Molecular Basis of Mutation

Knowledge of chemical structure is only a rough indicator of chemical mutagenicity. The rapidity of the growth of knowledge of the molecular basis of mutation implies that further research will lead to much better prediction of mutagenic potential on the basis of chemical structure. 

J. W. Drake, The Molecular Basis of Mutation, Holden-Day, San Francisco, California, 1970. 

T16. Tolan, D. R Molecular basis of hereditary fructose intolerance Mutations and polymorphisms in the human aldolase B gene. Hum. Mutat. 6,210-218 (1995). 

Kwon, B. S., Halaban, R., and Chintamaneni, C. (1989a). Molecular basis of mouse Himalayan mutation. Biochem. Biophys. Res. Commun. 161 252-260. 

Zdarsky, E., Favor, J., and Jackson, I. J. (1990). The molecular basis of brown, an old mouse mutation, and of an induced revertant to wild type. Genetics 126 443-449. 

Although the evolutionary trace method applied to GPCRs (175,185) fails to detect any residues responsible for the subtype-specific heterodimerizafion that has recently been demonstrated for opioid (96), somatostatin (106), and chemokine (98) receptors, correlated mutation analysis had already been demonstrated to be able to identify useful details of molecular specificity (184). Thus, the molecular basis of specificity was hypothesized to reside in outward (i.e., lipid) facing residues of TM5 and TM6 that exhibited evolutionarily correlated mutations and differed between receptor subtypes (184) in the case of dimerization. In the case of oligomers, the key interface between different subtypes was suggested to be the 2,3-interface (152) rather than the 5,6-interface. 

The molecular basis of medium chain acyl-CoA dehydrogenase deficiency survey and evolution of 985A—G transition, and identification of five rare types of mutation within the medium chain acyl-CoA dehydrogenase gene. 

The isolation and characterization of genes may be divided into three epochs. Prior to the 1980s, investigators interested in the molecular basis of a particular disorder had a limited number of tools available. During this classical period, the approach usually consisted of biochemically purifying proteins that were either mutated themselves or directly affected by the mutation of another protein. This approach was severely limited as it required that the protein of interest be overproduced in order to allow for its purification. This is the case for many metabolic disorders in which a specific enzyme in a series of enzymatic steps is mutated... 

Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare, and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)—drugs that also are cytochrome P450 substrates. 

Most recently mutations in apoAV have also been identified as the molecular basis of chylomicronemia. Their identification needs sequencing of the apoAV gene. 

Fouchier SW, Kastelein JJ, Defesche JC (2005) Update of the molecular basis of familial hypercholesterolemia in The Netherlands. Hum Mutat 26 550-556... 

Kundu JK, Surh Y-J. 2004. Molecular basis of chemoprevention by resveratrol NF-kappaB and AP-1 as potential targets. Mutat Res 555 65-80. 

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