II. Examples of metabolic errors

Terms

I. Metabolic errors (also called inborn errors of metabolism or metabolic blocks) is a term applied to inherited enzyme deficiencies.

A. Garrod (1902) was the first to propose the existence of metabolic errors, based primarily on his studies of alkaptonuria.
1. The many chemical conversions in the body are referred to collectively as metabolism. Many occur as sequential chemical steps, called a metabolic pathway.

2. The breakdown of tyrosine in the body involves a number of discrete chemical steps. Garrod's studies indicated that only one step in this metabolic pathway is defective, leading to accumulation of substances that cannot get past this block. Garrod recognized that alkaptonuria appeared to be inherited as a recessive trait. He therefore proposed that a metabolic error or block could be inherited.

B. In the decades that followed, it was shown that:
1. Enzymes are proteins that catalyze specific metabolic steps.

2. Many enzymes catalyze a single step; most catalyze only a few. Enzymes are highly specific with respect to the substrates on which they act.

3. Many metabolic pathways consist of a series of chemical reactions, each catalyzed by a separate enzyme.

C. With the subsequent discovery of the genetic role of DNA and its structure as well as greater understanding of protein structure, the genetic bases for inherited changes in protein function were clarified.

D. Changes in the structure of a gene are likely to change the structure of the enzyme. Most random changes are likely to make the enzyme function less well, and many mutations completely abolish the activity of the enzyme. Most are recessive, since only one functional copy of the gene is often sufficient to carry out the required enzyme activity.

E. Many proteins consist of two or more distinct polypeptide subunits, each coded by a different gene. Mutations in any one of the genes may interfere with function of the enzyme, producing similar or indistinguishable phenotypes.

A. Phenylketonuria (PKU) is an example of a metabolic error in the conversion of the amino acid phenylalanine to tyrosine.
1. PKU occurs when the enzyme phenylalanine hydroxylase (PAH) is nonfunctional.

2. Many different mutations in the PAH gene are known that cause PAH to be inactive.

3. The excess phenylalanine that accumulates in PKU can be avoided by restricting the dietary intake of phenylalanine (protein).

4. Females who have been succesfully treated for PKU by management of diet are able to have children. The typical mating would be pp × PP, producing all Pp children, who should develop normally. However, prenatal exposure to the mother's high levels of phenylalanine will cause irreversible damage to the central nervous system. Therefore, pregnant PKU women must regulate their phenylalanine intake carefully.

5. The artificial sweetner Nutrasweet is a dipeptide, aspartyl-phenylalanyl-methyl ester. Persons with PKU must avoid this substance.

B. Galactosemia is a metabolic error in the metabolism of galactose, a component of lactose (the sugar in milk). Its accumulation causes profound mental retardation and often death. The detrimental effects can be prevented by avoiding milk.

C. Lesch-Nyhan syndrome is due to a defect in the enzyme hypoxanthine phosphoribosyl transferase (HPRT). It is an X-linked recessive; hence only males are affected. Very high blood levels of uric acid are a consequence. If the gene is changed so that the HPRT enzyme is moderately active rather than completely inactive, the only symptoms are a mild form of gout. Thus mutations in the same gene can lead to two quite different diseases.

D. Tay-Sachs disease results from absence of the enzyme hexosaminidase A, which is necessary in lysosomes to break down certain large lipid molecules. It occurs with rather high frequencies (1/3600 births) among Ashkenazic Jews but much lower than that in other populations. Children who have this disorder are phenotypically normal at birth but by two years of age begin to have degeneration of the central nervous system that is always fatal.

Back To:
ZOO 317 / Course info / Lecture sched / Last lecture / Next lecture / On-line resources