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

 

I. DEAMINATION

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.

        PLP-dependent

        serine + H2O pyruvate + NH4+

2. Histidine Ammonia Lyase

        Fig. 20-17, Reaction 8.

        histidine urocanate + NH4+

 

UREA CYCLE

 

        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

 

Antiport: (cytosolic ornithine mitochondria) coupled to (mitochondrial citrulline cytosol).

 

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.