Overview Three possible fates enter citric acid cycle form ketone bodies substrates for gluconeogenesis Urea cycle function degrade excess amino acids and safely remove nitrogen surplus amino acids cannot be stored produce urea pathway aspartate and carbamoyl phosphate provide nitrogens carbamoyl phosphate synthesized from NH4+ + HCO3- + 2 ATP via carbamoyl phosphate synthetase I rate determining step of pathway requires N-acetylglutamate which regulates the cycle only produced when excess amino acids are present nitrogen added from systemic pool via alanine cycle one turn of the cycle: aspartate + NH3 + CO2 + 3 ATP → urea (containing 2N)+ fumarate + 2 ADP + Pi + AMP + PPi + 3 H20 connected to citric acid cycle via aspartate-argininosuccinate shunt fumarate of urea cycle → malate of citric acid cycle oxaloacetate of citric acid cycle → aspartate of urea cycle location cellularly formation of carbamoyl phosphate occurs in the mitochondrial matrix addition of aspartate and removal of fumarate and urea occurs in the cytoplasm systemic liver and kidney deficiencies common presentation hyperammonemia + ↑ [glutamine]blood + ↓ blood urea nitrogen (BUN) onset shortly after birth (< 1-3 day) hyperammonemia intoxication presents with cerebral edema, vomiting, hyperventilation, lethargy, blurring vision α-ketoglutarate consumed stops TCA cycle carbamoyl phosphate synthase I creates carbamoyl phosphate AR inheritance pattern orotic aciduria absent ornithine transcarbamoylase forms citrulline from carbamoyl phosphate XR inheritance pattern most common urea cycle disorder orotic aciduria because excess carbamoyl phosphate is shunted into the UMP synthetic pathway in which orotic acid is an intermediate. treatment low protein diet benzoate or phenylbutyrate chelate nitrogen by becoming aminated Ammonia transport function safely move nitrogenous wastes from tissues to kidney and intestine in the form of glutamine pathway ammonia loaded via glutamine synthetase NH3 + glutamate → glutamine occurs in nearly all tissues ammonia unloaded via glutaminase glutamine → NH3 + glutamate specific to kidneys and intestine (and low concentration in liver) induced by acidosis Glucose-alanine cycle function transport pyruvate from muscle to liver for gluconeogenesis pathway involves reversible aminotransferase reactions alanine aminotransferase (ALT) glutamate + pyruvate → α-ketoglutarate + alanine in muscle α-ketoglutarate + alanine → glutamate + pyruvate in liver requires vitamin B6 aspartate aminotransferase (AST) glutamate + oxaloacetate → α-ketoglutarate + aspartate in liver relationship between amino acids andα-keto acids alanine - NH3 = pyruvate aspartate - NH3 = oxaloacetate glutamate - NH3 = α-ketoglutarate Defects in specific amino acid catabolism all are part of newborn screening program phenylketonuria (PKU) inability to break down phenylalanine deficient in phenylalanine hydroxylase ↓ tetrahydrobiopterin cofactor presentation ↑ phenylalanine, ↓ tyrosine requires tyrosine supplementation mental retardation microcephaly musty/mousy odor to sweat and urine restriction of phenylalanine in the diet though cannot eliminate as it essential for protein synthesis very strict adherence to diet during pregnancy for a mother with PKU avoid aspartame maple syrup urine disease inability to breakdown branched-chain amino acids (Val, Leu, Ile) deficient in branched-chain ketoacid dehydrogenase presentation infantile onset normal for first week progressive onset of symptoms lethargy weight loss hyper/hypotonia mental retardation urine smells of maple syrup death if dietary intake of Val, Leu, Ile is not restricted alkaptonuria inability to breakdown homogentisic acid (breakdown product of tyrosine and phenylalanine) deficient in homogentisate oxidase presentation arthritis accumulates over years in the cartilage (ochronosis) onset prior to third decade urine that darkens upon sitting in air dark coloration of the sclera Hartnup's disease deficiency of neutral amino acid transporter leads to ↓ tryptophan absorption presentation pellagra result of niacin deficiency (niacin produced from tryptophan) homocystinuria inability to breakdown homocystinuria (methionine degradation pathway) causes cystathionine synthase deficiency ↓ affinity of cystathionine synthase for pyridoxal phosphate (B6) homocysteine methyltransferase deficiency deficiency in folate, B6 or B12 in the diet can produce elevated levels of homocysteine presentation vessel damage DVT atherosclerosis MI before 2nd decade of life similar to Marfan's mental retardation lens dislocations downward as opposed to upward in Marfan syndrome tall with long extremities ↑ homocysteine in the urine treatment varies by cause cystathionine synthase deficiency ↓ intake of Met, ↑ intake of Cys, B12 and folate ↓ affinity of cystathionine synthase for pyridoxal phosphate ↑ intake of B6 propionyl-CoA carboxylase/methylmalonyl-CoA deficiency inability to handle Val, Met, Ile, Thr part of propionic acid pathway presentation ketoacidosis propionyl-CoA carboxylase deficiency has ↑ propionic acid, methyl citrate, hydroxypropionic acid methylmalonyl-CoA mutase deficiency has ↑ methylmalonic acid treat by restricting Val, Met, Ile, Thr in the diet