Introduction to Inborn Error Of Phenyl alanine, Tyrosine Metabolism
- Most common inborn error in amino acid metabolism
- High phenylalanine can cause neurologic damage
- Unusual compounds: phenyl-pyruvate; phenyl- lactate; phenylacetate
- Brain toxicity: reduced uptake of other aromatic amino acids
- Tyrosine deficiency may lead to hypopigmentation
Phenylalanine accumulates in all body fluids and converts to phenylpyruvate.
- Defect in myelination of nerves
- The brain weight is below normal.
- Mental and physical retardations.
- The life expectancy is drastically shortened.
- phenylalanine level in the blood
- FeCl3 test
- Guthrie test
- DNA probes (prenatal)
- Significance: One of the genetic diseases made mandatory in USA in screening for infant defects
- Deficiency of Phenylalanine hydroxylase: Increase of plasma Phe since birth – rising levels – impairs brain development, after 6M – severe mental retardation.
- Must screen for phenylalanine after child has been exposed to phenylalanine in breast milk
- Decreased pigmentation of hair and skin .
- Mousy body (phenylacetate in sweat) odor in affected individual. Vomiting simulating congenital pyloric stenosis
Restrict phenylalanine and restrict aspartame (contains phenylalanine) from diet.
Pregnant woman with PKU must restrict phenylalanine from diet or neurotoxic damage will develop in the fetus in uterus.
PKU II (Malignant PKU)
- Dihydrobiopterine raductate (DHFR): cofactor for Phenylalanine hydroxylase. which converts Phenylalanine to tyrosine
- Similar to classic PKU I
- Neurological problems occur regardless of restricting phenylalanine intake .inability to metabolize tryptophan or tyrosine (require BH4), which causes synthesis of neurotransmitters (serotonin and dopamine, respectively)
- Restrict Phenylalanine in diet; administer L –dopa and 5-hydroxytryptophan to replace neurotransmitters and BH4 replacement
- Alkaptonuria has great historical importance.
- It was first described by Lusitanus in 1649 and characterized in 1859.
- Garrod conceived the idea of inborn errors of metabolism from his observation on alkaptonuria.
Alkaptonuria is inherited disorder of the tyrosine metabolism caused by the absence of homogentisate oxidase.
- homogentisic acid is accumulated and excreted in the urine turns a black color upon exposure to air
- urine in diaper may darken
- darkening of the ear
- dark spots on the sclera and cornea
- Albinism is an inborn error, due to the lack of synthesis of the pigment melanin.
- It is an autosomal recessive disorder with a frequency of 1 in 20, 000.
- Biochemical Basis: The color of skin and hair is controlled by a large number of genes.
- Genetic disease
- Classical defect is tyrosinase (tyrosine hydroxylase)
- Formation of little or no skin pigment -> sun sensitivity
- The melanin synthesis can be influenced by a variety of factors.
- Deficiency of enzyme tyrosinase
- Decrease in melanosomes of melanocytes.
- Impairement in melanin polymerization
- Limitation of substrate availability
- Presence of inhibitors of tyrosinase.
Symptoms of albinism
- inhibition of production or lack of melanin in skin, hair, eyes
- increased sensitivity to sunlight
- increased risk of skin cancer development
- sun burns
- decrease of vision acuity
In some individuals, a reduced synthesis of melanin is often observed. Hypo pigmentation disorder may be
- Either diffuse or localized.
- A good example of diffuse hypopigmentation is oculocutaneous albinism which is mostly due to mutation in tyrosinase genes.
TYROSINOSIS OR TYROSINEMIA TYPE 1
- This is due to deficiency of the enzyme
- Fumarylacetoacetate isomerase and or maleyl acetoacetate isomerase.
- Tyrosinosis is a rare but serious disorder.
- It causes liver failure, rickets, renal tubular dysfunction and polyneuropathy.
Tyrosenemia type 2
- This disorder also known as Richner – Hanhart syndrome, is due to defect in the enzyme tyrosine transaminase.
- The result is a blockade in the routine degradative pathway of tyrosine.
Accumulation and excretion of tyrosine and its metabolites namely
- p-hydroxyphenyl – pyruvate,
- p – hydroxy phenyl acetate,
- N- acetyltyrosine and
- tyramine are observed.
- Tyrosinemia type 2 is characterized by skin (dermatitis) eye lesions and rarely mental retardation.
- A disturbed self – coordination is seen in these patients.
- The absence of enzyme p – hydroxy phenyl pyruvate dioxygenase.
- This is mostly a temporary condition and Usually respond to ascorbic acid.
- It is explained that the substrate inhibition Of enzyme is over come by the presence of ascorbic acid.
- Containing an indole ring
- Essential amino acid
- Both glucogenic and ketogenic
- Several biologically important compounds are synthesized from tryptophan e.g. NAD+, NADP+ and serotonin
The metabolism of tryptophan has many branching points. It can be studied in two different pathways
- Kynurenin-Nicotinate pathway
- Serotonin-Melatonin pathway
- Through this pathway tryptophan is oxidised to finally yield acetyl CoA.
- Niacin coenzymes are also synthesized through this pathway
- Nearly half the body’s niacin coenzymes are synthesized by tryptophan
- The remaining half are obtained by diet.
Free niacin cannot be obtained from tryptophan, only its coenzymes are formed from tryptophan
Tryptophan degradation requires several oxygenases
Biosynthesis of Nicotinic Acid
Biological Role of Serotonin
- Serotonin is a vasoconstrictor and causes smooth muscle contraction in arterioles and bronchioles
- It serves as excitatory neurotransmitter in the brain
- Serotonin causes peristalsis and causes the release of peptide hormones from GI tract
- It is capable of influencing the behavioral patterns in humans
- Serotonin plays a role in the regulation of prolactin secretion
- Serotonin acts as a sleep inducer
- It plays a role in the regulation of blood pressure and body temperature
- Mostly synthesized at night, is involved with circadian rhythms
- It regulates the processes of the sleep and wakefulness
- Melatonin inhibits the secretion of MSH and ACTH
- It also acts as a neurotransmitter. It acts by inhibiting the synthesis of other neurotransmitter like dopamine and GABA in the brain
INBORN ERROR OF TRYPTOPHAN
- This disorder was first described in the family of Hartnup, hence the name Hartnup’s Disease.
- It is hereditary disorder of Tryptophan metabolism.
- The clinical symptoms include dermatitis, ataxia, mental retardation etc.
- Hartnup’s disease characterized by low plasma levels of tryptophan and other neutral amino acids and their elevated urinary excretion.
- Pellagra like symptoms are common in these patients.
- Hartnup’s disease is now believed to be due to an impairment in the absorption and transport of tryptophan and other neutral amino acids
- True hypertryptophanuria can be caused either by a defect in the conversion of tryptophan to kynurenine or by an abnormality in renal amino acid transport.
- Aminoacidurias are clinically very important.
- It is estimated that about 20 to 25 % inmates of psychiatric hospitals are suffering from one of the aminoacidurias.
- Most of them manifest as MENTAL RETARDATION.
ONE CARBON METABOLISM
- One carbon groups play a vital role in donating carbon atoms for synthesis of different types of compounds
- One carbon groups are carried by THFA
- THFA is produced from folic acid
- N5 and N10 atoms of THFA carry the 1-carbon groups
Different one carbon compounds
Most of the one-carbon transfers are promoted by one of three cofactors:
- The one carbon group is covalently linked to THF at positions N5 or N10 or both.
- THF carries one carbon groups at 30 oxidation states, which are interconvertible
Most reduced – methyl
Intermediate – methylene
Most oxidised – formyl, formimino and methenyl
Generation of one carbon unit
- Conversion of serine to glycine forms N5, N10-methylene THF. Glycine cleavage also contributes methylene groups
- Tryptophan contributes formyl THF
- Histidine donates formimino group to produce N5-formimino THF
- Choline and betaine contribute hydroxymethyl groups
Functions of Polyamines
- They play a role in the synthesis of proteins, DNA and RNA
- They are required for cell growth and proliferation
- They also act as growth factors
Polyamines levels are elevated in cancer affected tissues. They are excreted in large concentrations in several types of malignancies
Other Biochemistry Notes
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