Themolecular basis ofornithine transcarbamylase deficiency: modelling the humanenzyme andtheeffects ofmutations

Human ornithine transcarbamylase isa trimerwith46% aminoacidsequence homologytothecatalytic subunit ofE coli aspartate transcarbamylase. Secondary structure predictions, distributions ofhydrophilic andhydrophobic regions, and thepattern ofconserved residues suggest thatthethreedimensional structures of thetwoproteins arelikely tobesimilar. A threedimensional modelofornithine transcarbamylase wasgenerated fromthe crystal structure ofthecatalytic subunit ofEcoli aspartate transcarbamylase inthe holoenzyme, by aligning thesequences, building ingaps,andminimising theenergy. Thebinding sites forcarbamyl phosphateinbothenzymesaresimilar andthe ornithine binding siteinornithine transcarbamylase appearstobeinthesame location astheL-aspartate binding site in aspartate transcarbamylase, withnegatively charged sidechainsreplaced by positively chargedresidues. Mutations intheornithine transcarbamylase gene foundinpatients withhyperammonaemia ofthe"neonatal type"areclustered in important structural or functional domains, either intheinterior oftheprotein, attheactive site, orattheinterchain interface, whilemutations foundinpatients withmilder"lateonset"disease arelocatedprimarily onthesurface oftheprotein. Thepredicted effects ofallknown missense mutations andinframedeletions intheornithine transcarbamylase geneon thestructure andfunction ofthemature enzymearedescribed. (JMedGenet1995;32:680-688)