Amino Acid Synthesis & Degradation

Introduction:
Amino acid degradation involves two steps: 1. Relaease of -amino group (NH3 release) 2. 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

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A. Glucogenic amino acids

Amino acids whose catabolism yields pyruvate or one of the intermediates of the citric acid cycle are termed glucogenic or glycogenic. These intermediates are substrates for gluconeogenesis. E.g. Alanine, Arginine, Histidine, Methionine etc

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B. 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.g. Leucine, Lysine.

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Amino Acids Degradation: Classification

A. B. C. D. E. F.

Amino acids that form Oxaloacetate Amino acids that form -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.

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A. Amino acids that form Oxaloacetate

Leukemic

cells are unable to synthesize sufficient asparagine to support their growth. Which therefore require asparagine from the blood.

Asparaginase, which hydrolyzes asparagine to aspartate, can be administered systemically to treat leukemic patients. It lowers the level of asparagine in the plasma and, therefore, deprives cancer cells of a required nutrient.
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B. Amino acids that form -ketoglutarate

1.

Glutamine: Glutaminase Glutamine ------------------ Glutamate Transamination Glutamate ----------------- -ketoglutarate

Oxidative Deamination

2. Proline: Oxidation Proline -------------- Glutamate Glutamate ---------- -ketoglutarate

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B. Amino acids that form -ketoglutarate

3. Arginine: Arginine -------------------- Ornithine Ornithine ------------------- -ketoglutarate 4. Histidine:

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C. Amino acids that form Pyruvate

1.

2.
3.

Alanine: Serine: Glycine:

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C. Amino acids that form Pyruvate

4. Cystine: NADH+ Cystine ---------------- Cysteine Desulfuration Cysteine -------------- Pyruvate 5. Threonine: Threonine ---------- Pyruvate Threonine ---------- -ketoButyrate
Succinyl Co-A
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D. Amino acids that form Fumarate

Tyrosin Phenylalnoin

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E. Amino acids that form Succinyl Co-A.

1.

2.

3.

Valine & Isoleucine: These branchedchain amino acids generate propionyl CoA, which is converted to succinyl CoA by biotin- and vitamin B12requiring reactions. Threonine: This amino acid is dehydrated to -ketobutyrate, which is converted to propionyl CoA and then to succinyl CoA. Mehtionine: Mthionine degradation and resynthesis pathway is given as below:
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E. Amino acids that form Acetyl CoA or Acetoacetyl CoA.

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F. Amino acids that form Acetyl CoA or Acetoacetyl CoA.

1. 2.

3.

4.

Leucine: This amino acid is exclusively ketogenic in its catabolism, forming acetyl CoA and acetoacetate. Isoleucine: This amino acid is both ketogenic and glucogenic, because its metabolism yields acetyl CoA and propionyl CoA. Lysine: An exclusively ketogenic amino acid, this amino acid is unusual in that neither of its amino groups undergoes transamination as the first step in catabolism. Lysine is ultimately converted to acetoacetyl CoA. Tryptophan: This amino acid is both glucogenic and ketogenic because its metabolism yields alanine and acetoacetyl CoA.
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Catabolism Of The Branched-chain Amino Acids

The branched-chain amino acids, isoleucine, leucine, and valine, are essential amino acids. In contrast to other amino acids, they are metabolized primarily by the peripheral tissues (particularly muscle), rather than by the liver. Their degradative pathway steps are as follows:
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Steps:
1.

2.

Transamination: Removal of the amino groups of all three amino acids is catalyzed by a single, vitamin B6requiring enzyme, - amino acid aminotransferase. Oxidative Decarboxylation: Removal of the carboxyl group is catalyzed by a single multienzyme complex, -keto acid dehydrogenase complex. It uses thiamine pyrophosphate, lipoic acid, FAD, NAD+, and CoA as its coenzymes.
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Steps: (continued)
3. Dehydrogenation: Oxidation of the products

4.

formed in the above reaction yields -unsaturated acyl CoA derivatives. End Products: The catabolism of isoleucine yields acetyl CoA (ketogenic) and succinyl CoA (glucogenic). Valine yields succinyl CoA (glucogenic). Leucine is ketogenic, being metabolized to acetoacetate and acetyl CoA.
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Folic acid: a carrier of one-carbon units

The active form of folic acid, tetrahydrofolic acid (THF), is produced from folate by Dihydrofolate Reductase in a two-step reaction requiring two moles of NADPH. The carbon unit carried by THF is bound to nitrogen N5 or N10, or to both N5 and N10. THF allows one-carbon compounds to be recognized and manipulated by biosynthetic enzymes.
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Biosynthesis of Nonessential Amino Acids

These are synthesized from intermediates of metabolism or, as in the case of tyrosine and cysteine, from the essential amino acids phenylalanine and methionine, respectively. The synthetic reactions for the nonessential amino acids are described below:

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A. Synthesis From -keto Acids:

Alanine, aspartate, and glutamate are synthesized by transfer of an amino group to the -keto acids pyruvate, oxaloacetate, and -ketoglutarate, respectively.

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

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C. Proline

Glutamate is converted to proline by cyclization and reduction reactions.

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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.
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Cysteine:

1.

2.

This amino acid is synthesized by two consecutive reactions: Homocysteine combines with serine, forming cystathionine. Which then is hydrolyzed to ketobutyrate and cysteine.
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Tyrosine:

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

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Metabolic Defects in Amino Acid Metabolism

Phenylketonuria Maple Syrup Urine Disease Albinism Homocystinuria Alkaptonuria

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1. Phenylketonuria (PKU)

Autosomal recessive genetic disorder Caused by hepatic phenylalanine hydroxylase deficiency When PAH is deficient, phenylalanine accumulates and is converted into phenylpyruvate which is detected in the urine(musty odor urine)

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

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Hyperphenylalaninemia:

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Characteristics of PKU

Hyperphenylalaninemia CNS symptoms: Mental retardation, failure to walk or talk, seizures, hyperactivity, tremor, microcephaly, and failure to grow. Hypopigmentation: Fair hair, light skin color, and blue eyes The hydroxylation of tyrosine by tyrosinase, which is the first step in the formation of the pigment melanin, is competitively inhibited by the high levels of phenylalanine present in PKU.
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Treatment:
Avoid diet rich in phenylalanine. Use synthetic amino acid preparations containing low contents of phenylalanine. But Phenylalanine is an essential amino acid.

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2. Maple Syrup Urine Disease

A rare (1:185,000), autosomal recessive disorder Characterized by a partial or complete deficiency in branched-chain -keto acid dehydrogenase, an enzyme complex that decarboxylates leucine, isoleucine, and valine Disease is characterized by feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic maple syrup odor to the urine. If untreated, the disease leads to mental retardation, physical disabilities, and even death.
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Classes of MSUD:
a. Classic form:

The most common type of MSUD Leukocytes or cultured skin fibroblasts show little or no branched-chain -keto acid dehydrogenase activity Infants show symptoms within the first several days of life. If not diagnosed and treated, is lethal in the first weeks of life.
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Classes of MSUD: (continued..)

b. Intermediate Form:

A higher level of enzyme activity (approximately 315% of normal). The symptoms are milder and show an onset from infancy to adulthood.
Increased activity of branched-chain -keto acid dehydrogenase if given large doses of this vitamin.
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c. Thiamine Responsive Form:

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Treatment:

A synthetic formula that contains limited amounts of leucine, isoleucine, and valine Early diagnosis and lifelong dietary treatment is essential if the child with MSUD is to develop normally.

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

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Albinism: (continued..)

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

Patient with oculocutaneous albinism, showing white eyebrows and lashes.

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4. 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.

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Causes:

The most common cause of homocystinuria is a defect in the enzyme cystathionine synthase, which converts homocysteine to cystathionine.

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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 -synthase.
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Treatment:

Restriction of methionine intake and supplementation with vitamins B6, B12, and folate.

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

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Treatment:

Diets low in proteinespecially in phenylalanine and tyrosinehelp reduce the levels of homogentisic acid, and decrease the amount of pigment deposited in body tissues.

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