Animal models of inherited metabolic diseases : proceedings of the International Symposium on Animal Models of Inherited Metabolic Disease held in Bethesda, Maryland, October 19-20, 1981 / editors: Robert J. Desnick, Donald F. Patterson, Dante G. Scarpelli.
- International Symposium on Animal Models of Inherited Metabolic Disease (1981 : Bethesda, Md.)
- Date:
- [1982]
Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Credit: Animal models of inherited metabolic diseases : proceedings of the International Symposium on Animal Models of Inherited Metabolic Disease held in Bethesda, Maryland, October 19-20, 1981 / editors: Robert J. Desnick, Donald F. Patterson, Dante G. Scarpelli. Source: Wellcome Collection.
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![ities. An increased K (decreased substrate binding) or a decreased V (reduceff product formation due to defective product rel^a^e or enzyme instability) would lead to ab normal substrate accumulation. In addition, the incorpor ation of an inappropriate amino acid, particularly if charged differently, may significantly alter the enzyme's configuration and render it unstable and susceptible to degradation by endogenous proteases; it is anticipated that most stability mutations would be catalytically inactive and CRM-negative. Of the enzymatic defects characterized to date, most residual activities have had markedly in creased K values or both increased K and decreased V values. The latter presumably reflects mutations which alter substrate binding as well as render the enzyme less stable. Missense or nonsense mutations in the structural gene exons may also alter the enzyme's ability to interact norm ally with critical small molecules, such as allosteric effectors and cofactors. A number of human inborn errors have been identified that involve enzymes requiring the binding of a specific vitamin cofactor for the normal expression of enzymatic activity (Fleisher and Gaull, 1980). These mutations often fall into two groups - those that respond to cofactor supplementation therapy and those that do not. Presumably, the former mutations represent defects in the coenzyme binding site of the enzyme that increase the K for tne coenzyme, whereas the latter group represents defects that severely deform the coenzyme bind ing or other crucial sites. Similarly, multimeric enzyme proteins may be inactive if subunit assembly cannot occur due to a mutation in the structural gene coding for one polypeptide of a heteromultimeric enzyme or for the common subunits of a homomultimer. 2) Posttranslational defects . Missense or nonsense mutations in genes controlling the posttranslational modif ications of the enzyme protein also may cause catalytic deficiencies. For example, one type of posttranslational modification involves processes which control the subcellu- lar compartmentalization of an enzyme, including the cleav age of a peptide leader sequence (Blobel et al_., 1979; Maccecchini ejt a]_., 1979), the synthesis of a specific membrane binding or transport protein, or the addition of specific oligonucleotide moieties. Such abnormalities have been elegantly demonstrated for the (J-glucuronidase iso-](https://iiif.wellcomecollection.org/image/b18027842_0064.JP2/full/800%2C/0/default.jpg)
