Amino acids genetic disease

Variations in protein structures are not limited to differences between species. Individuals differ from one another. Serious genetic diseases sometimes result from the replacement of a single amino acid unit in a protein by a different amino acid. Genetic deviations from the "normal" structure of a protein result from mutations. Many mutations, whether they occurred initially in our own cells or in those of our ancestors, are detrimental. 

Phenylalanine, an essential amino acid, can be converted to tyrosine in the liver, catalyzed by the enzyme phenylalanine hydroxylase. If phenylalanine hydroxylase is genetically insufficient, phenylketonuria results, with the excretion of phenylpyruvate. In this disease, tyrosine becomes an essential amino acid. This disease can be treated by feeding low-phenylanine diets. 

Other leukodystrophies are associated with the lysosomal and peroxisomal disorders in which specific lipids or other substances accumulate due to a deficiency in a catabolic enzyme - for example Krabbe s disease, meta-chromatic leukodystrophy (MLD) and adrenoleuko-dystrophy (ALD) [1,2]. (These are discussed in detail in Ch. 40.) Similarly, disorders of amino acid metabolism can lead to hypomyelination - for example phenylketonuria and Canavan s disease (spongy degeneration) [1, 2, 25] (Ch. 40). The composition of myelin in the genetically... 

A much more serious genetic disease, first described by Foiling in 1934, is phenylketonuria. Here the disturbance in phenylalanine metabolism is due to an autosomal recessive deficiency in liver phenylalanine hydroxylase (Jervis, 1954) which normally converts significant amounts of phenylalanine to tyrosine. Phenylalanine can therefore only be metabolized to phenylpyruvate and other derivatives, a route which is inadequate to dispose of all the phenylalanine in the diet. The amino acid and phenylpyruvate therefore accummulate. The condition is characterized by serious mental retardation, for reasons which are unknown. By the early 1950s it was found that if the condition is diagnosed at birth and amounts of phenylalanine in the diet immediately and permamently reduced, mental retardation can be minimized. The defect is shown only in liver and is not detectable in amniotic fluid cells nor in fibroblasts. A very sensitive bacterial assay has therefore been developed for routine screening of phenylalanine levels in body fluids in newborn babies. 

Another application of bioinformatics is the use of pharmacogenomics. There are some diseases, such as sickle cell anemia (Exhibit 2.3), in which the difference of one amino acid group can have drastic consequences. These differences in nucleotides are termed single nucleotide polymorphisms (SNPs). SNPs, whether due to genetic origins or environmental factors, translate to individual differences. By understanding these SNPs using bioinformatics, more individualized medicines with better efficacy and less adverse effects can be prescribed. 

Other Genetic Diseases Associated With Amino Acid Metabolism... 

Since elucidation of the sequences of the genes encoding the alr a2, and subtypes of adrenoceptors, it has become clear that there are relatively common genetic polymorphisms for many of these receptor subtypes in humans. Some of these may lead to changes in critical amino acid sequences that have pharmacologic importance. Often, distinct polymorphisms occur in specific combination termed haplotypes. Some of these polymorphisms have been consistently shown to alter the susceptibility to diseases such as heart failure, to alter the propensity of a receptor to desensitize, and to alter therapeutic responses to drugs in diseases such as asthma. This remains an area of active research because studies have reported inconsistent results as to the pathophysiologic importance of some polymorphisms. 

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