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Amino Acid Synthesis & Degradation

Introduction:
Amino acid degradation involves two steps: 1. Relaease of α-amino group (NH3 release) 2. α – ketoacids formation: that enters into intermediary pathway and liberates energy.

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Essential Amino Acids:

The essential amino acids cannot be synthesized (or produced in sufficient amounts) by the body and, therefore, must be obtained from the diet in order for normal protein synthesis to occur. e.g. Cystein, Tyrosine, Histidine, Valine.

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Non-Essential Amino Acids:

Nonessential amino acids can be synthesized in sufficient amounts from the intermediates of metabolism or, as in the case of cysteine and tyrosine, from essential amino acids. E.g. Alanine, Arginine, Tyrosine etc

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Classification of Essential & NonEssential Amino Acids 12/25/2012 5 .

A.g. Glucogenic amino acids    Amino acids whose catabolism yields pyruvate or one of the intermediates of the citric acid cycle are termed glucogenic or glycogenic. Alanine. Histidine. Methionine etc 12/25/2012 6 . E. Arginine. These intermediates are substrates for gluconeogenesis.

Leucine.B.g. Lysine. Ketogenic Amino Acids:   Amino acids whose catabolism yields either acetoacetate or one of its precursors (acetyl CoA or acetoacetyl CoA) are termed as ketogenic. E. 12/25/2012 7 .

D. 12/25/2012 8 . Amino acids that form Oxaloacetate Amino acids that form α-ketoglutarate Amino acids that form Pyruvate Amino acids that form Fumarate Amino acids that form Succinyl CoA Amino acids that form Acetyl CoA or Acetoacetyl CoA. E. C. B.Amino Acids Degradation: Classification A. F.

deprives cancer cells of a required nutrient. therefore. • Asparaginase. which hydrolyzes asparagine to aspartate. • Which therefore require asparagine from the blood. • It lowers the level of asparagine in the plasma and. Amino acids that form Oxaloacetate • Leukemic cells are unable to synthesize sufficient asparagine to support their growth. 12/25/2012 9 . can be administered systemically to treat leukemic patients.A.

  Glutamine: Glutaminase Glutamine ------------------ Glutamate Transamination Glutamate ----------------- α-ketoglutarate Oxidative Deamination 2.B. Proline: Oxidation  Proline -------------- Glutamate  Glutamate ---------- α-ketoglutarate 12/25/2012 10 . Amino acids that form α-ketoglutarate 1.

B. Amino acids that form α-ketoglutarate 3. Arginine:  Arginine -------------------- Ornithine  Ornithine ------------------- α-ketoglutarate 4. Histidine: 12/25/2012 11 .

Amino acids that form Pyruvate 1. 3.C. 2. Alanine: Serine: Glycine: 12/25/2012 12 .

Amino acids that form Pyruvate 4. Cystine: NADH+ Cystine ---------------- Cysteine Desulfuration Cysteine -------------- Pyruvate 5.C. Threonine: Threonine ---------- Pyruvate Threonine ---------- α-ketoButyrate Succinyl Co-A 12/25/2012 13 .

D. Amino acids that form Fumarate   Tyrosin Phenylalnoin 12/25/2012 14 .

Amino acids that form Succinyl Co-A. which is converted to succinyl CoA by biotin. 2. 1. 3.E. Mehtionine: Mthionine degradation and resynthesis pathway is given as below: 15 12/25/2012 . Threonine: This amino acid is dehydrated to α-ketobutyrate.and vitamin B12–requiring reactions. which is converted to propionyl CoA and then to succinyl CoA. Valine & Isoleucine: These branchedchain amino acids generate propionyl CoA.

Amino acids that form Acetyl CoA or Acetoacetyl CoA. 12/25/2012 16 .E.

this amino acid is unusual in that neither of its amino groups undergoes transamination as the first step in catabolism. 2. Lysine is ultimately converted to acetoacetyl CoA. Amino acids that form Acetyl CoA or Acetoacetyl CoA. forming acetyl CoA and acetoacetate. 4. 3. Leucine: This amino acid is exclusively ketogenic in its catabolism. because its metabolism yields acetyl CoA and propionyl CoA. Isoleucine: This amino acid is both ketogenic and glucogenic. Tryptophan: This amino acid is both glucogenic and ketogenic because its metabolism yields alanine and acetoacetyl CoA. Lysine: An exclusively ketogenic amino acid. 17 12/25/2012 . 1.F.

rather than by the liver. In contrast to other amino acids. Their degradative pathway steps are as follows: 18 12/25/2012 . and valine. are essential amino acids. leucine.Catabolism Of The Branched-chain Amino Acids    The branched-chain amino acids. they are metabolized primarily by the peripheral tissues (particularly muscle). isoleucine.

FAD. and CoA as its coenzymes. NAD+.amino acid aminotransferase. α-keto acid dehydrogenase complex. It uses thiamine pyrophosphate. 19 12/25/2012 .  Transamination: Removal of the amino groups of all three amino acids is catalyzed by a single. 2. vitamin B6–requiring enzyme. α. Oxidative Decarboxylation: Removal of the carboxyl group is catalyzed by a single multienzyme complex. lipoic acid.Steps: 1.

Steps: (continued……) 3. Leucine is ketogenic. End Products: The catabolism of isoleucine yields acetyl CoA (ketogenic) and succinyl CoA (glucogenic).    formed in the above reaction yields α-βunsaturated acyl CoA derivatives. Dehydrogenation: Oxidation of the products 4. being metabolized to acetoacetate and acetyl CoA. 20 12/25/2012 . Valine yields succinyl CoA (glucogenic).

or to both N5 and N10. 21 12/25/2012 . The carbon unit carried by THF is bound to nitrogen N5 or N10. THF allows one-carbon compounds to be recognized and manipulated by biosynthetic enzymes. tetrahydrofolic acid (THF). is produced from folate by Dihydrofolate Reductase in a two-step reaction requiring two moles of NADPH.Folic acid: a carrier of one-carbon units    The active form of folic acid.

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from the essential amino acids phenylalanine and methionine. The synthetic reactions for the nonessential amino acids are described below: 12/25/2012 23 . as in the case of tyrosine and cysteine. respectively.Biosynthesis of Nonessential Amino Acids   These are synthesized from intermediates of metabolism or.

A. 12/25/2012 24 . aspartate. Synthesis From α-keto Acids:  Alanine. oxaloacetate. and α-ketoglutarate. respectively. and glutamate are synthesized by transfer of an amino group to the α-keto acids pyruvate.

which contains an amide linkage with ammonia is formed from glutamate . Asparagine: This is formed from aspartate by asparagine synthetase. The reaction is driven by the hydrolysis of ATP. Glutamate: This amino acid. 25  2.B. using glutamine as the amide donor. 12/25/2012 . Synthesis By Amidation 1.

12/25/2012 26 .C. Proline  Glutamate is converted to proline by cyclization and reduction reactions.

27 12/25/2012 .Serine & Glycine Synthesis:   Serine: Serine can also be formed from glycine through transfer of a hydroxymethyl group by serine hydroxymethyl transfease. Glycine: This amino acid is synthesized from serine by removal of a hydroxymethyl group. also by serine hydroxymethyl transfease.

forming cystathionine. 28 12/25/2012 . Which then is hydrolyzed to αketobutyrate and cysteine.Cysteine:  1. This amino acid is synthesized by two consecutive reactions: Homocysteine combines with serine. 2.

therefore.Tyrosine:    Tyrosine is formed from phenylalanine by phenylalanine hydroxylase. 12/25/2012 29 . is formed from an essential amino acid and is. Tyrosine. nonessential only in the presence of adequate dietary phenylalanine. The reaction requires molecular oxygen and the coenzyme tetrahydrobiopterin (BH4). like cysteine.

Metabolic Defects in Amino Acid Metabolism      Phenylketonuria Maple Syrup Urine Disease Albinism Homocystinuria Alkaptonuria 12/25/2012 30 .

Phenylketonuria (PKU)    Autosomal recessive genetic disorder Caused by hepatic phenylalanine hydroxylase deficiency When PAH is deficient.1. phenylalanine accumulates and is converted into phenylpyruvate which is detected in the urine(musty odor urine) 12/25/2012 31 .

12/25/2012 32 .  BH4 is also required for tyrosine hydroxylase and tryptophan hydroxylase. such as serotonin and catecholamines. which regenerates BH4 from BH2. which catalyze reactions leading to the synthesis of neurotransmitters.Hyperphenylalaninemia may also be caused by  Deficiencies in dihydropteridine (BH2) reductase.

Hyperphenylalaninemia: 12/25/2012 33 .

which is the first step in the formation of the pigment melanin. hyperactivity. light skin color. 34 12/25/2012 . tremor. Hypopigmentation: Fair hair. failure to walk or talk.Characteristics of PKU      Hyperphenylalaninemia CNS symptoms: Mental retardation. seizures. and failure to grow. microcephaly. and blue eyes The hydroxylation of tyrosine by tyrosinase. is competitively inhibited by the high levels of phenylalanine present in PKU.

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Treatment: Avoid diet rich in phenylalanine.  12/25/2012 36 .  Use synthetic amino acid preparations containing low contents of phenylalanine. But  Phenylalanine is an essential amino acid.

and valine Disease is characterized by feeding problems. dehydration. severe metabolic acidosis. vomiting. physical disabilities. Maple Syrup Urine Disease     A rare (1:185. and a characteristic maple syrup odor to the urine. 37 12/25/2012 .2. If untreated.000). and even death. isoleucine. autosomal recessive disorder Characterized by a partial or complete deficiency in branched-chain α-keto acid dehydrogenase. the disease leads to mental retardation. an enzyme complex that decarboxylates leucine.

is lethal in the first weeks of life. If not diagnosed and treated. 38 12/25/2012 . Classic form:     The most common type of MSUD Leukocytes or cultured skin fibroblasts show little or no branched-chain α-keto acid dehydrogenase activity Infants show symptoms within the first several days of life.Classes of MSUD: a.

39 c. Thiamine Responsive Form:  12/25/2012 ..Classes of MSUD: (continued…. The symptoms are milder and show an onset from infancy to adulthood. Increased activity of branched-chain α-keto acid dehydrogenase if given large doses of this vitamin.) b. Intermediate Form:   A higher level of enzyme activity (approximately 3–15% of normal).

Treatment:   A synthetic formula that contains limited amounts of leucine. 12/25/2012 40 . isoleucine. and valine Early diagnosis and lifelong dietary treatment is essential if the child with MSUD is to develop normally.

It may be of different types like:  Autosomal recessive (primary mode). Albinism A defect in tyrosine metabolism results in a deficiency in the production of melanin.  12/25/2012 41 .  Autosomal dominant. or X-linked. hair. and eyes.  Result is the partial or full absence of pigment from the skin.3.

eyes. They are at increased risk for skin cancer. and skin It is the most severe form of the condition. affected individuals have vision defects and photophobia (sunlight hurts their eyes).Albinism: (continued….)   Complete albinism (also called tyrosinasenegative oculocutaneous albinism) results from a deficiency of tyrosinase activity. In addition to hypopigmentation. 42 12/25/2012 . causing a total absence of pigment from the hair..

) Patient with oculocutaneous albinism..Albinism: (continued…. showing white eyebrows and lashes. 12/25/2012 43 .

12/25/2012 44 . Homocystinuria    Defects in the metabolism of homocysteine Autosomal recessive illnesses Characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine.4.

Causes:  The most common cause of homocystinuria is a defect in the enzyme cystathionine βsynthase. which converts homocysteine to cystathionine. 12/25/2012 45 .

Homocystinuria: (continued) Symptoms include:  Ectopia lentis (displacement of the lens of the eye)  Skeletal abnormalities  Premature arterial disease  Osteoporosis  Mental retardation Patients can be responsive or nonresponsive to oral administration of pyridoxine (vitamin B6)—a coenzyme of cystathionine β-synthase. 12/25/2012 46 .

12/25/2012 47 .Treatment:  Restriction of methionine intake and supplementation with vitamins B6. B12. and folate.

Alkaptonuria A rare metabolic disease involving a deficiency in homogentisic acid oxidase Symptoms include:  Homogentisic aciduria.5.  Large joint arthritis  Black ochronotic pigmentation of cartilage and collagenous tissue  12/25/2012 48 .

and decrease the amount of pigment deposited in body tissues. 12/25/2012 49 .Treatment:  Diets low in protein—especially in phenylalanine and tyrosine—help reduce the levels of homogentisic acid.