Structural implications of a G170R mutation of alanine:glyoxylate aminotransferase that is associated with peroxisome-to-mitochondrion mistargeting.

[primary hyperoxaluria type 1]

In a subset of patients with the hereditary kidney-stone disease primary hyperoxaluria type 1 (PH 1 ), the liver -specific enzyme alanine :glyoxylate aminotransferase (AGT ) is mistargeted from peroxisomes to mitochondria . This is a consequence of the combined presence of the common P 11 L polymorphism and a disease-specific G 170 R mutation . In this paper , the crystal structure of mutant human AGT containing the G 170 R replacement determined at a resolution of 2 .6 A is reported . The crystal structure of AGT consists of an intimate dimer in which an extended N-terminal segment of 21 amino acids from one subunit wraps as an elongated irregular coil around the outside of the crystallographic symmetry-related subunit . In addition to the N-terminal segment , the monomer structure contains a large domain of 261 amino acids and a small C-terminal domain of 110 amino acids . Comparison of the mutant AGT structure and that of wild-type normal AGT shows that the two structures are almost identical , with a backbone-atom r .m .s . deviation of 0 .34 A . However , evidence of significant local structural changes in the vicinity of the G 170 R mutation might be linked to the apparent decrease in protein stability .

Diseases
Validation

Diseases presenting "crystallographic symmetry-related subunit" symptom

primary hyperoxaluria type 1

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