Molecular Insight into the Synergism between the Minor Allele of Human Liver Peroxisomal Alanine:Glyoxylate Aminotransferase and the F152I Mutation.

[primary hyperoxaluria type 1]

Human liver peroxisomal alanine :glyoxylate aminotransferase (AGT ) is a pyridoxal 5 '-phosphate (PLP )-dependent enzyme that converts glyoxylate into glycine . AGT deficiency causes primary hyperoxaluria type 1 (PH 1 ), a rare autosomal recessive disorder , due to a marked increase in hepatic oxalate production . Normal human AGT exists as two polymorphic variants : the major (AGT -Ma ) and the minor (AGT -Mi ) allele . AGT -Mi causes the PH 1 disease only when combined with some mutations . In this study , the molecular basis of the synergism between AGT -Mi and F 152 I mutation has been investigated through a detailed biochemical characterization of AGT -Mi and the Phe (152 ) variants combined either with the major (F 152 I -Ma , F 152 A -Ma ) or the minor allele (F 152 I -Mi ). Although these species show spectral features , kinetic parameters , and PLP binding affinity similar to those of AGT -Ma , the Phe (152 ) variants exhibit the following differences with respect to AGT -Ma and AGT -Mi : (i ) pyridoxamine 5 '-phosphate (PMP ) is released during the overall transamination leading to the conversion into apoenzymes , and (ii ) the PMP binding affinity is at least 200 -1400 -fold lower . Thus , Phe (152 ) is not an essential residue for transaminase activity , but plays a role in selectively stabilizing the AGT -PMP complex , by a proper orientation of Trp (108 ), as suggested by bioinformatic analysis . These data , together with the finding that apoF 152 I -Mi is the only species that at physiological temperature undergoes a time-dependent inactivation and concomitant aggregation , shed light on the molecular defects resulting from the association of the F 152 I mutation with AGT -Mi , and allow to speculate on the responsiveness to pyridoxine therapy of PH 1 patients carrying this mutation .

Diseases
Validation

Diseases presenting "hyperoxaluria" symptom

cystinuria

neonatal adrenoleukodystrophy

primary hyperoxaluria type 1

This symptom has already been validated