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18.2 Nitrogen Excretion and the Urea Cycle
Produced in liver
Blood
Kidney urine
Urea Cycle in Mitochondria
Formation of carbamoyl phosphate; preparatory step
NH4+ + HCO3
- + 2 ATP carbamoyl phosphate + 2 ADP + Pi
Carbamoyl phosphate synthetase I
- ATP-dependent reaction
1st step in the urea cycle;
Ornitine + carbamoyl phosphate citrulline + Pi
Ornitine transcarbamoylase
Urea Cycle in Cytosol
2nd step; formation of argininosuccinate Incorporation of the second N from aspartate Argininosuccinate synthetase ATP requirement Citrullyl-AMP intermediate
3rd step; formation of arginine & fumarate Arginosuccinase; only reversible step in the cycle
4th 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, CO2
Tetrahydrofolate (H4 folate) ; One-carbon transfer of intermediate oxidation states or methyl groups S-adenosylmethionine ; one-carbon transfer of most reduced state, -CH3
Tetrahydrofolate
folate (vitamin) to H4 folate Dihydrofolate reductase
Primary source of one-carbon unit
Carbon removed in the conversion of Ser to Gly
Oxidation states of H4 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 N5-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 H4folate in Ser/Gly metabolism
3rd 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
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