Human biochemical genetics / by H. Harris.

  • Harris, Harry, 1919-1994.
Date:
1966
Catalogue details

Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Credit: Human biochemical genetics / by H. Harris. Source: Wellcome Collection.

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    INBORN ERRORS OF METABOLISM 5 Garrod developed a simple hypothesis which he thought might explain in a general way the common features of the various ' inborn errors of metabolism'. He suggested that in each condition the body was unable to perform some particular step in the normal course of metabolism. This was presumably due to the congenital absence of the enzyme usually concerned in catalysing the step in question, and as a result a block occurred at this point in the metabolic processes. The unusual concentrations of metabolites in the body fluids and excretions, and the various chnical signs and symptoms with which they might be associated, could all ultimately be traced back to the inability to perform this single step in the metabolic sequence. Thus, if we consider a series of reactions which can be written Á —^C ->Z) -^E cc ß y 8 the congenital absence of the enzyme 7 would be expected to result in a failure to form the metabolite D from its precursor C, and in consequence С would tend to accumulate and perhaps be excreted in unusual amount. The formation of С in excessive quantities or the failure to form D might result in diverse consequences for the organism. Their effect on its viability and fitness would depend on the character of the particular metabolites involved, and on the relative importance of the disturbed sequence of reactions in the overall biochemical economy of the body. There is Httle doubt that this concept of an inborn metabolic block provides an accurate and useful way of understanding the biochemical disturbances to be found in many inherited abnormalities. For example, the sequence of reactions which are believed to take place during the normal oxidation of phenylalanine and tyrosine are shown in Fig. 2. The peculiar composition of the body fluids and urine in phenylketonuria can largely be accounted for in terms of a metabolic block at the point A, and it has now been demonstrated directly that the enzyme system necessary to carry out this step is indeed deficient in phenylketonuria. Similarly a block at point В would be expected to result in the kind of changes which are observed in alkaptonuria. Here again a specific deficiency of the relevant enzyme has been demonstrated directly. However, it should be pointed out that not all the conditions which Garrod originally regarded as examples of metabolic errors can be explained in terms of abnormaUties of intermediary metaboUsm. The