Molecular basis of hyperargininemia: structure-function consequences of mutations in human liver arginase.
Hyperargininemia is a rare autosomal recessive disorder that results from a deficiency of hepatic type I arginase. At the genetic level, this deficiency in arginase activity is a consequence of random point mutations throughout the gene that lead to premature termination of the protein or to substitution mutations. Given the high degree of sequence homology between human liver and rat liver enzymes, we have mapped both patient and nonpatient mutations of the human enzyme onto the structure of the rat liver enzyme to rationalize the molecular basis for the low activities of these mutant arginases. Mutations identified in hyperargininemia patients affect the structure and function of the enzyme by compromising active-site residues, packing interactions in the protein scaffolding, and/or quaternary structure by destabilizing the assembly of the arginase trimer.
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. deash@astro.ocis.temple.edu
D E
DE
Ash
L R
LR
Scolnick
Z F
ZF
Kanyo
J G
JG
Vockley
S D
SD
Cederbaum
D W
DW
Christianson
D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D001119:Arginase / Q000737:chemistry / Q000235:genetics*; D001120:Arginine / Q000097:blood*; D001665:Binding Sites; D001704:Biopolymers; D006801:Humans; D008099:Liver / Q000201:enzymology*; D015394:Molecular Structure; D009154:Mutation; D051381:Rats
D001704:Biopolymers; D001120:Arginine; D001119:Arginase