AMINO ACID METABOLISM
• Amino acids (AAs) are precursors for proteins.
• Precursors for many other biological N-containing compounds.
• Energy metabolites: When degraded, amino acids produce glucose, carbohydrates and ketone bodies.
• Excess dietary AAs are neither stored nor excreted. Rather, they are converted to common metabolic intermediates.
Fate of Amino Group
1. Ureotelic: urea for excretion most terrestrial vertebrates
2. Uricotelic: uric acid for excretion birds, reptiles
3. Ammonotelic: NH4+ for excretion aquatic animals
Fate of Carbon Skeletons
Converted into 7 common metabolites:
• pyruvate; • acetyl-CoA; • acetoacetate; • a-ketoglutarate;
• succinyl-CoA; • fumarate; • oxaloacetate
FATE OF AMINO GROUP
A. Transamination by Aminotransferase (or Transaminase)
• Funnel a-amino groups from a variety of AAs to glutamate by reacting with a-ketoglutarate.
amino acid + a-ketoglutarate ⇌ a-keto acid + glutamate
· Does not result in any net deamination.
B. Oxidative Deamination
1. Glutamate Dehydrogenase (in mitochondria)
· See p.692
· Glu + NAD+ (or NADP+) + H2O ⇌ NH4+ + a-ketoglutarate + NAD(P)H +H+
· An enzyme unusual (but not the only one as stated in the Textbook) in being able to use NAD+ and NADP+.
· Plays a central role in AA metabolism. In most organisms glutamate is the only AA which has such an oxidative deamination enzyme.
· Glutamate DH is allosterically regulated. It is inhibited by GTP and ATP, and activated by GDP and ADP.
· The NH4+ so obtained can feed into urea cycle.
2. L-Amino Acid Oxidase
· Requires FAD as a cofactor.
· D-Amino acid oxidase also exists in mammalian tissues. Real physiological function unknown.
C. Direct Deamination of Serine and Histidine
1. Serine Dehydratase
· Fig. 20-15.
· serine + H2O ® pyruvate + NH4+
2. Histidine Ammonia Lyase
· Fig. 20-17, Reaction 8.
· histidine ® urocanate + NH4+
· 1932 by Hans Krebs and Kurt Henseleit as the first metabolic cycle elucidated. See Fig. 20-9.
· Overall Reaction:
· NH3 + HCO3– + aspartate + 3 ATP + H2O ® urea + fumarate + 2 ADP + 2 Pi + AMP + PPi
· Requires 5 enzymes: 2 from mitochondria and 3 from cytosol.
1. Carbamoyl phosphate synthetase (Mitochondrial)
· Eukaryotes have two forms of CPS, the mitochondrial CPS I uses ammonia as the N donor for urea synthesis. The cytosolic CPS II uses glutamine as its N donor for pyrimidine biosynthesis.
· 2 ATP + HCO3– + NH3 ® carbamoyl phosphate + 2 ADP + Pi
2. Ornithine transcarbamoylase (Mitochondrial)
· carbamoyl phosphate + ornithine ® citrulline
3. Argininosuccinate synthetase (Cytosolic)
· citrulline + aspartate + ATP ® argininosuccinate + AMP + PPi
4. Argininosuccinase (Cytosolic)
· argininosuccinate ® fumarate + arginine
· The skeleton of Asp is recovered in fumarate. Up to this point, the reactions are the same for all organisms that are capable of synthesizing arginine.
5. Arginase (Cytosolic)
· Only the ureotelic animals have large amounts of the arginase.
· arginine + H2O ® urea + ornithine
REGULATION OF UREA CYCLE
1. Mitochondrial carbamoyl phosphate synthetase I (CPS I)
· CPS I catalyzes the first committed step of the urea cycle.
· CPS I is also an allosteric enzyme sensitive to activation by N-acetylglutamate which is derived from glutamate and acetyl-CoA.
· Increased rate of AA degradation requires higher rate of urea synthesis.
· AA degradation ® ↑glutamate concentration → ↑synthesis of N-acetylglutamate ® ↑CPS I activity ® ↑urea cycle efficiency
2. All other urea cycle enzymes are controlled by the concentrations of their substrates.
· Deficiency in an E ® ↑(substrate) ® ↑rate of the deficient E.