Catabolism of amino acid

Catabolism of amino acid

Objective

•       At the end of this lecture, student will be able to

–      Explain the catabolism of amino acid

–      Explain Transamination

–      Describe Deamination

–      Describe Decarboxylation

–      Explain ammonia toxicity

Amino acid pool

•       Protein turnover is the balance between protein synthesis and protein degradation

•        More synthesis than breakdown indicates an anabolic state –positive nitrogen balance, more breakdown than synthesis indicates a catabolic state negative nitrogen balance

Catabolism of amino acid

Ø  Amino group of aminoacid – utilized for formation of urea – excretory end product of protein metabolism

Ø  Carbon skeleton of amino acid converted to keto acid which meet one of the following

•       Utilized for energy

•       Used for synthesis of glucose

•       Formation of fat or ketone bodies

•       Production of non-essential aminoacids

Transamination

Ø  Transfer of amino group from amino acid to keto acid catalyzed by a group of enzymes transaminases or aminotransferases to form a new amino acid and keto acid - transamination

Ø  For this process pair of amino acids and a pair of keto acids are involved

Ø  It involves interconversion of a pair of amino acids and a pair of keto acids

Salient features of Transamination

•       All transaminases requires pyridoxal phosphate (PLP) co-enzyme, which is obtained from vit-B₆

•       Specific transaminases exist for each pair of amino and keto acids

•       No free NH₃ liberated, only transfer of amino group occurs

•       It is a reversible process

•       Important for production of Non-essential amino acids

•       Helps in energy generation

•       All amino acids except lysine, threonine, proline and hydroxy proline participate in transamination

Mechanism of Transamination

•       It occurs in two steps

1. Transfer of amino group to coenzyme pyridoxal phosphate to form pyridoxamine phosphate

2.       The amino group of pyridoxamine phosphate is then transfer to a keto acid to produce new amino acid and enzyme with PLP is regenerated

•       Glutamate + oxaloacetate   ----------- >           α-ketoglutarate + aspartate

                                                            pyridoxal phosphate

Deamination

•       The removal of amino group from amino acid as NH₃ - Deamination

•       Liberation of ammonia for urea cycle

•       It is classified in to two types

                1. Oxidative deamination

                2. Non oxidative deamination

Transamination and deamination occurs simultaneously, involving glutamate as central molecule

Oxidative Deamination

•       Liberation of free ammonia from the amino group of amino acids coupled with oxidation

•       Takes place mostly in liver and kidney

•       Purpose of oxidative deamination is to provide NH₃ for urea synthesis and α-keto acids for a variety of reactions, including energy generation

Role of Glutamate Dehydrogenase (GDH):

•       In the process of transamination, the amino groups of most amino acids are transferred to a-ketoglutarate to produce glutamate

•       Thus, glutamate serves as a collection centre for amino groups in the biological system

•       Glutamate rapidly undergoes oxidative deamination, catalysed by GDH to liberate ammonia

•       Enzyme is unique and utilize either NAD⁺ or NADP⁺ as a co-enzyme

•       Conversion of glutamate to α-ketoglutarate occurs through the formation of an intermediate, α-iminoglutarate

•       GDH is involved in both catabolic and anabolic reactions

Regulation of GDH activity:

•       GDH is a zinc containing mitochondrial enzyme

•       GDH is controlled by allosteric regulation

•       GTP and ATP inhibit GDH

•       GDP and ADP activate GDH

•       Steroid and thyroid hormones inhibit GDH

•       After ingestion of a protein rich meal, liver glutamate level is elevated

Oxidative deamination by amino acid oxidase

•       L-Amino acid oxidase and D-amino acid oxidase are flavoproteins, possessing FMN and FAD, respectively

•       Act on corresponding amino acids( L or D) to produce α-keto acids and NH₃

•       In this reaction, oxygen is reduced to H₂O₂, which is later decomposed by catalase

•       Activity of L-amino acid oxidase is much low while that of D-amino acid oxidase is high in tissues(mostly liver and kidney).

•       L –Amino acid oxidase does not act on glycine and dicarboxylic acids

•       This enzyme, due to its very low activity, does not appear to play any significant role in the amino acid metabolism

Non oxidative deamination

•       Some of the amino acids can be deaminated to liberate NH₃ without undergoing oxidation

a. Amino acid dehydrases:

•       Serine, threonine and homoserine are the hydroxy amino acids

•       They undergo non-oxidative deamination, catalysed by PLP-dependent dehydrases (dehydratase)

b. Amino acid desulfhydrases:

•       The sulfur amino acids, namely cysteine and homocysteine undergo deamination coupled with desulfhydrationto give keto acids

c. Deamination of histidine :

•       The enzyme histidase acts on histidine to liberate NH₃ by a non-oxidative deamination process

Decarboxylation

•       Tissues like liver and microorganisms of the intestinal tract contain enzymes called decarboxylases which require pyridoxal phosphate as coenzyme

•       They remove CO₂ from carboxylic group and convert aminoacid to its corresponding amine

•       The physiologically active amines epinephrine, nor-epinephrine, dopamine, serotonin, α-amino butyrate and histamine are formed through decarboxylation of the corresponding precursor amino acids

Function of ammonia

•       Ammonia is not just a waste product of nitrogen metabolism. lt is involved (directly or via glutamine) for the synthesis of many compounds in the body. These include nonessential amino acids, purines, pyrimidines, amino sugars, asparagine etc

•        Ammonium ions (NHa*) are very important to maintain acid-base balance of the body

Disposal of ammonia

•       The organisms, during the course of evolution, have developed different mechanisms for the disposal of ammonia from the body. The animals in this regard are of three different types

a. Ammoniotelic: The aquatic animals dispose of NH₃ into the    surrounding water

b. Uricotelic: Ammonia is converted mostly to uric acid e.g. reptiles and birds.

c. Ureotelic: The mammals including man convert NH₃ to urea. Urea is a non-toxic and soluble compound, hence easily excreted

Toxicity of ammonia

•       Even a marginal elevation in the blood ammonia concentration is harmful to the brain

•       Only traces 10-20 mg/dl is present in blood

•       When accumulates in the body, results in slurring of speech and blurring of the vision and causes tremors

•       lt may lead to coma and finally death, if not corrected

•       Hyperammonemia : Elevation in blood NH₃ level

•       lmpairment in urea synthesis due to a defect in any one of the five enzymes is described in urea synthesis

•       Hyperammonemia leads to mental retardation.

•       Acquired hyperammonemia may be due to hepatitis, alcoholism etc.

Summary

•       Protein turnover is the balance between protein synthesis and protein degradation

•       Transfer of amino group from amino acid to keto acid is known as transamination

•       Removal of amino group from amino acid as NH₃ is known as deamination

•       All transamination required PLP co-enzyme

•       Marginal elevation in blood ammonia concentration is harmful to the brain