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Nitrogen Balance N balance = Nin - Nout • In normal adults on adequate diet, nitrogen intake equal nitrogen excreted,this is the nitrogen balance. • Major dietary source of N is Protein (>95). • AA are used for protein synthesis & N containing compounds. • AA in excess are degraded (used for energy) N is disposed of in urea (80%), ammonia, uric acid or creatinine in urine with small amounts in fecal matter (undigested) Positive Nitrogen Balance Positive nitrogen balance,an excess of ingested over excreted nitrogen, occurs during growth, pregnancy, lactation and recovery from diseases. Negative Nitrogen Balance • Negative nitrogen balance, where output exceeds intake, may occur after surgery, in advanced cancer, low protein diet, malabsorption,starvation and some hormonal imbalance(eg.hyperthyrio -dism). Overall 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. Amino acid pool • • • • • Free amino acids are present throughout the body, for example, in cells, blood, and the extracellular fluids. all these amino acids are belonged to a single entity, called the amino acid pool. This pool is supplied by three sources: 1) amino acids provided by the degradation of body proteins, 2) amino acids derived from dietary protein, and 3) synthesis of nonessential amino acids from simple intermediates of metabolism . Conversely, the amino pool is depleted by three routes: 1) synthesis of body protein, 2) amino acids consumed as precursors of essential nitrogen-containing small molecules, and 3) conversion of amino acids to glucose, glycogen, fatty acids or CO2. Although the amino acid pool is small (comprised of about 90–100 g of amino acids) in comparison with the amount of protein in the body (about 12 kg in a 70kg man), it is at the center of whole-body nitrogen metabolism. 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. Protein turnover • 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 relatively constant, and cellular levels of the protein are controlled by selective degradation. • Rate of turnover: In healthy adults, the total amount of protein in the body remains constant, because the rate of protein synthesis is just sufficient to replace the protein that is degraded. This process, called protein turnover, leads to the hydrolysis and resynthesis of 300–400 g of body protein each day. • The rate of protein turnover varies widely for individual proteins. Shortlived proteins (for example, many regulatory proteins and misfolded proteins) are rapidly degraded, having half-lives measured in minutes or hours. Long-lived proteins, with half-lives of days to weeks, constitute the majority of proteins in the cell. Structural proteins, such as collagen, are metabolically stable, and have half-lives measured in months or years. Examples of Non-protein Nitrogenous Compounds • • • • • • • • • • • heme pyrimidines purines choline (serine) creatine bile salts (glycine) Melanin (tyrosine) porphyrins epinephrine (phenylalanine) nicotinic acid (tryptophan) Almost all nitrogen in human metabolism comes from dietary amino acids. Amino acid pool Catabolism of the Carbon Skeletons of Amino Acids – The catabolism of the 20 amino acids found in proteins involves the removal of α-amino groups, followed by the breakdown of the resulting carbon skeletons. – The breakdown of the resulting carbon skeletons funnel into 7 metabolic intermediates. – These intermediates 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 CO2 and water by the citric acid cycle. • Acetyl–CoA Ketogenic • Acetoacetyl–CoA • Pyruvate • α-Ketoglutarate • Succinyl–CoA • Fumarate • Oxaoloacetate Glucogenic 9 Glucogenic and Ketogenic A A • Amino acids can be classified as glucogenic, ketogenic, or both based on which of the seven intermediates are produced during their catabolism Glucogenic amino acids • Amino acids whose catabolism yields pyruvate or one of the intermediates of the citric acid cycle are termed glucogenic or glycogenic. These intermediates are substrates for gluconeogenesis and, therefore, can give rise to the net formation of glucose or glycogen in the liver and glycogen in the muscle. Ketogenic amino acids • Amino acids whose catabolism yields either acetoacetate or one of its precursors (acetyl CoA or acetoacetyl CoA) are termed ketogenic. • Carbon skeletons of ketogenic amino acids can be catabolized for energy in Krebs Cycle, or converted to ketone bodies or fatty acids. They cannot be converted to glucose. • Leucine and lysine are the only exclusively ketogenic amino acids found in proteins. Glucogenic and Ketogenic A A • • • • • Amino acids are grouped according to their major degradative end product. Some amino acids are listed more than once because different parts of their carbon skeletons are degraded to different end products. 14 amino acids are exclusively glucogenic. Four of the amino acids are both glucogenic and ketogenic. Only two amino acids, leucine and lysine, are exclusively ketogenic. Oxaloacetate ↓ phosphoenolpyruvate ↓ glucose Two Amino Acids are Converted to Oxaloacetate • Asparagine and aspartate are degraded to Oxaloacetate. • The carbon skeletons of asparagine and aspartate ultimately enter the citric acid cycle as oxaloacetate. • The enzyme asparaginase catalyzes the hydrolysis of asparagine to aspartate. • Aspartate undergoes transamination with ketoglutarate to yield glutamate and oxaloacetate. Two Amino Acids Can form Fumarate • Phenylalanine and tyrosine: Hydroxylation of phenylalanine leads to the formation of tyrosine . • This reaction, catalyzed by phenylalanine hydroxylase, is the first reaction in the catabolism of phenylalanine. • Thus, the metabolism of phenylalanine and tyrosine merge, leading ultimately to the formation of fumarate and acetoacetate. Phenylalanine and tyrosine are, therefore, both glucogenic and ketogenic. Catabolism of Phenylalanine and tyrosine Five Amino Acids Are Converted to α-Ketoglutarate • The carbon skeletons of five amino acids (proline, glutamate, glutamine, arginine, and histidine) enter the citric acid cycle as α ketoglutarate. • Glutamate is converted to α-ketoglutarate by transamination, or through oxidative deamination by glutamate dehydrogenase. • Proline,glutamine, arginine, and histidine are first converted to glutamate which is oxidatively deaminated to α –ketoglutarate by glutamate dehydrogenase. • Glutamine is converted to glutamate and ammonia by the enzyme glutaminase . Glutamate is converted to α-ketoglutarate by transamination, or through oxidative deamination by glutamate dehydrogenase • Proline,glutamate, and glutamine have five-carbon skeletons while arginine and histidine have 6 carbon skeletons. Proline • The cyclic structure of proline is opened by oxidation of the carbon most distant from the carboxyl group to create a Schiff base, then hydrolysis of the Schiff base to a linear semialdehyde, glutamate -semialdehyde. • This intermediate is further oxidized at the same carbon to produce glutamate. • Transamination or deamination of glutamate produces -ketoglutarate. Arginine and Histidine • Arginine and histidine contain five adjacent carbons and a sixth carbon attached through a nitrogen atom. • The catabolic conversion of these amino acids to glutamate is therefore slightly more complex than proline or glutamine. • Arginine is converted to the five-carbon skeleton of ornithine by arginase in the urea cycle, and the ornithine is transaminated to glutamate ᵞsemialdehyde which is converted to glutamate. • glutamate ᵞ-semialdehyde is a common intermediate in proline and arginine metabolism. • Conversion of histidine to the five-carbon glutamate occurs in a multistep pathway; the extra carbon is removed in a step that uses tetrahydrofolate as cofactor. • Histidine is oxidatively deaminated by histidase to urocanic acid, which subsequently forms N-formiminoglutamate (FIGlu). FIGlu donates its formimino group to tetrahydrofolate, leaving glutamate, which is degraded as described above. Six Amino Acids Are Degraded to Pyruvate • The carbon skeletons of six amino acids are converted in whole or in part to pyruvate. • These are alanine, tryptophan, cysteine, serine, glycine, and threonine. • All carbon atoms of gly, ala, cys, and ser are converted to pyruvate. • Only two carbon atoms of thr and three of trp form pyruvate. • The pyruvate can then be converted to either acetyl-CoA (a ketone body precursor) or oxaloacetate (a precursor for gluconeogenesis) or oxidized to CO2 and water. • Thus amino acids catabolized to pyruvate are both ketogenic and glucogenic. 21 Catabolic pathway of Glycine, serine, threonine, cysteine,alanine and tryptophan Alanine • Alanine yields pyruvate directly on transamination withketoglutarate. Tryptophan • Tryptophan the side chain of tryptophan is cleaved to yield alanine and aromatic part. • Alanine is transaminated to pyruvate. • The aromatic part can be converted to acetoacetyl COA. Serine • Serine can be converted to Gly. and also Pyruvate. • This amino acid can be converted to glycine and N5,N10methylenetetrahydrofolate by serine hydroxymethyl transferase . • Serine can also be converted to pyruvate by serine dehydratase • Both the β-hydroxyl and the α-amino groups of serine are removed in this single pyridoxal phosphate–dependent reaction. In this reaction the loss of water is followed by hydrolytic loss of ammonia. 25 Cysteine :Two different pathways then convert cysteine to pyruvate. 1st step transamination. 2nd step removal of sulfer atom. Threonine • There are two main pathways for threonine degradation. • One pathway leads to pyruvate via glycine. • The conversion to glycine occurs in two steps. • This is a relatively minor pathway in humans, accounting for 10% to 30% of threonine catabolism, but is more important in some other mammals. • The major pathway in humans leads to succinyl-CoA. Therionine to succinyl-CoA Glycine • Glycine is degraded via three pathways, only one leads to pyruvate. • 1- Glycine can be converted to serine by addition of a methylene group from N5,N10-methylenetetrahydrofolic acid. This reaction, catalyzed by serine hydroxymethyl transferase, requires the coenzymes tetrahydrofolate and pyridoxal phosphate. Glycine cont… • 2- Glycine undergoes oxidative cleavage to CO2, NH4 , and a methylene group (-CH2-). • This reversible reaction, catalyzed by glycine cleavage enzyme, and requires tetrahydrofolate, which accepts the methylene group. • In this oxidative cleavage pathway the two carbon atoms of glycine do not enter the citric acid cycle. • One carbon is lost as CO2 and the other becomes the methylene group of N5,N10-methylenetetrahydrofolate, (one carbon group donor in biosynthetic pathways). • This pathway predominates in animals. Glycine cont.. • 3- Glycine is a substrate for the enzyme D-amino acid oxidase. The glycine is converted to glyoxylate, an alternative substrate for hepatic lactate dehydrogenase. • Glyoxylate is oxidized in an NAD-dependent reaction to oxalate.