The biochemical genetics of man / edited by D.J.H. Brock, Oliver Mayo.

Date:
1972
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Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: The biochemical genetics of man / edited by D.J.H. Brock, Oliver Mayo. Source: Wellcome Collection.

    51/748 page 35
    1. STRUCTURE AND FUNCTION OF PROTEINS 35 the properties of 76 of the known variants, distinguishable by electro- phoretic or kinetic techniques is shown on p. 174. One common variant (A-]-), when compared with normal enzyme (B^-) has been shown by Yoshida (1967) to contain an amino acid substitution, asparagine-^aspartic acid, although the location of this change is not known. The variant enzyme is similar to the normal enzyme in most respects except electrophoretic mobility. Another common variant at the same genetic locus is the A— enzyme ; in this case it has been shown that the enzyme has a markedly shortened half-life in vivo, and the enzyme deficiency in ageing red cells leads to their suceptibility to haemolysis. A— enzyme has not as yet been purified, but the inference is that an amino acid substitution can importantly affect function by altering in vivo stability. The other variants of G6PDH have widely varying properties. Most are associated with an overall reduction in amount of enzyme per red cell, but in one example (G6PDH Hektoen) the level of enzyme is four times normal. About half of them have altered binding constants for the substrates. Alteration of the kinetic behaviour of an enzyme would be analogous tp the haemoglobins M. Such alterations might affect the binding constants for the substrates, for effector molecules, the subunit inter¬ actions or any other of the points discussed above. A well-studied example, in which the specific mutational event is not known, is that of citrullinaemia (Tedesco and Mellman, 1967). Here the altered argininosuccinate synthetase had a binding affinity for citrulline at least 25 times greater than that of normal enzyme. The changes in atypical serum Cholinesterase (Harris, 1970) seems to be of a similar nature. Frimpter (1965) has reported that in another disease, cystath- ioninuria, addition of abnormally large amounts of coenzyme would activate the defective enzyme (see p. 415). In cases in which no enzyme activity can be detected and in which no protein which cross-reacts with antibody prepared against normal enzyme is present, it is usually assumed that a mutation in a controller gene has occurred. Such an assumption does not rest on a firm foundation. Antibodies against normal enzyme may merely have failed to react with an extensively altered enzyme (Aebi, 1966). Schlesinger (1967) prepared antibodies against denatured E. coli alkaline phosphate and found that they would react with an enzymatically inactive protein from mutant E. coli lacking the enzyme. The wide variety of changes in behaviour of proteins with single substitutions and the specificity of antibodies should make it quite clear that mutations in structural genes with our present state of knowledge will frequently go undetected.
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