Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach.
We describe the prediction of the structural and functional effects of mutations on the enzyme galactose-1-phosphate uridyltransferase related to the genetic disease galactosemia, using a fully computational approach. One hundred and seven single-point mutants were simulated starting from the structural model of the enzyme obtained by homology modeling methods. Several bioinformatics programs were then applied to each resulting mutant protein to analyze the effect of the mutations. The mutations have a direct effect on the active site, or on the dimer assembly and stability, or on the monomer stability. We describe how mutations may exert their effect at a molecular level by altering H-bonds, salt bridges, secondary structure or surface features. The alteration of protein stability, at level of monomer and/or dimer, is the main effect observed. We found an agreement between our results and the functional experimental data available in literature for some mutants. The data and analyses for all the mutants are fully available in the web-accessible database hosted at http://bioinformatica.isa.cnr.it/GALT.
Facchiano
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Institute of Food Science, CNR, Via Roma, 64, 83100 Avellino, Italy.
Marabotti
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D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D005693:Galactosemias / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D017354:Point Mutation; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D005694:UTP-Hexose-1-Phosphate Uridylyltransferase