Disorder Of amino Acid Metabolism

 Introduction

In earlier units, you have studied the basics of metabolism. to recap your concept let us first define metabolism. metabolism is the sum of all the chemical reaction that take place in an organism. some of the reaction that are involved in breakdown of molecules to release energy and provide biosynthetic precursors are catabolic reaction while other that are involved in synthesis of biomolecules essential for development and maintenance are termed anabolic reaction.

All these reaction while are catalyzed by enzymes. a defect in an enzyme /protein required for any one reaction can lead to either accumulation of a toxic metabolite or loss of an essential metabolite. in most cases this can lead to a disease , which may be fatal ,if left unattended. this unit deals with six inborn of amino acid metabolism.

Understanding Inborn Errors Of Metabolism

An inborn error arises due a mutation in a gene that result in an abnormality in the quantity or quality of a protein concerned is an enzyme or a transporter involved in digestion absorption or metabolism of major biomolecules the disorder are classified as inborn errors of metabolism the disorder are classified as inborn errors metabolism 

this term was coined by Archibald Edward Garrod. to date more than 550 IEMs have identified. of required metabolites or build up of abnormal metabolites /toxic byproducts.

    

Disorders Of Amino Acids Metabolism

In this unit ,we are mainly concerned with a handful of IMEs that affect the metabolism of amino acids. they all follow an autosomal recessive pattern of inheritance and some of them are heterogeneous. Amongst than20 common amino acids present in proteins more than half of them are synthesized de novo in the human body. however, others have to be supplied in the diet and these are termed essential amino acids. 

Amino acids are catabolized by pathways that converge into few intermediate that could be fed to the TCA cycle for complete degradation. any of the enzyme catalyzing these steps may be deficient.

similarly a defect in transport of amino acids (s) could lead to decreased intestinal transport and /or an increased urinary excretion. sometimes an IEMs can result in the  deficiency of an amino acids. let us discuss some of these disorders.

Phenylketonuria (PKU)

Phenylketonuria (PKU) is one of the most prevalent inborn errors of amino acids metabolism, although 

frequency varies among ethnic groups. the most common cause of PKU is a deficiency in phenyalanine hydroxylase (PAH) enzyme. it is an autosomal recessive disorder and therefore arises when both alleles are mutated. this form of PKU is called classical PKU.

PAH is a mixed function oxidase that converts phenyalanine (phe )to tyrosine and required the cofactor tetranyhrobiopterin (BH4), molecules oxygen and iron. normally 3/4 of the phe is converted to tyrosine. loss of PAH activity /cofactor leads to increased concentration of phenyalanine i blood (hyperphenylalaninemia) ;excreation of phenyl keto acids in urine and accumulation of toxic metabolite in the brain. the initial description of PKU was based on the reaction of phenyl pyruvate (a ketone )with ferric chloride, which turns the urine green.

Do you know why there is an increase in phenylketones the deficiency of PAH allows minor routes of catabolism to overtake. 

About 1-2% of cases of PKU are due to mutation in genes coding for enzyme involved in synthesis /reduction of biopterin, an essential cofactor will also affect the synthesis of biomolecules that have one or more reaction dependent of tetrahydrobiopterin.

The presentation of PKU in children is characterized by following symptoms:

High urinary excretion of phenlypruvate and phenyllactate that gives urine a characteristic musty odor 

Hypopigmentation of skin and hair due to a secondary deficiency of tyrosine the precursor of melanin. many also develop other skin disorder such as ecozema,

Most patients show general developmental delay defective neural development ,behavioural  abnormalities ,spasticity, seizures and motor dysfunction. they are mentally retarded (low IQ levels).this may be due to an increased entry of phenylalanine from plasma into the brain mediated by large entry neutral amino acid carrier ,namely ,L-amino acid transporter (LAT-1 )which damage nerve system cells by affecting their myelination and neurotransmission.

In untreated PKU, life expectancy is drastically reduced.

Individuals with non classified PKU additional have a deficiency of hormones /neurotransmitters whose synthesis is dependent on BH4 .

The best therapy for PKU is a low protein diet with restriction on intake of phenylalanine ,supplement with tyrosine. even foods sweetened with aspartame should be avoided. however the foetal  brain is protected by maternal metabolism during gestation. early detection ,through prenatal/ neonatal screening ,and the implementation of dietary restrictions of phenylalanine in the first two or three weeks of life in cases of classical PKU result in near normal development . the efficacy and success of this dietary therapy diet is however dependent on continual monitoring of plasma phenylalanine concentration. the treatment  can be terminated after 5-6 years of age. 

It is important to rule out biopterin deficiency before initiating treatment. patients with BH4  deficient have a more variable clinical course. they require lipophilic biopterin supplements and do not benefits from a phenylalanine restricted diet.