The molecular basis of ornithine transcarbamylase deficiency: modelling the human enzyme and the effects of mutations.

摘要: Human ornithine transcarbamylase is a trimer with 46% amino acid sequence homology to the catalytic subunit of E coli aspartate transcarbamylase. Secondary structure predictions, distributions hydrophilic and hydrophobic regions, pattern conserved residues suggest that three dimensional structures two proteins are likely be similar. A model was generated from crystal in holoenzyme, by aligning sequences, building gaps, minimising energy. The binding sites for carbamyl phosphate both enzymes similar site appears same location as L-aspartate transcarbamylase, negatively charged side chains replaced positively residues. Mutations gene found patients hyperammonaemia "neonatal type" clustered important structural or functional domains, either interior protein, at active site, interchain interface, while mutations milder "late onset" disease located primarily on surface protein. predicted effects all known missense frame deletions function mature enzyme described.