Carbamoyl phosphate synthetase I

18.2 Nitrogen Excretion and the Urea Cycle
Produced in liver
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
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  a-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
 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
- a-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, a-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
 folate (vitamin) to H4 folate
 Dihydrofolate reductase
 Primary source of one-carbon
 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 onecarbon units (except N5-methyltetrahydrofolate)
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
 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
norephinephrine, epinephrine