Crystal structure of the S187F variant of human liver alanine: glyoxylate [corrected] aminotransferase associated with primary hyperoxaluria type I and its functional implications.

[primary hyperoxaluria type 1]

The substitution of Ser 187 , a residue located far from the active site of human liver peroxisomal alanine :glyoxylate aminotransferase (AGT ), by Phe gives rise to a variant associated with primary hyperoxaluria type I . Unexpectedly , previous studies revealed that the recombinant form of S 187 F exhibits a remarkable loss of catalytic activity , an increased pyridoxal 5 '-phosphate (PLP ) binding affinity and a different coenzyme binding mode compared with normal AGT . To shed light on the structural elements responsible for these defects , we solved the crystal structure of the variant to a resolution of 2 .9 Ã…. Although the overall conformation of the variant is similar to that of normal AGT , we noticed : (i ) a displacement of the PLP-binding Lys 209 and Val 185 , located on the re and si side of PLP , respectively , and (ii ) slight conformational changes of other active site residues , in particular Trp 108 , the base stacking residue with the pyridine cofactor moiety . This active site perturbation results in a mispositioning of the AGT -pyridoxamine 5 '-phosphate (PMP ) complex and of the external aldimine , as predicted by molecular modeling studies . Taken together , both predicted and observed movements caused by the S 187 F mutation are consistent with the following functional properties of the variant : (i ) a 300 - to 500 -fold decrease in both the rate constant of L-alanine half -transamination and the kcat of the overall transamination , (ii ) a different PMP binding mode and affinity , and (iii ) a different microenvironment of the external aldimine . Proposals for the treatment of patients bearing S 187 F mutation are discussed on the basis of these results .

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Diseases presenting "primary hyperoxaluria type i" symptom

primary hyperoxaluria type 1

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