TAILIEUCHUNG - Báo cáo khoa học: The narrow substrate specificity of human tyrosine aminotransferase – the enzyme deficient in tyrosinemia type II

Human tyrosine aminotransferase (hTATase) is the pyridoxal phosphate-dependent enzyme that catalyzes the reversible transamination of tyrosine to p-hydrophenylpyruvate, an important step in tyrosine metabolism. hTATase deficiency is implicated in the rare metabolic disorder, tyrosine-mia type II. | iFEBS Journal The narrow substrate specificity of human tyrosine aminotransferase - the enzyme deficient in tyrosinemia type II Sharada Sivaraman and Jack F. Kirsch Department of Molecular and Cell Biology University of California Berkeley CA USA Keywords human aminotransferase phenylketonuria substrate specificity tyrosinemia Correspondence J. F. Kirsch Department of Molecular and CellBiology 239 A Hildebrand Hall 3206 University of California Berkeley CA 94720-3206 USA Fax and Tel 1 510 6426368 E-mail jfkirsch@ Received 22 December 2005 revised 16 February 2006 accepted 27 February 2006 doi Human tyrosine aminotransferase hTATase is the pyridoxal phosphatedependent enzyme that catalyzes the reversible transamination of tyrosine to p-hydrophenylpyruvate an important step in tyrosine metabolism. hTATase deficiency is implicated in the rare metabolic disorder tyrosine-mia type II. This enzyme is a member of the poorly characterized Iy subfamily of the family I aminotransferases. The full length and truncated forms of recombinant hTATase were expressed in Escherichia coli and purified to homogeneity. The pH-dependent titration of wild-type reveals a spectrum characteristic of family I aminotransferases with an aldimine pKa of . I249A mutant hTATase exhibits an unusual spectrum with a similar aldimine pKa . hTATase has very narrow substrate specificity with the highest enzymatic activity for the Tyr a-ketoglutarate substrate pair which gives a steady state kcat value of 83 s-1. In contrast there is no detectable transamination of aspartate or other cosubstrates. The present findings show that hTATase is the only known aminotransferase that discriminates significantly between Tyr and Phe the kcat Km value for Tyr is about four orders of magnitude greater than that for Phe. A comparison of substrate specificities of representative Ia and Iy aminotransferases is described along with the physiological significance of .

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