Dr Carty Lecture 2 Amino Acid Metabolism 2024-25 PDF

Amino acid metabolism 1. Amino acid degradation (catabolism) 2. Urea cycle 3. Amino acid biosynthesis (anabolism) 4. Amino acids: precursors of nitrogen-containing compounds Chapters 19-21, Lippincott Biochemistry Dr. Michael P. Carty, Biochemistry, School...

Amino acid metabolism 1. Amino acid degradation (catabolism) 2. Urea cycle 3. Amino acid biosynthesis (anabolism) 4. Amino acids: precursors of nitrogen-containing compounds Chapters 19-21, Lippincott Biochemistry Dr. Michael P. Carty, Biochemistry, School of Biological and Chemical Sciences, University of Galway 1 Amino acid degradation (catabolism) 2  Examples of importance of amino acid metabolism in medicine. 1. Genetic defects in amino acid metabolism: serious diseases e.g. phenylketonuria (PKU) PKU esp. common in Ireland. 2. Methionine breakdown generates homocysteine: risk factor for heart disease. 3. Amino acid breakdown generates ammonia, and urea: toxicity 4. Nutritional aspects: need for sufficient amino acids in health and disease 3 Amino acid degradation – disposal of amino group nitrogen 4  Transamination of amino acids generates metabolites that feed into the TCA cycle acetoacetate pyruvate Glucose A. OXALOACETATE B. -KETOGLUTARATE C. PYRUVATE D. FUMARATE E. SUCCINYL CoA F. ACETYL-CoA TCA G. ACETOACETATE cycle * *  Transamination of amino acids also generates glutamate Example of alanine: Amino acid degradation – disposal of amino group nitrogen Converted to urea by the Urea Cycle in liver cells 7  Glutamate is broken down by glutamate dehydrogenase Amino groups from amino acids transferred to -ketoglutarate Generates glutamate Glutamate dehydrogenase releases ammonia from glutamate: termed ‘oxidative deamination’ Urea Cycle 8 Transamination, ammonia formation and the urea cycle combine to dispose of amino acid nitrogen One nitrogen in urea comes from ammonia One nitrogen in urea comes from aspartate Urea Goes to kidneys 9  Ammonia is converted to non-toxic urea by the Urea Cycle Arginine is hydrolysed The Urea cycle only occurs in to generate urea the mitochondria and cytosol of hepatocytes (liver cells), since the enzyme arginase* is only expressed in liver cells * Ornithine is regenerated at the end of the cycle Ammonia and HCO3- are condensed in the first step (from Lippincott) 10  Urea cycle disorders Urea cycle defects are examples of Inborn errors of metabolism (1/~8500 births) Symptoms in neonates between 24 and 72 hours: lethargy, nausea, convulsions, coma Urea cycle defects result from mutations in genes for UC enzymes This leads to deficiencies in key enzymes in the cycle Causes hyperammonemia (high blood concentration of ammonia) Restrict protein in diet Drug treatments (phenylbutyrate) to use up ammonia, and reduce circulating ammonia levels. http://www.nucdf.org/ 11 http://www.nucdf.org/ 12  Examples of Urea Cycle disorders Disease Enzyme defective Effects Arginemia Arginase Developmental delay Argininosuccinate Argininosuccinate lyase Convulsions, vomiting acidemia Carbamoyl phosphate Carbamoyl phosphate Convulsions, lethargy, synthase I deficiency synthase I early death Lead to hyperammonemia (increased level of ammonia in the bloodstream). 13  Urea cycle disorders Case: High-protein diet combined with defect in urea cycle Urea cycle enzyme activity could deal with the level of ammonia released by normal amino acid breakdown, but not when amino acid breakdown increased as a consequence of eating a high-protein diet. 14  Summary Amino acids classified as essential or non-essential in diet Amino acids can be degraded for energy, or converted to glucose (glucogenic) or to ketone bodies (ketogenic). Amino acids converted to intermediates that feed into TCA cycle. Genetic defects in amino acid metabolism lead to important human diseases (examples are PKU; homocystinuria) or have benign symptoms (alcaptonuria). Amino group nitrogen is disposed of via the urea cycle. 15 Amino acid biosynthesis (anabolism) 16 Essential amino acids must be provided in diet Non-essential amino acids can be made in body 17  Biosynthesis of non-essential amino acids Transamination of -keto acids gives alanine, aspartate and glutamate 18  Biosynthesis of amino acids Urea Arginine: can be synthesised by humans, cycle but may be required in diet also. Arginine: made via the reactions of the Urea cycle. Most of the arginine formed in the liver is broken down to urea and ornithine. Arginine synthesis may not be sufficient for needs under certain conditions e.g. growing children. Arginine needed for creatine biosynthesis; and for nitric oxide formation. Arginine is therefore an essential amino acid under some conditions. Tyrosine becomes an essential amino acid in PKU patients 19 Amino acids as precursors of nitrogen-containing compounds 20  What are amino acids required for in the body? 1. Majority of amino acids 3. used in protein synthesis Proportion used as precursors of other nitrogen compounds 2. Proportion is: (i) completely metabolised for energy or (ii) used to form glucose or ketone bodies 21 Amino acids as precursors of other nitrogen-containing compounds Compound Amino acid(s) required Heme Glycine Dopamine Tyrosine Histamine Histidine Nitric oxide Arginine Creatine Arginine, Glycine Thyroxine (thyroid hormone) Tyrosine Serotonin Tryptophan Glutathione (anti-oxidant) Glycine, Cysteine, Glutamate Purines Glutamine, Aspartate, Glycine Pyrimidines Glutamine, Aspartate 22 Tyrosine is the precursor of dopamine, norepinephrine and epinephrine 23  Important biomolecules derived from amino acids Tryptophan is a precursor of serotonin, a critical neurotransmitter Serotonin = 5-hydroxytryptamine Decarboxylase and Hydroxylase Serotonin is broken down by monoamine oxidase (MAO) Many drugs for psychiatric disorders are MAO inhibitors 24  Nitric oxide is formed from arginine Blood vessel dilation (at low concentrations) Kills pathogens (at high concentrations) Nitroglycerin: generates NO in vivo: treatment for angina 25  Important biomolecules derived from amino acids Heme Nitrogen containing compound made in liver in pre-erythrocytes in bone marrow Important in haemoglobin (oxygen transport) and in some enzymes e.g. cytochrome p450s (detoxification) The nitrogen in heme comes from glycine Porphyrias: Defects in heme synthesis Jaundice, incl. neonatal jaundice, indicates defective heme breakdown (bilirubin accumulates in skin, eyes) 26  Porphyrias: defects in heme biosynthesis 1. Chronic porphyria (porphyria cutanea tarda) Deficiency in uroporphyrinogen decarboxylase Most common porphyria Cutaneous symptoms 2. Acute hepatic porphyrias: Buildup of intermediates of heme synthesis, in liver 3. Erythropoietic porphyrias: deficiency of heme synthesis enzymes in erythrocytes. Build-up of toxic intermediates: gastrointestinal, neurological effects. Photosensitivity if porphyrin ring intermediates build-up. 27  Summary 1. Amino acids broken down to intermediates that feed into TCA cycle. 2. Glucogenic and ketogenic acids. 3. Amino acid nitrogen detoxified by the urea cycle 4. Defects in amino acid metabolism clinically important. 5. Amino acid biosynthesis. 6. Amino acids are precursors of many nitrogen-containing compounds. 28