BIOCHEMISTRY AND HUMAN NUTRITION

Module 3. Metabolism

Lesson 23
AMINO ACID CATABOLISM

23.1 Introduction

• The catabolism of the amino acids usually begins by removing the amino group.
• Amino groups can then be disposed of in urea synthesis.
• The carbon skeletons produced from the standard amino acids are then degraded to TCA intermediates or their precursors so that they can be metabolized to CO₂ and H₂O or used in gluconeogenesis.

23.2 Catabolic Pathway of Amino Acids Involves three Common Stages

• Removal of alpha-amino group from amino acids (amino acid deamination) and conversion of amino group to ammonia.
• Incorporation of ammonia into urea.
• Conversion of amino acid’s carbon skeletons to common metabolic intermediate.
  

Fig. 23.1 General pathway showing the stages of amino acid catabolism

23.3 Amino Acid Deamination

The removal of the α-amino group from amino acids involve two types of biochemical reactions: transamination and oxidative deamination.

23.3.1 Transamination

• The dominant reactions involved in removing amino acid nitrogen are known as transaminations.
• This class of reactions funnel nitrogen from all free amono acids into a small number of compounds; then, either they are oxidatively deaminated, producing ammonia, or their amino groups are converted to urea by the urea cycle.
• Transaminations involve moving an α-amino group from a donor α-amino acid to the keto carbon of an acceptor α-keto acid. As a result of transfer, α-keto derivatives of amino acid and corresponding amino acid forms.
• All amino acids except lysine, threonine and proline participate in transamination during catabolism.
• Transamination is readily reversible. This reaction is catalyzed by enzyme called aminotransferase (also called transaminase). Each aminotransferase is specific for one or at most a few amino group donors. Aminotransferases are named after the specific amino group donor, because the acceptor of the amino group is almost always α-ketoglutarate, that get aminated to glutamate

Fig. 23.2 Transamination

• Aminotransferases require participation of an aldehyde-containing coenzyme, pyridoxal-5-phosphate, a derivative of pyridoxine (vitamin B6¬).
• Pyridoxal -5-phosphate is covalently attached to the enzyme via a schiff base linkage formed by the condensation of its aldehyde group with the α-amino group of lysine residue.
• Aminotransferases act by transferring the amino group of an amino acid to the pyridoxal part of the coenzyme to generate pryidoxamine phosphate. The pyridoxamine form of the coenzyme then reacts with an α-keto acid to form an amino acid and regenerates the original aldehyde form of the coenzyme.
• The most common compounds involved as a donor/acceptor pair in transamination reactions are glutamate and α-ketoglutarate, which participate in reactions with many different aminotransferases.

• All the amino nitrogen from amino acid that undergo transamination can be concentrated in glutamate. This is important because L-glutamate is the only amino acid that undergoes oxidative deamination at an appreciable rate.

Fig. 23.3 Example of transamination

23.3.2 Glucose-alanine cycle

In skeletal muscle, excess amino groups are generally transferred to pyruvate to form alanine, which finally enters into the liver where it undergoes transamination to yield pyruvate for use in gluconeogenesis. The resulting glucose is returned to the muscles, where it is glycolytically degraded to pyruvate.

Fig. 23.4 Glucose alanine cycle

23.3.3 Oxidative deamination

• Transamination does not result in any net deamination. During oxidative deamination, an amino acid is converted into the corresponding keto acid by the removal of the amine functional group as ammonia and the amine functional group is replaced by the ketone group. the ammonia eventually goes into the urea cycle.
• As the recipient of amino groups from many sources, glutamate now sheds it as ammonia for excretion, and the product a-ketoglutarate can recycle as a nitrogen acceptor, enter the TCA cycle, or serve as a precursor in gluconeogenesis
• Deamination occurs mainly through the oxidative deamination of glutamate by glutamate dehydrogenase. The reaction requires an oxidizing agent NAD⁺ or NADP⁺. Glutamate dehydrogenase is allosterically inhibited by GTP and NADH and activated by ADP and NAD⁺.

Fig. 23.5 Oxidative deamination of glutamate

23.4 Urea Cycle

• Living organisms excrete the excess nitrogen resulting from the metabolic breakdown of amino acids in one of three ways.
• Many aquatic animals simply excrete ammonia. Where water is less plentiful, however, processes have evolved that convert ammonia to less toxic waste products that therefore require less water for excretion. One such product is urea and other is uric acid.
• Accordingly, living organisms are classified as being either ammonotelic (ammonia excreting), ureotelic (urea excreting) or uricotelic (uric acid excreting).
• Urea is formed from ammonia, CO₂ and aspartate in a cyclic pathway referred to as the urea cycle. Because the urea cycle was discovered by Krebs and Henseleit, it is often referred to as Krebs-Henseleit cycle.
• Urea synthesis, which occurs in the hepatocytes (liver cells), consists of five sequential enzymatic reactions. The first two reactions occur in the mitochondria and the remaining three reactions take place in the cytosol.
• Urea cycle begins with the formation of carbamoyl phosphate in the mitochondria. The substrates for this reaction, catalyzed by carbamoyl phosphate synthetase I (CPSI), are NH₄⁺ and HCO₃^-. Because two molecules of ATP are required in carbamoyl phosphate synthesis, this reaction is essentially irreversible (one is used to avtivate HCO₃^- and the second molecule is used to phosphorylate carbamate).
• Carbamoyl phosphate subsequently reacts with ornithine to form citrulline. Citrulline passes into the cytosol.

• Next three steps that occur in cytosol involves formation of argininosuccinate by ATP dependent reaction of citrulline with aspartate (aspartate provides second nitrogen that is ultimately incorporated into urea).
• Formation of arginine from argininosuccinate. This reaction releases fumarate, which enters the critic acid cycle. Formation of urea and regeneration of ornithine.

Fig. 23.6 Urea cycle

Net reaction of urea cycle;
CO2 + NH4⁺ + Aspartate + 3ATP + 2H₂O ⇒ Urea + Fumarate + 2ADP + AMP
i.e., four high energy phosphates are consumed in the synthesis of one molecule of urea.