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1 Fate of absorbed amino acids Enter in the formation of A.A. pool AA pool ~ 80 % in muscles ~ 10 % in liver ~ 5 % in kidney ~ 5 % in blood • Definition: AA POOL It include the free a.as distributed throughout the body • The a.a. pool contains 100 gm a.as.50% of these a.as are in the form of glutamate & glutamine (Why?) • In contrast to the amount of protein in the body (about 12 Kg in 70 Kg man), the a.a. pool is small (only 100 gm) AA pool is not reserve !! There is not a specific protein reserve in human body in contrast to saccharides (liver glycogen) and lipids (adip. tissue) !! 3 Overall metabolism of proteins • All proteins in the body are continuously degraded (metabolized) and newly synthesized • Free AA from food, tissue proteins and non-essential AA from synthesis , make AA pool • AA pool is used for: i. New body proteins ii. Specialized products (amines, NO, porphyrines, NA bases ...) iii. Catabolic proceses (energy gain) 4 ►SOURCES & FATE OF THE AA. POOL: Diatery proteins Non essential a.a.s synthesized in the body Tissue proteins a.a.s Amino acid pool Anabolism Catabolism(Deamination) Synthesis of Fate of deamination products Proteins Other nitrogenous compounds ►Aminosugars ►Nitrogenous bases ►Tissue proteins of phospholipids ►Plasma proteins ►Purines & pyrimidines ►Neurotransmitters ►Enzymes ►Niacin ►Some hormones ►Creatine ►Milk ►Heme α- keto acid Ammonia Krebs cycle glucose Ketone bodies CO2+H2O +ENERGY Non essential a.a.synthesis Synthetic pathway Urea Catabolic pathway glutamine Excreted in urine 6 GENERAL STRATEGY Removal of N from amino acid by transamination (generally first or second step of amino acid catabolic pathways) and collection of N in glutamic acid Deamination of glutamic acid with release of NH4+ by glutamate dehydrogenase Collection of N in glutamine or alanine for delivery to liver Removal of NH4+ by : i. secretion; or ii. Conversion to urea or other less toxic form. 8 9 10 11 TRANSAMINATION ► α-ketoglutarate & glutamate are often involved in transamination reactions Coenzyme: PLP (Pyridoxal phosphate) 12 13 In transaminations, nitrogen of most AA is concentrated in glutamate Glutamate then undergoes oxidative deamination and releases free ammonia NH3 14 DEAMINATION . α- a.a. ◄ ► α- keto glutarate ◄ GLUTAMATE DEHYDROGENASE GLUTAMATE TRANSAMINASE α- keto acid ◄ ► Glutamic acid ◄ ► NH3 ►NAD(P)H+H NAD(P) ► H2O Intracellular localization Transamination glutamate cytosol mitochondria NH3 Glutamate glutamate Dehydregenase urea synthesis cytosol Glu + NH3 Gln 16 Dehydrogenation deamination of glutamate is a reversible reaction GMD HOOC CH CH2CH2COOH NH2 HOOC C CH2CH2COOH - 2H NH NAD(P)+ glutamát glutamate 2-iminoglutarate 2-iminoglutarát H2O main source of ammonia in cells NH3 + HOOC C CH2CH2COOH O 2-oxoglutarát 2-oxoglutarate 17 GMD = glutamate dehydrogenase Deamination products NH3 α- keto acid ►IMPORTANCE OF OXIDATIVE DEAMINATION glutamate dehydrogenase enzyme is the only enzyme by which a.a. undergoes oxidative deamination in the mammalian tissue. Oxidative deamination by glutamate dehydrogenase is an essential component of TRANSDEAMINATION. 20 ■Diagnostic value of transamination : Transaminases are normally intracellular enzymes. They are elevated in the blood when damage to the cells producing these enzymes occurs. * Increase level of both ALT & AST indicates possible damage to the liver cells. * Increase level of AST ALONE suggests damage to heart muscle , skeletal muscle or kidney. Q. Which cofactor is used by aminotransferases? 22 Pyridoxal phosphate R CH COOH NH 2 H C HO O O CH 2O P OH OH H 3C N 23 Q. What are two main sources of ammonia in human body? 24 Two main sources of ammonia in body • Dehydrogenation deamination of glutamate in cells of most tissues ! • Bacterial fermentation of proteins in large intestine ammonia diffuses freely into portal blood portal blood has high concentration of NH3 ! NH3 is eliminated by liver (under normal cond.) 25 Three ways of ammonia detoxication Feature Urea Glutamine (Gln) Glutamate (Glu) Relevance Compound type H2CO3 diamide γ-amide of Glu α-aminoacid Reaction urea cycle Glu + NH3 hydrog. amin. 2-OG Enzyme 5 enzymes Gln-synthase GMD 3 ATP 1 ATP 1 NADHa mitoch. + cytosol cytosol mitochondria only liver liver + other mainly brain Energy needs Intracell localiz. Organ localiz. a Equivalent of 3 ATP (compare respiratory chain). 26