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Transcript
The catabolism of amino acids and the urea cycle. Aminohappojen katabolia ja ureasykli. Aminosyrornas kataboli och ureacykeln. Lehninger 5ed Ch18 (Ch18.3 Pathways of amino acid degradation) Ch22 (Ch22.1 Overview of nitrogen metabolism) (Ch22.2 Biosynthesis of amino acids) (Ch22.4 Biosynthesis and degradation of nucleotides) Ove Eriksson BLL/Biokemia [email protected] Lecture content: How do amino acids differ from carbohydrates and fat? • The route of nitrogen in our organism • There is no storage form of amino acids in the human. • The urea cycle • Amino acids contain nitrogen. • Metabolic profiles of tissues The nitrogen cycle HUMAN • Ammonia is toxic to the central nervous system. From azotobacter to human The gastrointestinal channel The destiny of ingested proteins Stomach: -pepsin Pancreas: -trypsin -chymotrypsin -carboxypeptidase The destiny of ingested proteins Amino acids can undergo oxidative degradation. About 18% of her body weight is protein. 1. During normal synthesis and degradation of cellular proteins. Muscle proteins are actively metabolized. 2. When intake of protein exceeds the body’s need. 3. During starvation and diabetes mellitus. Degradation of intracellular proteins by autophagy (=eating itself) or the proteasome. General layout of the amino acid catabolism General layout of the amino acid catabolism General layout of the amino acid catabolism 1. How is the NH3-group separated from the carbon ”skeleton” of the amino acid? 2. How is ammonia converted to urea? 3. What happens with the carbon ”skeleton”? - amino acid – -keto acid NH2 - amino acid – -keto acid O O O O O NH2 O O Pyruvate O O Aspartic acid - amino acid – -keto acid O O O O Alanine O Oxaloacetic acid - amino acid – -keto acid O O HS O NH2 NH2 O O O O O Glutamic acid O ketoglutaric acid HS O O O O Cysteine O Mercaptopyruvate - amino acid – -keto acid HO Transamination reactions HO NH2 O O O Tyrosine O O Hydroxyphenylpyruvate Amino groups are transferred to -ketoglutarate. Free ammonia is formed by deamination of glutamate dehydrogenase Transamination -transaminases Deaminationglutamate dehydregenase Transaminases are used in the diagnosis of tissue damage The cell membrane is destroyed in many diseases. Cytoplasmic enzymes -> leak -> blood stream Increased concentrations of transaminases is used for the diagnosis of: -myocardial infaction -toxic liver damage -muscle diseases General layout of amino acid catabolism 1. How is the NH3-group separated from the carbon ”skeleton” of the amino acid? Glutamine, alanine and glutamic acid play a central role in amino acid metabolism. 2. How is ammonia converted to urea? 3. What happens with the carbon ”skeleton”? Transport of amino groups from periferal tissues to the liver by glutamine. General layout of the amino acid catabolism In muscle In liver Ammonia excreted in different forms in different organisms. Ammonia is metabolized to urea in liver and kidney. Ammonia is toxic to the CNS. Ammonia is toxic to the CNS. Hepatic encephalopathy: -due to accumulation of ammonia and other toxic compounds. Depletion of Krebs cycle intermediates and decreased oxidative phosphorylation. Alcoholic liver disease Alcoholic liver disease 1 Risk factors: intake of ethanol men > 60 g/day women > 40 g/day for > 10 years 1. Normal liver; extremely smooth 2. Cirrhosis; liver distorted and shrunken, large nodules of cell death 3. End stage liver; intense bile pigmentation, connective tissue bands 2 3 Symtoms: in the beginning - no symtoms later - fatigue, icterus, ascites end stage - hepatic encephalopathy Urea is produced in the urea cycle. Carbamoyl phosphate synthetase Most common protein in liver and kidney mitochondria Synthesis of carbamoyl phosphate requires ATP. Urea is produced in the urea cycle Addition of the 1st amino group Urea is produced in the urea cycle Addition of the 2nd amino group Urea is produced in the urea cycle Removal of fumarate Urea is produced in the urea cycle General layout of the amino acid catabolism Formation of urea General layout of amino acid catabolism 1. How is the NH3-group separated from the carbon ”skeleton” of the amino acid? 2. How is ammonia converted to urea? 3. What happens with the carbon ”skeleton”? Glucogenic and ketogenic amino acids The glucose-alanine cycle (compare with Cori cycle): The human can synthesize some but not all amino acids from TCA-cycle intermediates. Transfer of amino groups from periferal tissues to the liver by alanine. Amino acids are precursors for the synthesis of a large number of biologically important compounds. Metabolism of erythrocytes Overview over the main metabolic pathways of various cells and tissues. tissues. For clarity the amino acid metabolism has been excluded Metabolism of neural cells Metabolism of muscle cells (myocytes) Metabolism of white fat cells (adipocytes) Metabolism of brown fat cells Metabolism of liver cells (hepatocytes) hepatocytes) The liver has a central position in the energy metabolism. Plenty of nutrients? Starvation? Recently detected in adult humans Uncoupling protein, also called thermogenin. Metabolism of liver cells (hepatocytes) Plenty of nutrients Modification of enzymes in the well fed state Metabolism of liver cells (hepatocytes) Plenty of nutrients Induction of enzymes in the well fed state Metabolism of liver cells (hepatocytes) Metabolism of liver cells (hepatocytes) Starvation Starvation Modification of enzymes during starvation Metabolism of betabeta-cell Induction of enzymes during starvation Metabolism of the betabetacell • Very catabolic cell. • Glucose and amino acids are oxidized in the TCA-cycle. • Does not have lactate dehydrogenase. Glucose (fuel) sensing sensing by the betabeta-cell How does the betabeta-cell fuel sensor work? THE END