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Too late for second guessing, too late to go back to sleep …

number33

Done byOmar Sami

Corrected byWaseem abu obeida

DoctorDiala

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Just try defying gravity …

This sheet will be divided to two parts, Biosynthesis of Nonessential Amino Acids & Metabolic defects in amino acid metabolism.

Part 1Biosynthesis of Nonessential Amino Acids

Let us find an easier way to remember both essential and non-essential amino acids …

Essential Amino Acid: In case you are Call Of Duty gamer, you must know “ PVT TIM HLL”…

P: Phe / V:Val / T:Thr / T: Trp / I: Ile / M:Met / H:His / L: Leu / L: Lys

Non-Essential Amino Acids:all amino acids which starts with an “A”, “G”, Cys, Pro, Ser, Tyr.

Nonessential amino acids synthesis

Nonessential amino acids are synthesized from:

1. Metabolic intermediates.

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2. Or from the essential amino acids.

Remember that:

Phe gives rise to Tyr.

Met gives rise to Cys.

Synthesis from -Keto acids:

α-keto acids such as pyruvate, oxaloacetate, and α-ketoglutarate are synthesized by aDeamination reaction of alanine, aspartate & glutamate respectively.

So, the aforementioned amino acids can be simply synthesized by an amination reactions of the already mentioned keto acids.

However, remember that Glu can also be synthesized by the reverse of oxidative deamination, catalysed by glutamate dehydrogenase, through a process called “Reductive Amination”.

Synthesis by amidation:

Amidation: is the addition of Amine to form an Amide Group.

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And the two amino acids that contain this amide linkage are:

1. Gln: is formed from Glu by glutamine synthetase.

2. Asn: is formed from Asp by asparagine synthetase, using glutamine as the amide donor.

Proline:

Remember that Proline possesses a Ring structure between the R group & Amino Group.

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Notice that reduction, dehydration and reduction are the reactions that occur to reach proline. Nevertheless, Glutamate is converted to proline by cyclization and reduction.

Serine, glycine, and cysteine

1- Serine:

→ Ser arises from 3-phosphoglycerate that is oxidized to 3 phosphopyruvate, and then transaminated to 3-phospho serine. Serine is formed by hydrolysis of the phosphate ester.

→ Ser can also be formed from glycine through transfer of a hydroxymethyl group by serine hydroxymethyl transferase.

→ N5,N10-methylene- THF is the one carbon donor.

2- Glycine:

Gly is synthesized from serine by removal of a hydroxymethyl group, also by serine hydroxymethyl transferase.

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- THF is the one carbon acceptor.

3- Cysteine:

→ Cys is synthesized by two consecutive reactions in which Homocysteine combines with serine, forming cystathionine that is hydrolysed to α-ketobutyrate and Cys.

→ Homocysteine is derived from Met.

→ Because Met is an essential amino acid, Cys can be synthesized when the Met dietary intake is adequate.

Tyrosine

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• Tyr (non essential AA) is formed from Phe (essential AA) by phenylalanine hydroxylase.

• The reaction requires molecular oxygen and the coenzyme tetrahydrobiopterin (BH4).

• BH4 can be synthesized from GTP.

• One atom of molecular oxygen becomes the hydroxyl group of Tyr, and the other atom is reduced to water.

• BH4 is oxidized to dihydrobiopterin (BH2). • BH4 is regenerated from BH2 by NADH-requiring

dihydro pteridine reductase.

Remember that: Biopterine must be in the reduced form.

Part 2

Metabolic defects in amino acid metabolism

We are going to study a variety of Daily-Heard diseases that we must be familiar with, however, the inherited defects of AA metabolism if stay untreated result in mental

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retardation or other developmental abnormalities because of the harmful accumulation of metabolites.1- Phenylketonuria (PKU):

• The most common inborn error of amino acid metabolism (prevalence 1:15,000).

• Due to phenylalanine hydroxylase deficiency.

• Biochemical changes: accumulation of phenylalanine (and a deficiency of tyrosine).

• Early detection of PKU can save the child from being mentally retarded for the rest of his life.

What are the classical characteristics of PKU:

1- Elevated phenylalanine in tissues, plasma, and urine.

2- The characteristic musty “mousey” urine odor due to phenyllactate, phenylacetate, and phenylpyruvate.

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3- CNS symptoms: Mental retardation (IQ < 50), failure to walk or talk, seizures, hyperactivity, tremor, microcephaly, and failure to grow.

Q: But why mental retardation will occur?

Ans: as a response that the body exerts due to the accumulation of Phe, Phenylanine will be converted to other forms such as Phenylacetate & Phenyllactate, which will penetrate and affect the CNS.

4- Hypopigmentation: fair hair, light skin color, and blue eyes because the hydroxylation of Tyr by tyrosinase (the first step in melanin formation) is competitively inhibited by the high levels of Phe.

5- These days, PKU is a part of the screening made for the newborns as a routine procedure.

Neonatal screening and diagnosis of PKU:

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• PKU is treatable by dietary restriction.

• Lack of neonatal symptoms, so laboratory testing for elevated blood levels of Phe is mandatory.

• The infant with PKU frequently has normal blood levels of Phe at birth because the mother clears the extra Phe through placenta.

• Exposure protein feeding for 24–48 hours elevates Phe, thus, screening should be done after this to avoid false negatives.

Prenatal diagnosis of PKU:

- Caused by any of 100 or more different mutations in the gene that codes for phenylalanine hydroxylase (PAH).

- PKU is often doubly heterozygous (the PAH gene has a different mutation in each allele).

Treatment of PKU

-Dietary restriction: synthetic amino acid preparations low in Phe, supplemented with natural foods low in Phe content (fruits, vegetables, and certain cereals).

-Earlier treatment (prevents neurologic damage days of life) prevents neurologic complications (mental retardation).

-Tyr cannot be synthesized from Phe and becomes an essential amino acid.

-Aspartame (synthetic sweetener) should be avoided since it contains Phe.

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Maternal PKU

-Some cases, the fetus is exposed to high concentrations of Phe, just because his mother lack Phe Hydroxylase, and thus high blood Phe levels in the mother cause microcephaly, mental retardation, and congenital heart abnormalities in the fetus.

- Phenylalanine is a teratogen; can develop teratoma (type of cancer) in the newborn.

- Dietary control of blood phenylalanine must begin prior to conception, and must be maintained throughout the pregnancy.

Notice that:

In the case of non-maternal PKU, the fetus isn’t under any danger of developing mental retardation or any of the unwanted effects while occupying his mother uterus, even though his mother (whom already has the required enzyme) may be exposed to Phe; as the fetus doesn’t need to process any kind of digestion.

2- Hyperphenylalaninemia:

• Phenylalanine Hydroxylase is intact in this case. However, remember that Phe Hydroxylase requires a cofactor (BH4) which must be maintained in the reduced state by the action of Dihydropteridine reductase.

• Dihydropteridine reductase is involved in many reactions, one of which are Tyrosine, Catecholamine & Serotonin synthesis.

• Dihydropteridine reductase deficiency will not reduce BH2 back to BH4, and thus all reactions that require such a cofactor will no longer proceed.

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Dihydropteridine reductase deficiency:

Restricting dietary Phe does not reverse the CNS effects due to deficiencies in neurotransmitters.

Replacement therapy with BH4 or L-DOPA and 5-hydroxytryptophan (products of the affected tyrosine hydroxylase–and tryptophan hydroxylase–catalyzed reactions) improves the clinical outcome.

→→→ More symptoms are expected to be seen due to the inhibition of more than one reaction and not only Tyrosine synthesis.

3- Maple syrup urine disease (MSUD)

• Rare (1:185,000)

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• Autosomal recessive (AR) disorder, most cases are heterozygotes.

• Partial or complete deficiency in branched-chain α-keto acid dehydrogenase complex that decarboxylates Leu, Ile, and Val.

• Branched-chain amino acids are an important energy source in times of metabolic need.

• Accumulation in the blood causes a toxic effect that interferes with brain functions.

• Signs and symptoms: feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic maple syrup odor to the urine.

• If untreated, MSUD leads to mental retardation, physical disabilities, and even death.

MSUD is classified to two main forms:

Classic type & several variant forms

Classic MSUD: symptoms within the first several days of life. If not diagnosed and treated, classic MSUD is lethal in the first weeks of life. → the whole pathway is blocked

Intermediate forms have a higher level of enzyme activity (3–15% of normal) resulting in milder symptoms and delayed onset. → Only part of the pathway is blocked & thus it is less severe.

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Screening and diagnosis: prenatal diagnosis and neonatal screening are available.Treatment: a synthetic formula that contains limited amounts of Leu, Ile, and Val to provide the branched-chain amino acids necessary for normal growth and development without producing toxic levels.

Early diagnosis and lifelong dietary treatment is essential for child normal development.

4- Albinism

• Mainly, a deficiency in Tyrosinase enzyme, or any other enzyme in the pathway of tyrosine synthesis, but it is mainly related to Tyrosinase enzyme.

• Agroup of conditions in which a defect in Tyr metabolism results in a deficiency in the production of melanin.

• Partial or full absence of pigment from the skin, hair, and eyes.

• Inheritance modes: Autosomal Recessive (primary mode), Autosomal Dominant, or X-linked.

• Complete albinism:

1- (tyrosinase-negative oculocutaneous albinism) results from a deficiency of copper-requiring tyrosinase.

2- The most severe form. Total absence of pigment from the hair, eyes, and skin, vision defects and

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photophobia (sunlight hurts their eyes). Higher risk for skin cancer.

5- Homocystinuria

• As the name indicates; Homocysteine in the urine, and thus cysteine won’t be formed, so it will be an essential amino acid.

• Defects in the metabolism of homocysteine.

• Mode of inheritance: AR

• High plasma and urinary levels of homocysteine and Met and low levels of Cys.

• The most common cause is a defect in cystathionine β-synthase that converts homocysteine to cystathionine.

• Symptoms:

Homozygous individuals exhibit ectopia lentis(displacement of the lens of the eye), skeletal abnormalities, a tendency to form thrombi, osteoporosis, and neurological deficits.

• Treatment: oral administration of pyridoxine (vitamin B6) may help If responsive to vitamin B6, symptoms are milder and disease onset is delayed Restriction of methionine intake and supplementation with vitamins

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B6, B12, and folate.

6- Alkaptonuria (Alcaptonuria)

• A rare metabolic condition.

• A deficiency in homogentisic acid oxidase, resulting in the accumulation of homogentisic acid (a reaction that occurs in the degradative pathway of Tyr).

• Characteristic symptoms: Not life threatening.

• Homogentisic aciduria.

• Large joint arthritis.

• Black ochronotic pigmentation of cartilage and collagenous tissue.

• Patients are usually asymptomatic until age 40.

• Dark staining (in the urine) of the diapers can indicate the disease in infants.

• Treatment: diets low in protein—especially in phenylalanine and tyrosine help reduce homogentisic acid levels, and the pigment deposited in body tissues.

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