18.2 Nitrogen Excretion and the Urea Cycle Produced in liver Blood Kidney  urine

Urea Cycle in Mitochondria Formation of carbamoyl phosphate; preparatory step NH HCO ATP  carbamoyl phosphate + 2 ADP + P i Carbamoyl phosphate synthetase I - ATP-dependent reaction 1 st step in the urea cycle; Ornitine + carbamoyl phosphate  citrulline + P i Ornitine transcarbamoylase

Urea Cycle in Cytosol 2 nd step; formation of argininosuccinate Incorporation of the second N from aspartate Argininosuccinate synthetase  ATP requirement  Citrullyl-AMP intermediate 3 rd step; formation of arginine & fumarate Arginosuccinase; only reversible step in the cycle 4 th step; Cleavage of arginine to urea & ornithine Arginase

Asparatate-argininosuccinate shunt Metabolic links between citric acid and urea cycles In cytosol  Fumarate to malate  citric acid cycle in mitochondria In mitochondria  OAA + Glu   -ketoglutarate + Asp  urea cycle in cytosol Energetic cost Consumption 3 ATP for urea cycle Generation Malate to OAA 1 NADH = 2.5 ATP

Regulation of the Urea Cycle Long term regulation  Regulation in gene expression  Starving animals & very-high protein diet  Increase in synthesis of enzymes in urea cycle Short term regulation  Allosteric regulation of a key enzyme  Carbamoyl phosphate synthetase I  Activation by N-acetylglutamate

Treatment of genetic defects in the urea cycle Genetic defect in the urea cycle  ammonia accumulation; hyperammonemia  Limiting protein-rich diet is not an option  Administration of aromatic acids; benzoate or phenylbutyrate  Administration of carbamoyl glutamate  Supplement of arginine

18.3 Pathways of Amino Acid Degradation

Amino Acid Catabolism Carbon skeleton of 20 amino acids  Conversion to 6 major products - pyruvate - acetyl-CoA -  -ketoglutarate - succinyl-CoA - fumarate - oxaloacetate

Glucogenic or Ketogenic Amino Acids Ketogenic amino acids  Conversion to acetyl-CoA or acetoacetyl-CoA  ketone bodies in liver  Phe, Tyr, Ile, Leu, Trp, Thr, Lys  Leu : common in protein  Contribution to ketosis under starvation conditions Glucogenic amino acids  Conversion to pyruvate,  -ketoglutarate, succinyl-CoA, fumarate, and OAA  glucose/glycogen synthesis  Both ketogenic and glucogenic  Phe, Tyr, Ile, Trp, Thr

Enzyme cofactors in amino acid catabolism One-carbon transfer reactions ; common reaction type, involvement of one of 3 cofactors Biotin ; one-carbon tranfer of most oxidized state, CO 2 Tetrahydrofolate (H 4 folate) ; One-carbon transfer of intermediate oxidation states or methyl groups S-adenosylmethionine ; one-carbon transfer of most reduced state, -CH 3

Tetrahydrofolate folate (vitamin) to H 4 folate  Dihydrofolate reductase Primary source of one-carbon unit  Carbon removed in the conversion of Ser to Gly Oxidation states of H 4 folate ; One-carbon groups bonded to N-5 or N-10 or both - Methyl group (most reduced) - Methylene group - Methenyl, formyl, formimino group (most oxidized)  Interconvertible & donors of one- carbon units (except N 5 -methyl- tetrahydrofolate)

S-adenosylmethionine (adoMet) Cofactor for methyl group transfer Synthesized from Met and ATP  Methionine adenosyl transferase  Unusual displacement of triphosphate from ATP Potent alkylating agent  Destabilizing sulfonium ion  inducing nucleophilic attack on methyl group

Six amino acids are degraded to pyruvate Ala, Trp, Cys, Ser, Gly, Thr  pyruvate   acetyl-CoA  citric acid cycle or gluconeogenesis

Interplay of PLP and H 4 folate in Ser/Gly metabolism

3 rd pathway of glycine degradation - D -amino acid oxidase detoxification of D -amino acid high level in kidney - Oxalate  crystals of calcium oxalate (kidney stones)

Seven Amino Acids Are Degraded to Acetyl-CoA Trp, Lys, Phe, Tyr, Leu, Ileu, Thr  acetoacetyl-CoA  acetyl-CoA

Intermediates of Trp catabolism be precusors for other biomolecules

Catabolic pathways for Phe & Tyr Phe & Tyr are precusors dopamine norephinephrine, epinephrine melanin