amino acid synthesis & degradation

7/30/2019 Amino Acid Synthesis & Degradation

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Amino Acid Synthesis &

Degradation



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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 normalprotein 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 & Non-

Essential 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, Methionineetc



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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. Amino acids that form Oxaloacetate

B. Amino acids that form α-ketoglutarate

C. Amino acids that form PyruvateD. Amino acids that form Fumarate

E. Amino acids that form Succinyl CoA

F. 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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1. Glutamine:

Glutamine ------------------ Glutamate

Glutamate ----------------- α-ketoglutarate

2. Proline:

Proline --------------

Glutamate Glutamate ---------- α-ketoglutarate

Glutaminase

Oxidative

Deamination

Transamination

Oxidation



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3. Arginine:

Arginine -------------------- Ornithine

Ornithine ------------------- α-ketoglutarate

4. Histidine:



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C. Amino acids that form Pyruvate

1. Alanine:

2. Serine:

3. Glycine:



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C. Amino acids that form Pyruvate

4. Cystine:

Cystine ---------------- Cysteine

Cysteine -------------- Pyruvate

5. Threonine:

Threonine ---------- Pyruvate

Threonine ----------

α

-ketoButyrate

NADH+

Desulfuration

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. Valine & Isoleucine: These branched-

chain amino acids generate propionyl CoA,

which is converted to succinyl CoA by

biotin- and vitamin B12 –requiring reactions.2. Threonine: This amino acid is dehydrated

to α-ketobutyrate, which is converted to

propionyl CoA and then to succinyl CoA.3. Mehtionine: Mthionine degradation and re-

synthesis 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. Leucine: This amino acid is exclusively ketogenic in itscatabolism, forming acetyl CoA and acetoacetate.

2. Isoleucine: This amino acid is both ketogenic andglucogenic, because its metabolism yields acetyl CoA

and propionyl CoA.3. Lysine: An exclusively ketogenic amino acid, this

amino acid is unusual in that neither of its amino groupsundergoes transamination as the first step in catabolism.Lysine is ultimately converted to acetoacetyl CoA.

4. Tryptophan: This amino acid is both glucogenic andketogenic because its metabolism yields alanine andacetoacetyl 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 aremetabolized 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. Transamination: Removal of the aminogroups of all three amino acids is catalyzedby a single, vitamin B6 –requiring enzyme,α

- amino acid aminotransferase .2. Oxidative Decarboxylation: Removal of

the carboxyl group is catalyzed by a singlemultienzyme complex, α -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

formed in the above reaction yields α-β-

unsaturated acyl CoA derivatives.

4. 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 berecognized 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 α-keto Acids:

Alanine, aspartate, and

glutamate are

synthesized by transfer

of an amino group to

the α-keto acids

pyruvate, oxaloacetate,

and α-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.

2. Asparagine: This is

formed from aspartate by

asparagine synthetase ,

using glutamine as the

amide donor.



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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 alsobe formed from glycinethrough transfer of ahydroxymethyl group by

serine hydroxymethyl transfease.

Glycine: This amino acidis synthesized fromserine by removal of a

hydroxymethyl group,also by serine hydroxymethyl transfease.



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Cysteine:

This amino acid is

synthesized by two

consecutive reactions:

1. Homocysteinecombines with serine,

forming cystathionine.

2. Which then is

hydrolyzed to α-ketobutyrate and

cysteine.



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Tyrosine:

Tyrosine is formed fromphenylalanine byphenylalanine hydroxylase .

The reaction requiresmolecular oxygen and thecoenzymetetrahydrobiopterin (BH4).

Tyrosine, like cysteine, isformed from an essentialamino acid and is,

therefore, nonessential onlyin the presence of adequatedietary 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)

http://en.wikipedia.org/wiki/Dominance_(genetics)

http://en.wikipedia.org/wiki/Genetic_disorder

http://en.wikipedia.org/wiki/Phenylalanine_hydroxylase


http://en.wikipedia.org/wiki/Urine

http://en.wikipedia.org/wiki/Urine




http://en.wikipedia.org/wiki/Genetic_disorder

http://en.wikipedia.org/wiki/Dominance_(genetics)



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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 andcatecholamines.



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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 pigmentmelanin, 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 α-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 α-keto acid dehydrogenase activity

Infants show symptoms within the firstseveral days of life.

If not diagnosed and treated, is lethal in thefirst weeks of life.



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Classes of MSUD: (continued…..)

b. Intermediate Form: A higher level of enzyme activity

(approximately 3 –15% of normal).

The symptoms are milder and show an onsetfrom infancy to adulthood.

c. Thiamine Responsive Form:

Increased activity of branched-chain α-keto acid dehydrogenase if given large doses of this vitamin.



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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 todevelop 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 tyrosinase -negative oculocutaneous albinism) resultsfrom a deficiency of tyrosinase activity,causing a total absence of pigment from thehair, eyes, and skin

It is the most severe form of the condition. Inaddition to hypopigmentation, affected

individuals have vision defects andphotophobia (sunlight hurts their eyes). Theyare at increased risk for skin cancer.



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Albinism: (continued…..)

Patient with oculocutaneous albinism, showingwhite 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 β-

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 β-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



Treatment:

Diets low in protein—especially in

phenylalanine and tyrosine—help reduce the

levels of homogentisic acid, and decrease the

amount of pigment deposited in body tissues.

amino acid synthesis & degradation

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