Functional consequences of the G235R mutation in liver arginase leading to hyperargininemia.
Hyperargininemia is a rare autosomal disorder that results from a deficiency in hepatic type I arginase. This deficiency is the consequence of random point mutations that occur throughout the gene. The G235R patient mutation has been proposed to affect the catalytic activity and structural integrity of the protein [D. E. Ash, L. R. Scolnick, Z. F. Kanyo, J. G. Vockley, S. D. Cederbaum, and D. W. Christianson (1998) Mol. Genet. Metab. 64, 243-249]. The G235R (patient) and G235A (control) arginase mutants of rat liver arginase have been generated to probe the effects of these point mutations on the structure and function of hepatic type I arginase. Both mutant arginases were trimeric by gel filtration, but the control G235A mutant had 56% of wild-type activity and the G235R mutant had less than 0.03% activity compared to the wild-type enzyme. The G235R mutant contained undetectable levels of tightly bound manganese as determined by electron paramagnetic resonance, while the G235A mutant had a Mn(II) stoichiometry of 2 Mn/subunit. Molecular modeling indicates that the introduction of an arginine residue at position 235 results in a major rearrangement of the metal ligands that compromise Mn(II) binding.
Lavulo
Lopeti T
LT
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania, 19140, USA.
Emig
Frances A
FA
Ash
David E
DE
D000818:Animals; D001119:Arginase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D001665:Binding Sites; D002850:Chromatography, Gel; D004578:Electron Spin Resonance Spectroscopy; D004795:Enzyme Stability; D020162:Hyperargininemia / Q000201:enzymology / Q000209:etiology; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008345:Manganese / Q000737:chemistry; D008670:Metals / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D051381:Rats; D013329:Structure-Activity Relationship; D013696:Temperature
D008670:Metals; D008345:Manganese; D001119:Arginase