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
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Diseases presenting "and" symptom

achondroplasia

adrenomyeloneuropathy

aniridia

carcinoma of the gallbladder

cutaneous mastocytosis

cystinuria

esophageal squamous cell carcinoma

harlequin ichthyosis

hodgkin lymphoma, classical

hydrocephalus with stenosis of the aqueduct of sylvius

kallmann syndrome

liposarcoma

locked-in syndrome

neonatal adrenoleukodystrophy

omenn syndrome

oral submucous fibrosis

pleomorphic liposarcoma

primary hyperoxaluria type 1

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

sneddon syndrome

triple a syndrome

trochlear dysplasia

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