Two pairs of ?-ketoacid/?-amino acid d. In most transaminases, one of the pairs is ?-ketoglutarate/glutamate

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transaminases require

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pyridoxal phosphate (PLP) which is derived from vitamin B6

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Aspartate transaminase

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The other pair is oxaloacetate/aspartate This enzyme can also work with other amino acids, but aspartate is preferred presence in blood indicates muscle damage

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Alanine transaminase

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The other pair is pyruvate/alanine presence in blood indicates muscle damage

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if nitrogen is radiolabeled in original AA it will show up in the if the carbon is radiolabeled in original AA it will show up in

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secondary AA pyruvate (alanine) or oxaloacetate (aspartate)

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All amino acids can undergo transamination with ?-ketoglutarate except

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Lysine, Threonine and Proline

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II. Oxidative deamination is catalyzed

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by glutamate dehydrogenase

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glutamate dehydrogenase is located in...and utilizes...

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is located in the mitochondria as well as in the cytoplasm. It utilizes either NAD+ or NADP+

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Regulation of glutamate dehydrogenase

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The enzyme is under allosteric control GTP and ATP are allosteric inhibitors; GDP and ADP are activators

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Transaminases and glutamate dehydrogenase are

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the most important enzymes to release amino nitrogen from amino acids in the form of ammonia for subsequent conversion into urea.

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Nonoxidative deamination of Serine and Threonine via

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Serine dehydratase and threonine dehydratase catalyze the deamination

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Hydrolytic deamination: Mainly for the deamination of

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glutamine and asparagine

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Hydrolytic deamination enzymes

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glutaminase and asparaginase respectively

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Renal glutaminase is an important source of

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ammonia for the neutralization of acidic urine.

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Amino acid metabolism can also be

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Organ-specific

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Skeletal muscle is a major releaser of

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alanine and glutamine into blood to be handled subsequently by the liver.

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Mechanism of Skeletal Muscle alanine and glutamine formation

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Amino acids undergo transamination with: ?-ketoglutarate to form glutamate, and pyruvate to form alanine. Ammonia released from amino acids by other mechanisms is used to convert glutamate into glutamine via glutamine synthetase.

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Brain releases significant amounts of

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glutamine into blood

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Mechanism of Brain on glutamine formation

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Amino acids are transaminated with ?-ketoglutarate to form glutamate. Ammonia released from amino acid metabolism via other mechanisms is used to synthesize glutamate from ?-ketoglutarate by the reverse reaction of glutamate dehydrogenase and then to convert glutamate into glutamine via glutamine synthetase.

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Thus, brain synthesizes glutamate and glutamine as a means of

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detoxifying ammonia.

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Liver takes up

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glutamine released by skeletal muscle and brain and metabolizes it.

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Hepatic Encephalopathy

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no alpha-ketoglutarate for TCA as used to get rid of NH4+ > none for TCA > less ATP > neurodegeneration (problem not due to urea)

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In liver, ammonia is released from glutamine by glutaminase forming

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Glutamate

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Glutamate formed from this reaction is further metabolized by

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glutamate dehydrogenase to release another molecule of ammonia

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Ammonia is then converted into

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urea for excretion by the kidney

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Alanine released from skeletal muscle is also taken up by the liver and converted into

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into pyruvate and glutamate by transamination

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This Glutamate is then broken down to

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?-ketoglutarate and ammonia

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Ammonia is subsequently converted into

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urea

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Pyruvate is used for

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gluconeogenesis

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Thus, there is an alanine-glucose cycle operating between

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the skeletal muscle and liver

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Kidney extracts what from the blood and does what to it?

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Glutamine from blood and converts it into glutamate and ammonia by glutaminase and then alpha-ketoglutarate and ammonia via glutamate DH

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Ammonia is then used to

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excrete protons in the form of ammonium ions in urine. This is critical for the role of kidney in the management of metabolic acidosis

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In metabolic acidosis, glutamine extraction by the kidney is

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stimulated and the enzyme glutaminase is induced to facilitate ammonia formation in the tubular epithelial cells to promote the excretion of protons.

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The Urea cycle

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The major mechanism of nitrogen disposal in man

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The Urea cycle Overal Rxn

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The reaction requires four ATP equivalents. The reaction is compartmentalized between the cytosol and the mitochondria

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Individual steps: In the liver

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Synthesis of carbamoyl phosphate Formation of Citrulline Formation of argininosuccinate Formation of arginine Formation of urea

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Synthesis of carbamoyl phosphate

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1) Carbamoyl phosphate synthetase I 2) Reaction is irreversible 3) Enzyme requires N-acetylglutamate (synthesized by N- acetylglutamate synthetase) for activity (mutation > urea cycle disorder) 4) Enzyme located in the mitochondria

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N-acetyglutamate synthesis

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activated by arginine more arginine > more N-acetyglutamate > more CPS I activity > more urea cycle

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Formation of Citrulline

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1) Enzyme is ornithine transcarbamoylase 2) Carbamoyl group is transferred to ornithine 3) Carbamoyl phosphate has a high energy bond which drives the reaction 4) Enzyme is located in the mitochondria

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Formation of argininosuccinate

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1) Argininosuccinate synthetase 2) Utilizes Aspartate and ATP 3) AMP and PPi are generated. The hydrolysis of PPi drives the reaction 4) Enzyme is in cytosol. aspartate is the donor of the second amino group in urea as first comes from NH4+

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Formation of arginine

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1) Arginonosuccinase aka arginosuccinate lyase 2) Cleaves arginonosuccinate to arginine and fumarate 3) Located in cytosol 4) Arginine can be synthesized this way Note that fumarate is formed

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Future of Fumarate

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fumurate released in cytosol (not mito for TCA) so cytosolic fumarase converts into malate > oxaloacetate > aspartate via aspartate transaminase to donate another amino group in a later urea cycle

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Formation of urea

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1) Arginase 2) Cleaves arginine to urea and ornithine which is used in the cycle 3) Located in the cytosol

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Note how the urea cycle and the TCA cycle are connected

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The fumarate formed in the urea cycle can be converted to aspartate in the TCA cycle which is then used again in the Urea cycle

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Ammonia toxicity

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1. Urea is produced in the liver whereas ammonia is produced in most tissues. 2. Glutamine acts as a transport molecule for ammonia to the liver and kidney. 3. Loss of function of liver leads to ammonia toxicity (cirrhosis due to alcohol consumption is an example).

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Ammonia toxicity leads to

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a. High ammonia leads to depletion of ?-ketoglutarate from the TCA cycle. b. A decrease in ATP synthesis occurs. C. Brain is sensitive to decreases in ATP

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Deficiencies of enzymes of the urea cycle, including N-acetylglutamate synthetase lead to impaired

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CNS activity and high blood ammonia levels (Hyperammonemia, protein intolerance, neuropsychiatric dysfunction, and mental retardation).

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Patients with a total absence of any of the urea cycle enzymes do not

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survive the neonatal period.

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The symptoms are more severe with the deficiency of

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the first two enzymes of the cycle (carbamoyl phosphate synthetase I and ornithine transcarbamoylase

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Type II hyperammonemia

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CPS II

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Symptoms can be improved by

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putting the patients on a low protein diet administering the ?-ketoacids of the essential amino acids removing excess ammonia in the form of glycine by administering benzoate or in the form of glutamine by administering phenylacetate

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Nitrogen balance describes the

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the difference between body nitrogen gains and losses

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premise of nitrogen balance

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nitrogen equilibrium is attained when protein supply is adequate to replace nitrogen loss through the urine, stools, wounds and sweat

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A positive nitrogen balance is a reflection that

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nitrogen intake exceeds nitrogen loss

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Nitrogen balance is positive in

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growing children, pregnant women, adults gaining weight or recovering from illness or injury

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A negative nitrogen balance is a reflection that

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nitrogen loss exceeds nitrogen intake

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Nitrogen balance is negative during

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during starvation, catabolism or absence of even single non-essential amino acid.

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In a non-stressed patient, urinary urea nitrogen (UUN) accounts for

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80-90% of total urinary nitrogen

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measurement of UUN

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Molecular weight of urea is 60 of which 28 is from nitrogen. So UUN is calculated as urinary urea*28/60 which is approximately equal to urinary urea/2.

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Equation used to measure nitrogen balance is as follows:

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nitrogen balance (g/day) = nitrogen intake (g/day) - nitrogen losses (g/day); where nitrogen intake=dietary protein (g/day)/6.25 and nitrogen losses = UUN + nonurea urinary nitrogen (2 g) + fecal nitrogen (2 g)

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Genetic disorders of amino acid transport

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Hartnup disease and Cystinuria

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Hartnup disease is due to a

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genetic defect in the amino acid transport system responsible for the absorption of neutral amino acids across the brush border membrane of intestinal mucosal cells and brush border membrane of renal tubular epithelial cells "Blue Diaper Disease"

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This results in the increased

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excretion of neutral amino acids in the urine

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Symptoms of the disease in developed countries are

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minor--considered as a benign disorder niacin deficiency due to decreased availability of tryptophan for endogenous synthesis of the vitamin (pellagra) no protein malnutrition because protein digestion products are absorbed in the intestinal brush border predominantly as small peptides via PEPT1 rather than as free amino acids.

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Symptoms of the disease in underdeveloped countries are more severe

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protein malnutrition decreased plasma levels of Trp, Phe, and Tyr niacin deficiency (pellagra) involvement of central nervous system with severe neurological complications derangement of neutransmitters such as serotonin, dopamine, and norepinephrine which are synthesized from the above - mentioned aromatic, neutral amino acids.

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Cystinuria is due to a genetic defect in the

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amino acid transport system responsible for the absorption of basic amino acids (Lys, Arg, and ornithine) and the disulfide amino acid cystine across the brush border membrane of the intestinal mucosal cells and brush border membrane of the renal tubular epithelial cells

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This results in the increased

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increased excretion of lysine, arginine, ornithine, and cystine in the urine.

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Symptoms are related to

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the limited water solubility of cystine. When cystine levels go up in the kidney tubules due to the defect in the reabsorption, this amino acid crystallizes and forms kidney stones (calculi), causing kidney damage. This occurs in developed countries as well as in underdeveloped countries. Plasma levels of cystine are normal.

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marasmus

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Deficiency of proteins as well as energy (i.e., carbohydrate and fat) in the diet - (starvation)

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sx marasmus

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manifested by stunted growth, loss of adipose tissue, generalized wasting of protein mass, and no edema

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Plasma levels of insulin are low while the plasma levels of glucagon and glucocorticoids (cortisol) are

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high

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This enhances gluconeogenesis from

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glycerol (increased lipolysis) and glucogenic amino acids (increased muscle protein breakdown) to maintain blood glucose levels to support brain

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Increased fatty acid mobilization from adipose tissue to the liver causes

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causes increased production of ketone bodies (ketoacidosis) which can also function as substrates for energy production in the brain

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kwashiorkor

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Deficiency of protein in the diet with adequate energy intake in the form of carboydrate and fat.

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Sx kwashiorkor

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growth failure, edema, hypoalbuminemia, and fatty liver

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Plasma levels of insulin are elevated whereas plasma levels of glucagon and glucocorticoids

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are low

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Lipolysis in the adipose tissue is

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inhibited and fatty acid synthesis in liver is enhanced (fatty liver).

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Mobilization of amino acids from muscle is

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inhibited due to elevated insulin and decreased glucocorticoids

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Deficiency of dietary protein results in

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decreased levels of amino acids in the blood. This causes decreased protein synthesis in the liver, resulting in hypoalbuminemia

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hypoalbuminemia produces

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edema due to osmotic water accumulation in extracellular fluid in tissues. There is decreased protein synthesis in the muscle, leading to growth failure.

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Biosynthesis of nonessential amino acids: Alanine is formed from

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the transamination of pyruvate Pyruvate + Glutamate > Alanine + ?-ketoglutarate. a. This is the reverse of the catabolism of alanine. b. Note that alanine is also a product of tryptophan catabolism. This represents a very minor contribution to the synthesis of alanine.

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Aspartate is synthesized

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from oxaloacetate via transamination Oxaloacetate+Glutamate > Aspartate + ?-ketoglutarate a. The hydrolysis of asparagine by asparaginase also generates aspartate

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Asparagine is synthesized from

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aspartate by glutamine dependent asparagine synthetase. Aspartate + Glutamine + ATP + H2O > Asparagine + Glutamate + AMP + PPi

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Cysteine is produced during

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methionine degradation from Cystathionine a. Note that the sulfur atom comes from homocysteine but the carbon skeleton comes from serine.

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Glutamate can be synthesized from

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a number of precursors. a. The transamination of ?-ketoglutarate. ?-Ketoglutarate + Aspartate > Oxaloacetate + Glutamate. b. The reversal of the glutamate dehydrogenase reaction. ?-Ketoglutarate + NH4+ + NADPH + H+ > Glutamate + NADP+ + H2O. c. The hydrolysis of glutamine via glutaminase Glutamine + H2O > Glutamate + NH4+ d. Glutmate is also a product of the catabolism of proline, ornithine, and histidine

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Glutamine is synthesized from

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Glutamine is synthesized from 1. Glutamate + ATP + NH4+ > Glutamine + ADP + Pi a. The regulation of glutamine synthesis plays a major role in controlling nitrogen metabolism.

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Glycine is produced from

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serine by serine transhydroxymethylase Serine + THF > Glycine + Methylene THF + H2O a. This reaction represents a major souce of one carbon units for transfer by tetrahydrofolate (THF) b. Enzyme requires pyridoxal phosphate.

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Proline is synthesized from

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glutamate by a reversal of the catabolic process

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Serine is synthesized from

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3-phosphoglycerate (an intermediate of glycolysis)

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Tyrosine is synthesized from

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phenylalanine by phenylalanine hydroxylase Phenylalanine + O2 + THB > Tyrosine + DHB + H2O a. Remember PKU is associated with a defect in this enzyme. b. Enzyme requires tetrahydrobiopterine as a cofactor

Amino Acid Metabolism (Nitrogen)

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