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Nitrogen Disposal
- 1. NITROGEN DISPOSAL Nitrogen disposal,ch 19, Lippincottās
- 2. OVERALL NITROGEN METABOLISM ā¢Nitrogen enters the body in a variety of compounds esp. dietary protein. ā¢ Nitrogen leaves the body as urea, ammonia, and other products derived from amino acid metabolism. ā¢ AMINO ACID POOL ā¢ All of the FAAs present in cells and ECF throughout the body ā¢ Supplied by 1) degrad. Of body proteins; 2) degrad. Of dietary proteins; 3) synthesis of non-essential (ne) aa from intermediates of metabolism ā¢ Depleted by 1) synthesis of body proteins (bp); 2) synthesis of N-containing small molecules purines/pyrimidines/creatinine etc.; 3) conversion of aa into glucose/glycogen/ketone bodies/CO2+H2O
- 3. ā¢ PROTEIN TURNOVER ā¢The phenomenon of simultaneous synthesis and degradation of proteins. ā¢ For most proteins, conc. Is determined mainly by reg. of their synthesis and degradation being not so reg. ā¢ rate= 300-400g protein being degraded and resynthesized each day
- 4. PROTEIN DEGARADTION ā¢ a.Ubiquitināproteasome proteolytic pathway: ā¢ Selective; atp dependent; ā¢ Selection of protein to be degraded; covalent attachment of protein with UBIQUITIN (4-molecules)>> catalyzed by 3 enzymes using ATP>> producing a polyubiquitinated protein; recognized by PROTEASOME complex>> unfolds, deubiquitinates, and cuts the target protein into fragments>> fragments then further degraded by cytosolic proteases to aas
- 6. PROTEIN DEGRADATION ā¢ ATP-independentdegadative enzyme system of the lysosomes ā¢ Non-selective; atp-independent ā¢ Lysosomes use acid hydrolases to no selectively degrade intracellular proteins (āautophagyā) and extracellular proteins (āheterophagyā), such as plasma proteins, that are taken into the cell by endocytosis
- 7. DIGESTION OF DIETARYPROTEINS 247 ā¢ A. Digestion by gastric secretion ā¢ Digestion begins in stomach by gastric juice containing HCl (parietal cells) and pepsinogen (chief cells) ā¢ HCl>> minor role in protein digestion due to dilution but denatures protein and kills microbes ā¢ Pepsinogen>pepsin (by HCl or pepsin itself)> hydrolyses proteins to polypeptides and some faa ā¢ Pepsin>> endopeptidase
- 8. ā¢ B. Digestionby pancreatic enzymes ā¢ Include both endopeptidases and exopeptidases; trypsin; chymotrypsin; elastase; carboxypeptidase; produce oligopepides and faas ā¢ All are zymogens; secretion regulated by cholecystokinin and secretin ā¢ All these enzymes have different specificity for the amino acid R-groups adjacent to the susceptible peptide bond see figure ā¢ Enter peptidase activates trypsin and trypsin then activates all other pancreatic zymogens ā¢ Bicarbonate raises pH
- 9. ā¢ C. Digestion of oligopeptides by enzymes of the s mall intes tine ā¢ Aminopeptidase(exopeptidase); di,tri-peptidases ā¢ Converts oligopeptides to further small peptides and faas ā¢
- 10. ā¢ D. Absorption of amino acids and s mall peptides ā¢ Faas> enterocytes via sodium linked co trapsport ā¢ Di, tri peptides> enterocytes via proton linked transport; in cells they are then converted into faas ā¢ Faas enter portal system (hepatic portal vein etc.) via facilitated diffusion ā¢ Faas> liver > degradation or enter circulation ā¢ From circulation faas enter body cells via active transport systems (7- different systems are known for their transport) ā¢ Cystinuria
- 11. REMOVAL OF NITROGENFROM AMINO ACIDS ā¢ In form of a-amino acids; aa canāt be degraded; remove NH2- group then aa can be metabolized ā¢ This removal involves ā¢ Trans amination: the funneling of amino groups to glutamate ā¢ Oxidative deamination of amino acids ā¢ These processes provide aspartate and ammonia for synthesis of urea in urea cycle
- 12. ā¢ A. Transamination: the funneling of amino groups to glutamate ā¢ Transfer of amino group (ag) from aa to akg (alpha-ketoglutarate); ā¢ aa>> aka(alpha-keto acid) and akg>> glutamate (glm) ā¢ Glm produced may either be oxidatively deaminized or used in the synthesis of neaa ā¢ Reactions catalyzed by aminotransferases; ALT & AST; all reversible reactions ā¢ ALANINE AMINO TRASNFERASE; transfers NH2- from alanine to akg ā¢ Alanine>> pyruvate & akg>> glm ā¢ ASPARTATE AMINOTRANSFERASE; Transfers NH2- from glm to OAA ā¢ Glm>> akg & oaa>> aspartate ā¢ ALT AND AST USED AS DIAGNOSIC BIOMARKER FOR LIVER DISEASES
- 14. ā¢ B. Oxidativedeamination of amino acids ā¢ the simultaneous loss of ammonia coupled with the oxidation of the carbon skeleton ā¢ Removal of NH2- group (primarily from glutamate) and formation of NH3 and aka ā¢ NH3 liberated exists as NH4+ ā¢ Glutamate >> oxidative deamination>> NH3 + akg ā¢ Reaction catalyzed by GDH and coenzyme NADH + H+ ā¢ Akg >> reductive amination >> glutamate ā¢ Reaction catalyzed by GDH and coenzyme NADPH + H+ ā¢ DIRECTIONS OF RXs ā¢ Meal> high protein> high glutamate> aa degradation> NH3 synthesis ā¢ High NH3 levels> glutamate (aa) synthesis ā¢ ADP (low energy levels) > aa degradation> NH3 synthesis by GDH ā¢ GTP (high energy levels) > glutamate synthesis by GDH
- 16. ā¢ C. Transportof ammonia to the liver ā¢ Two mechanisms; both involving muscles a) glutamine formation b) alanine formation ā¢ A) NH3 + Glutamate> GLUTAMINE (in muscle) > glutamine transported to LIVER> where it is cleaved by Glutaminase into glutamate and NH3. NH3 is used in urea synthesis. ā¢ B) glucose> pyruvate via glycolysis in muscle; succinyl coA to pyruvate also in muscles; pyruvate is then converted into ALANINE by transamination catalyzed by ALT; alanine transported out from muscles through blood into LIVER. ā¢ In liver alanine is converted to pyruvate via transamination by ALT producing glutamate. ā¢ Glutamate produced in both mechanisms is acted upon by GDH and is converted into akg and NH3. again NH3 is used for UREA synthesis
- 19. UREA CYCLE ā¢ Onenitrogen from free ammonia (by oxidative deamination of glm) and other from aspartate ā¢ Carbons of urea are derived from HCO3- ā¢ 1st 2 reactions occur in mitochondrial matrix while the remaining occur in cytosol ā¢ 1. Formation of carbamoyl phosphate : ā¢ Carbamoyl phosphate synthase I (CPS-I) converts one molecule of NH3 and HCO3- using 2 molecules of ATP to form 1 molecule of carbamoyl phosphate (CP) ā¢ CPS-I requires N-acetylglutamate as an allosteric activator ā¢ 2. Fo rmatio n o f c itrulline : ā¢ Ornithine transcarboxylase (OTC) transfers carbamoyl portion of CP to ornithine to form citrulline. ā¢ Inorganic phosphate is released ā¢ Ornithine and citrulline move across mitochondrial membranes via co transporters
- 20. ā¢ 3. Synthesisof argininosuccinate : ā¢ Argininosuccinate synthetase combines citrulline with aspartate (containing 2nd nitrogen of urea) to form argininosuccinate ā¢ 1 ATP is used and converted into AMP; last ATP of urea cycle; total 3 ATPs are utilized ā¢ 4. Cleavage of argininosuccinate: ā¢ Argininosuccinate lyase cleaves argininosuccinate into fumarate and arginine. ā¢ Arginine serves as a precursor of urea ā¢ Fumarate is hydrated into malate; malate enters mitochondria via malate-aspartate shuttle and is oxidized into OAA by ongoing TCA-cycle in matrix. ā¢ OAA may be used ā¢ in gluconeogenesis to form glucose ā¢ For formation of aspartate by transamination carried out by AST
- 21. ā¢ 5. Cleavageof arginine to ornithine and urea: ā¢ Arginase hydrolyses arginine to ornithine and urea ā¢ Arginase is present only in liver ā¢ 6. Fate of urea: ā¢ Urea diffuses from liver into blood and is transported to the kidneys where it is excreted ā¢ Part of urea is left unexcreted and goes to intestine via blood where bacterial UREASE cleaves it into NH3. this ammonia is removed in feces. ā¢ Kidney failure of urea excretion> more urea in blood> more urea to reach intestine> more bacterial urease activity> more NH3 production> hyperammonemia> may be treated with antibiotics to kill intestinal bacteria containing UREASE ā¢ Overall stoichiometry of the urea cycle ā¢ Aspartate + NH3 + HCO3ā + 3 ATP + H2O ā urea + fumarate + 2 ADP + AMP + 2 P i + PP i
- 23. METABOLISM OF AMMONIA ā¢A. Sources of ammonia ā¢ 1. From glutamine: produced from catabolism of branched chain aa; transported via blood to liver kidneys and intestine ā¢ Liver and kidneys produce NH3 from glutamine by the action of glutaminase and GDH. ā¢ NH3 produced is converted into urea in case of liver and excreted ā¢ in case of kidneys, NH3 is excreted as NH4+ in urine therefore plays role in maintaining acid-base balance ā¢ In intestine intestinal mucosal cells produce NH3 by the action of intestinal glutaminase on glutamine. This ammonia either enters blood or is removed via feces ā¢ 2. From bacterial action in the intestine: urea produced in liver enters blood and reaches kidneys and to some extent intestine. In intestine, bacterial urease converts urea to NH3. This ammonia either enters blood or is removed via feces ā¢ 3. From amines : ā¢ 4. From purine s and pyrimidines :
- 24. ā¢ B. Transportof ammonia in the circulation ā¢ Ammonia in its free form can be vey toxic for CNS. Therefore it is transported in blood in form of glutamine or alanine rather than as free NH3 ā¢ NH3 can be converted into urea for safe disposal via kidneys ā¢ Or NH3 can be converted into glutamine by combining glutamate and NH3 in the presence of glutamine synthase. Glutamine is a safe transport and storage form of NH3 ā¢ Glutamine formation occurs mostly in muscles but is of significant importance in CNS to avoid toxic levels of NH3
- 25. HYPERAMMONEMIA ā¢ Normal NH3levels 5-35 micromole/liter ā¢ Elevated levels due either to liver disease (acquired hyperammonemia) or genetic defects (congenital hyperammonemia) can raise the NH3 blood levels above 1000 micromoles/liter ā¢ Elevated concentrations of ammonia in the blood cause the symptoms of ammonia intoxication, which include tremors, slurring of speech, somnolence (drowsiness), vomiting, cerebral edema, and blurring of vision. ā¢ At high concentrations, ammonia can cause coma and death