Amino acid metabolism

metabolism of amino acid

1. AMINO ACID METABOLISM DEVIPRIYA P V M PHARM

2. CONTENTS General reactions of amino acid metabolism: Transamination , deamination & decarboxylation Urea cycle and its disorders Catabolism of phenylalanine and tyrosine and their metabolic disorders ( Phenyketonuria , Albinism, alkeptonuria , tyrosinemia ) Synthesis and significance of biological substances; 5-HT, melatonin, dopamine, noradrenaline , adrenaline Catabolism of heme Hyperbilirubinemia and jaundice

3. Metabolism of amino acid The amino group of the amino acids is utilized for the formation of urea which is an excretory end product of protein metabolism. The carbon skeleton of the amino acids is first converted to keto acids (by transamination ) which meet one or more of the following fates. Utilized to generate energy. Used for the synthesis of glucose. Diverted for the formation of fat or ketone bodies. lnvolved in the production of non-essential amino acids .

4. Transamination The transfer of an amino (- NH 2 ) group from an amino acid to a keto acid. It involves the interconversion of a pair of amino acids and a pair of keto acids, catalysed by a group of enzymes called transaminases . All transaminases require pyridoxal phosphate (PLP), a coenzyme derived from vitamin B6. Aspartate transaminase and Alanine transaminase -make a significant contribution for transamination . Only transfer of amino group occurs (free NH 3 is not liberated). Transamination is reversible

5. Transamination is very important for the redistribution of amino groups and production of non essential amino acids, as per the requirement of the cell. Transamination diverts the excess amino acids towards energy generation. The amino acids undergo transamination to finally concentrate nitrogen in glutamate. All amino acids except lysine, threonine , proline and hydroxyproline participate in transamination . Transamination is not restricted to α -amino groups only. Serum transaminases are important for diagnostic and prognostic purposes .

6. Deamination The removal of amino group from the amino acids as NH 3 is deamination . Deamination may be either oxidative or non-oxidative. Oxidative deamination is the liberation of free ammonia from the amino group of amino acids coupled with oxidation. This takes place mostly in liver and kidney . The purpose of oxidative deamination is to provide NH 3 for urea synthesis and α -keto acids for a variety of reactions, including energy generation.

7. Non-oxidative deamination : Some of the amino acids can be deaminated to liberate NH 3 without undergoing oxidation Amino acid dehydrases : Serine, threonine and homoserine are the hydroxy amino acids undergo non-oxidative deamination . Amino acid desulfhydrases : The sulfur amino acids ( cysteine and homocysteine ) undergo deamination coupled with desulfhydration to give keto acids. Deamination of histidine : The enzyme histidase acts on histidine to liberate NH 3

8. Decarboxylation The decarboxylation of amino acids acids or their derivatives results in the formation of amines. This is carried out by a group of enzymes called decarboxylases . Examples: Tryptophan 5- Hydroxytryptophan 5- Hydroxytryptamine . Histidine Histamine PLP PLP CO 2 CO 2

9. Urea cycle Urea is the end product of protein metabolism. The nitrogen of amino acids, converted to ammonia, is toxic to the body. lt is converted to urea and detoxified. Urea is synthesized in liver and transported to kidneys for excretion in urine. Steps involved in urea cycle: Synthesis of carbamoyl phosphate. Formation of citrulline . Synthesis of arginosuccinate . Cleavage of arginosuccinate Formation of urea.

10. Disorders of urea cycle All the disorders invariably lead to a build-up in blood ammonia ( hyperammonemia ), leading to toxicity. The clinical symptoms associated with defect in urea cycle enzymes include vomiting, lethargy, irritability, ataxia and mental retardation.

11. Catabolism of Phenylalanine and Thyrosine Under normal conditions, degradation of phenylalanine mostly occurs through tyrosine . Phenylalanine is hydroxylated at para -position by phenylalanine hydroxylase to produce tyrosine(p- hydroxy phenylalanine)

12. DEGRADATION OF TYROSINE : The metabolism of phenylalanine and tyrosine is considered together. Tyrosine first undergoes transamination to give p- hydroxy phenyl pyruvate, catalysed by tyrosine transaminase . p- Hydroxyphenylpyruvate hydroxylase catalyses oxidative decarboxylation as well as hydroxylation of the phenyl ring of p- hydroxyphenylpyruvate to produce homogentisate . Homogentisate oxidase cleaves the benzene ring of homogentisate to form 4-maleylacetoacetate. Maleylacetoacetate undergoes isomerization to form 4-fumaryl acetoacetate and this reaction is catalysed by maleyl acetoacetate isomerase . Fumaryl acetoacetase brings the hydrolysis of fumaryl acetoacetate to Iiberate fumarate and acetoacetate .

13. Disorders of Thyrosine (phenyl alanine) metabolism Phenylketonuria ( PKU): Due to the deficiency of the hepatic enzyme, phenylalanine hydroxylase , caused by an autosomal recessive gene. This enzyme deficiency impairs the synthesis of tetrahydro biopterin required for the action of phenylalanine hydroxylase Phenylketonuria causes the accumulation of phenylalanine in tissues and blood, and results in its increased excretion in urine. Effects on central nervous system : Mental retardation, failure to walk or talk, failure of growth, seizures and tremor. Effect on pigmentation: hypopigmentation that causes light skin colour, fair hair, blue eyes etc ( ie , inhibit melanin formation)

14. PKU is mostly detected by screening the newborn babies for the increased plasma levels of phenylalanine( PKU, 20-65 mg/dl ; normal 1-2mg/dl ) - Guthrie test. plasma phenylalanine concentration can be maintained within the normal range by selecting foods with low phenylalanine content and/or feeding synthetic amino acid preparations, low in phenylalanine. In some seriously affected PKU patients, treatment includes administration of 5-hydroxytryptophan and dopa

15. Albinism: Occurs due to the lack of synthesis of the pigment melanin. lt is an autosomal recessive disorder Causes for Albinism: Deficiency or lack of the enzyme tyrosinase (enzyme most responsible for the synthesis of melanin). Decrease in melanosomes of melanocytes . lmpairment in melanin polymerization. Lack of protein matrix in melanosomes . Limitation of substrate(tyrosine) availability. Presence of inhibitors of tyrosinase . Lack of melanin in albinos makes them sensitive to sunlight. Increased susceptibility to skin cancer (carcinoma) is observed. Photophobia (intolerance to light) is associated with lack of pigment in the eyes.

16. Alkaptonuria : Defect in enzyme homogentisate oxidase . Homogentisate accumulates in tissues and blood, and is excreted into urine. Homogentisate gets oxidized to the corresponding quinones , which polymerize to give black or brown colour (due to the presence of pigment alkapton ). For this reason, the urine of alkaptonuric patients resembles coke in colour . Alkapton deposition occurs in connective tissue, bones and various organs (nose, ear etc.) resulting in a condition known as ochronosis . consumption of protein diet with relatively low phenyl alanine content is recommended as treatment.

17. Tyrosinosis or Tyrosinemia Type I This is due to the deficiency of the enzymes fumaryl aceto acetate hydroxylase and/or maleyl acetoacetate isomerase . lt causes liver failure, rickets, renal tubular dysfunction and polyneuropathy . In acute tyrosinosis , the infant exhibits diarrhea, vomiting, and 'cabbage-like' odor. Death may even occur due to liver failure within one year. For the treatment, diets low in tyrosine, phenylalanine and methionine are recommended. Tyrosinemia type ll ( Richner - Hanhart syndrome) This is due to a defect in the enzyme tyrosine transaminase . Blockade in the routine degradative pathway of tyrosine. Accumulation and excretion of tyrosine and its metabolites(p- hydroxy phenyl pyruvate, p- hydroxyphenyl acetate, N- acetyltyrosine and tyramine ) are observed. The absence of the enzyme p- hydroxyphenylpyruvate dioxygenase causes neonatal tyrosinemia .

18. Serotonin / 5-hydroxytryptamine (5HT) Melatonin 5HT is a neurotransmitter, synthesized from tryptophan Functions: Serotonin is a powerful vaso -constrictor and results in smooth muscle contraction in bronchioles and arterioles. lt is involved in the regulation of cerebral activity (excitation). Serotonin controls the behavioural patterns, sleep, blood pressure and body temperature. Serotonin evokes the release of peptide hormones from gastro intestinal tract. lt is also necessary for the motility of GIT (peristalsis) Melatonin is a hormone, mostly synthesized by the pineal gland. The synthesis and secretion of melatonin from pineal gland is controlled by light. Functions: Melatonin is involved in circadian rhythms or diurnal variations (24 hr cyclic process) of the body. It playsa significant role in sleep and wake process. It inhibits the production of melanocyte stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH). lt has some inhibitory effect on ovarian functions. Melatonin also performs a neuro transmitter function. Synthesis and Significance of 5-HT, Melatonin

19. Synthesis of Catecholamines (Dopamine, Noradrenaline , Adrenaline ) Catechol refers to the dihydroxylated phenyl ring Amine derivatives of catechol are called catecholamines . Tyrosine is the precursor for the synthesis of catecholamines , namely dopamine, norepinephrine ( noradrenaline ) and epinephrine (adrenaline). The conversion of tyrosine to catecholamines occurs in adrenal medulla and central nervous system. Functions of catecholamines : Norepinephrine and epinephrine regulate carbohydrate and lipid metabolisms. They stimulate the degradation of triacylglycerol and glycogen. They cause an increase in the blood pressure. Dopamine and norepinephrine serve as neurotransmitters in the brain and autonomous nervous system.

20. Synthesis of catecholamines : Tyrosine is hydroxylated to 3,4-dihydroxyphenylalaine (DOPA) by tyrosine hydroxylase . This reaction requires tetra hydro biopterin as coenzyme. DOPA undergoes PLP- dependend decarboxylation to give dopamine which, in turn, is hydroxylated to produce norepinephrine . Methylation of norepinephrine by S- adenosyl methionine gives epinephrine. The difference between epinephrine and norepinephrine is only a methyl group ( norepinephrine has no methyl group).

21. Catabolism of Heme Heme is the non-protein part of Hemoglobin . Heme is the most important porphyrin containing compound. Porphyrins are cyclic compounds composed of 4 pyrrole rings held together by methenyl (=CH) bridges. lt is synthesized in the liver and bone marrow.

22. Heme oxygenase utilizes NADPH and 0 2 and cleaves the methenyl bridges between the two pyrrole rings (A and B) to form biliverdin . Simultaneously, ferrous iron (Fe 2+ ) is oxidized to ferric form (Fe 3+ ) and released. The products of heme oxygenase reaction are biliverdin (a green pigment), Fe 3+ and carbon monoxide (CO). Biliverdin's methenyl bridges (between the pyrrole rings C and D) are reduced to form bilirubin (yellow pigment). This reaction is catalysed by biliverdin reductase . Transport of bilirubin to liver : Bilirubin is lipophilic and therefore insoluble in aqueous solution. So it is non covalently bound to albumin and is transported.

23. Hyperbilirubinemia and Jaundice Hyperbilirubinemia represent the increased concentration of serum bilirubin . Jaundice is a clinical condition characterized by yellow colour of the white of the eyes ( sclerae ) and skin. This is due to the elevated serum bilirubin level, usually beyond 2 mg/dl (normal < 1 mg/dl). Hemolytic jaundice : is associated with increased hemolysis of erythrocytes In hemolytic jaundice, more bilirubin is excreted into the bile. Hemolytic jaundice is characterized by: Elevation in the serum unconjugated bilirubin . Increased excretion of urobilinogen in urine. Dark brown colour of feces

24. Hepatic ( hepatocellular ) jaundice is caused by dysfunction of the Iiver due to damage to the parenchymal cells. Hepatic jaundice is characterized by Increased levels of conjugated and unconjugated bilirubin in the serum. Dark coloured urine. lncreased activities of alanine transaminase (SGPT) and aspartate transaminase (SCOT) released into circulation due to damage to hepatocytes . The patients pass pale, clay coloured stools. Nausea and anorexia (loss of appetite) Obstructive (regurgitation) jaundice is due to an obstruction in the bile duct that prevents the passage of bile into the intestine. Obstructive jaundice is characterized by: Increased concentration of conjugated bilirubin in serum. Serum alkaline phosphatase is elevated Dark coloured urine. Feces contain excess fat nausea and gastrointestinal pain