Why Protein Based Diets Can Be Deadly for Some Individuals - Coursework Example

Protein based diets can be deadly for some individuals with inborn errors of amino acid metabolism Amino acid metabolism Amino acids make an important contribution to metabolic energy generation through their oxidative degradation. The body obtains its share of metabolic energy from amino acids through dietary proteins and tissue proteins. The essential amino acids which are not synthesised by the body are derived from dietary proteins and include phenylalanine, valine, tryptophan, threonine, leucine, isoleucine, methionine and lysine. Infants and growing children are also provided with sulphur containing amino acids like cysteine, aromatic amino acids like tyrosine, arginine and histidine in diet (Young and Borgonha, 2000). The dietary protein intake of individuals is determined by the metabolic demand which can be defined as the flow of amino acids through metabolic pathways which maintain the body structure and function. The pathways convert individual amino acids into important metabolites and then into nitrogenous end products including urea and other compounds in sweat, urine and faeces and also synthesise protein from the body as hair, skin and other secretions (WHO, 2007). Fates of amino groups in dietary proteins Ingested proteins are degraded into constituent amino acids in the stomach and small intestine by proteases. The initial step in the catabolism of amino acids is the removal of the amino group from its carbon skeleton by enzymes called transaminases. The amino group in most cases is transferred to α-ketogluterate to form glutamate requiring the coenzyme pyridoxal phosphate functioning as an intermediate carrier. Glutamate is transported from the cytosol to the mitochondria of liver cells where it releases the amino group as ammonia in a reaction catalysed by glutamate dehydrogenase. Ammonia being toxic to animal tissues is converted to a nontoxic compound in combination with glutamate to yield glutamine by the action of the enzyme glutamine synthetase. Ammonia formed in skeletal muscles are transported to the liver as the amino group of alanine through the glucose-alanine cycle in which deamination of alanine produces pyruvate which is converted to glucose in liver and transported back to the muscles (Nelson and Cox, 2005). Urea cycle The ammonia deposited in the liver mitochondria is converted into urea and is passed into the bloodstream and to the kidneys and excreted in urine. The urea cycle comprises of five enzymatic steps spanning the liver mitochondria and cytosol. Ornithine combines with ammonia in the form of carbamoyl phosphate to form citrulline by the action of carbamoyl phosphate synthetase I in the mitochondria. The second amino group enters through aspartate to form argininosuccinate with citrulline catalysed by the enzyme argininoauccinate synthetase in the cytosol. The reactionis followed by the formation of arginine and fumarate by the cleavage of argininosuccinate by the enzyme argininosuccinase. Fumerate joins the citric acid intermediates in the mitochondria while arginine is cleaved to yield urea and ornithine by the cytosolic enzyme arginase. Ornithine thus is regenerated in each turn of the urea cycle. The activity of the urea cycle is regulated at two levels. Regualations of the rates of the synthesis of the four urea cycle enzymes and allosteric regulation of carbamoyl phosphate synthetase I which catalyses the formation of carbamoyl phosphate (Brusilow and Horwich,2001). Amino acid degradation pathways The carbon skeletons of amino acids undergo oxidation after their amino group removal to enter the citric acid cycle for subsequent oxidation to CO2 and H2O. Tyrosine, phenylalanine, tyrosine, leucine, isoleucine, threonine, tryptophan and lysine yield ketone bodies and glucose depending upon the end product. Amino acid catabolism thus is integrated into intermediary metabolism and can be critical for survival in conditions in which amino acid degradation is a significant source of metabolic energy. Several enzyme cofactors are required in the reactions of the amino acid catabolism pathways which include tetrahydrobiopterin in phenylalanine oxidation by phenylalanine hydroxylase and tetrahydrofolate and S-adenosylmethionine in one carbon transfer reactions. Amino acid carbon skeletons enter citric acid cycle through acetyl-CoA, α-ketoglutarate, succinyl-CoA, fumarate and oxaloacetate. Tryptophan, serine, cysteine, glycine, alanine and threonine can be degraded to pyruvate which can be converted acetyl CoA which is a ketone body precursor or oxaloacetate which is a gluconeogenesis precursor. The amino acids which yield acetyl-CoA through acetoacetyl-CoA are phenylalaine, leucine, lysine and tryptophan. Tryptophan, leucine, isoleucine and threonine also form acetyl-CoA directly. Α ketogluterate producing amino acids are glutamate, glutamine, proline, histidine and arginine whereas valine, methionine, threonine and isoleucine produce Succinyl-CoA. Fumarate is formed by the four carbon atoms of phenylalanine and tyrosine and aspartate and asparagines produce oxaloacetate (Nelson and Cox, 2005). A number of genetic diseases are associated with inborn errors of amino acid metabolism and are outlined below. Urea cycle Disorders Free ammonia formed by the deamination of amino acids in excess of protein synthesis requirements in normal conditions are converted to urea and excreted in urine as ammonia is highly toxic. However absence of urea cycle enzymes due to an inherited genetic defect can result in hyperammonaemia or the building up of one or more intermediary metabolites of the urea cycle resulting in acute or chronic neurotoxicity (Kleppe, 2003). Since most urea cycle steps are not reversible, the absent enzyme activity can most often be identified by the presence of elevated concentration of the cycle intermediate in blood or urine or both. Some of the common genetic disorders that result in defective enzymes in the urea cycle are carbamoyl phosphate synthetase I deficiency, argininosuccinic acidaemia due to argininosuccinase defect and argininaemia due to arginase deficiency. Individuals with defective urea cycle enzymes cannot tolerate protein rich diet . However a protein free diet is not a treatment option as the essential amino acids not synthesized by the body should be provided in diet (Batshaw, 1994). Level of ammonia is lowered by the careful administration of aromatic acids benzoate or phenylbutyrate in diet. Benzoate gets converted to benzoyl CoA to form hippurate when combined with glycine. Glycine used up must be regenerated and ammonia is used up in the glycine synthase reaction. Phenylbutyrate follows a reaction in which it is converted to phenylacetate by β oxidation and then to phenylacetyl-CoA wich form phenylacetylglutamine combined with glutamine. Glutamine removal triggers its synthesis by glutamine synthetase which uses up ammonia. The compounds hippurate and phenylacetylglutamine are nontoxic and are excreted in urine (Wraith, 1989). Deficiency of N-acetylglutamate synthase leads to the absence of the normal activator of carbamoyl phosphate synthetase I. Administering carbamol glutamate, an analogue of N-acetylglutamate activates carbamoyl phosphate synthetase I. Treating deficiencies of ornithine transcrabamoylase, argininosuccinate synthetase and argininosuccinase use arginine as a diet supplement. In rare case of arginase deficiency arginine should be excluded from diet as it is the substrate of the defective enzyme (Batshaw, 1987). However a number of immediate treatment methods are to be enforced to force the removal of toxic compounds accumulated in order to minimise resulting organ disorders. Dialysis is the most common and effective method used to remove toxic metabolites (Prietsch, 2006). Genetic defects associated with amino acid metabolism Most amino acids being neurotransmitters or antagonists or precursors of neurotransmitters inborn errors of amino acid metabolism can cause defective neural development and resulting mental retardation. Defective enzymes due to genetic defects results in toxic accumulation of intermediates. Phenylketonuria (PKU) Phenylketonuria is an inherited genetic defect caused caused by the defective enzyme phenyl alanine hydroxylase involved in phenylalanine catabolism resulting in elevated levels of phenylalanine.It was among the first genetic defects of metabolism discovered in humans. In individuals with PKU phenylalanine undergoes transamination with pyruvate to form phenylpyruvate the accumulation of both of these occur in blood and tissues and are excreted in urine giving the disease its name. Accumulation of phenylalanine and its metabolites impairs normal brain development in early life possibly due to the excess phenylalanine competing with other amino acids to cross the blood-brain barrier leading to a deficit of required metabolites (Ledley, 1986). Rigid dietary control can prevent mental retardation if the condition is detected in early infancy. Protein rich diet must be curtailed and diet must be strictly monitored restricting the intake of phenyl alanine and tyrosine. Alkaptonuria Alkaptonuria is another less serious disease of phenylalanine catabolism which is caused due to the defective enzyme homogentisate dioxygenase. The disease is of historical significance as Archibald Garrod discovered that the disease was inherited and traced its cause to a missing enzyme. Large amount of homogentisate is excreted in the condition and its oxidation turns the urine black. Another effect of the condition is a form of arthritis developed by individuals with alkaptonuria. Homocystinuria Homocystinuria is an inborn metabolic disorder of the amino acid methionine due to the defective enzyme cystathionine β-synthase characterised by elevated levels of hoocysteine in the serum and increased homocysteine excretion in urine (Mudd, 1985). The defect results in faulty bone and neural development. A low methionine cysteine supplemented diet is used in treatment of neonates. Administration of pyridoxine and compound like betain which decreases the serum concentration of homocysteine is the conventional treatment strategy (Singh, 2004). Maple syrup urine disease (branched chain ketoaciduria) Maple syrup urine disease is an inborn metabolic disorder in which the three branched chain α-keto acids accumulate in blood due to defective branched chain α-keto acid dehydrogenase complex resulting in faulty degradation of isoleucine, leucine and valine. MSUD results in abnormal brain development leading to mental retardation if untreated (Dancis, 1959). Treatment involves branched chain amino acid free diet in a closely controlled diet regime as in other inherited errors of amino acid metabolism. Methylmalonic acidaemia Methylmalonic acidaemia is an inherited genetic disorder characterised by the accumulation of methylmalonic acid and its byproducts in serum. The defective enzyme causing the disorder is methylmalonyl-CoA mutase which catalyses the conversion reaction of propionyl-CoA to succinyl-CoA (Stokke, 1973). Infants and children with the condition are at risk for metabolic decompensation during conditions of increased catabolism such as trauma, psychological stress, intercurrent infections and surgery. Swift treatment in the form of restricted protein intake to limit protein catabolism is required. Carnitine is also used in treatment of acidaemias. A build up of acyl CoA esters in the cells due to metabolic block may cause a direct toxic effect on the tissues. Carnitine conjugates with these compounds to form acylcarnitine esters that are excreted through the kidney which results in a secondary carnitine deficiency. Carnitine supplementation is hence used in both acute and chronic treatment of organic acidaemias (Stanley, 1987). Conclusion The accumulation of toxic products due to protein catabolism shows various acute and chronic syndromes ranging from vomiting and feeding difficulties to severe encephalopathy and other neurological disorder. Research studies in recent years have shown significant advances in the early diagnosis and treatment of the disorders. Though complete cure has not yet materialized for these inborn metabolic disorders a better chance for survival and a better quality of life has been made possible with these advances. Main objective of treatment in inborn errors of metabolism is to re-establish the metabolic balance. Severe restriction of protein in diets are essential in patients with inborn errors of amino acid metabolism as the enzyme required for the metabolism is absent resulting in accumulation of the particular amino acid followed by its conversion into toxic products which could lead to severe complications in the patients. The composition and the quantities of ingested food including that of the composition of the micronutrients must be carefully monitored and regulated to ensure the the levels of amino acids are adequate to sustain normal metabolism but not high enough to be harmful to patients (Alexander, 1974). Bibliography Alexander, F.W., Clayton, B.E., Delves, H.T., 1974. Mineral and trace-metal balances in children receiving normal and synthetic diets, Q J Med, 43:89 Batshaw, M., Wachtel, R., Thomas, G., Starret, A., Brusilow, S., 1984. Arginine-responsive asymptomatic hyperammonaemia in the premature infant The Journal of Pediatrics, 105(1). Batshaw, M.L. , 1994. Inborn errors of urea synthesis. Annals of Neurology,35:133-1341 Brusilow, S.W., Horwich, A.L., 2001. Urea cycle enzymes. In : Scriver, C.R., Beaudet, A.C., Sly, W.S., Valle, D.,Childs, B., Kinzler, K.,Vogelstein, B., editors. The Meabolic Bases of Inherited Disease, 8th edition. New York: McGraw-Hill Companies Inc. Dancis, J., Levitz, M.,Mille,S.,Westall, R.G., 1959. Maple syrup urine disease, British Medical Journal, 1: 91-93 Kleppe, S., Mian, A., Lee, B., 2003. Urea cycle disorders, Current Treatment options in Neurology, 5 (4)309-319 Ledley, F.D., Levy, H.L., and Woo, S.L.C., 1986. Molecular analysis of the inheritance of phenylketon uria and mild hyperphenylalaninaemia n families with both disorders. New England Journal of Medicine. 314: 1276-1280 Mudd, S.H., Skovby, F., Levy, H.L., et al. 1985. The natural history of homocystinuria due to cystathionine beta-synthase deficiency.,American Journal of Human Genetics.37(1):1-31 Nelson, D.L., Cox, M.M, 2005. Amino acid oxidation and the production of urea, Lehninger Principles of Biochemistry, 4th edition. New York: W. H. Freeman and Company Prietsch, V, de Baulny, H.O., Saudubary, J.M., 2006. Treatment: Present Status and New Trends. In: Fernandes, J., Saudubray, J.M., Van den Berghe G., Walters,J. H., editors. Inborn Metabolic Diseases: Diagnosis and Treatment, 4th edition. Heidelberg: Springer Protein and amino acid requirements in human nutrition, 2007. WHO Technical Report Series, no: 935, Geneva: WHO Press Singh, R.H., Kruger, W.D., Wang, L., et al. 2004. Cystathionine beta-synthase deficiency: effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria. Genetics in Medicine. 6(2):90-95 Stanley, C. A., 1987. New genetic defects in mitochondrial fatty acid oxidation and carnitine deficiency, Advanced Pediatrics, 34. Stokke, O., Jellum, E., Eldjarn, L.,Schnitler, R. 1973. The occurrence of beta-hydroxy-n-valeric acid in a patient with propionic and methylmalonic acidemia. Clinica Chimica Acta. 45(4):391-401 Wraith, J.E., 1989. Diagnosis and management of inborn errors of metabolism, Archives of Disease in Childhood, 64. Young, V.R., Borgonha, S., 2000. Nitrogen and amino acid requirements: The Massachusetts Institute of Technology amino acid requirement pattern, Journal of Nutrition,130: 1841S-1849S Read More