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Published online before print August 31, 2007, 10.1110/ps.073022107
Protein Science (2007), 16:2184-2194. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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Crystal Structure of human pyridoxal kinase: Structural basis of M+ and M2+ activation

Faik N. Musayev1, Martino L. di Salvo2, Tzu-Ping Ko3, Amit K. Gandhi1, Ashwini Goswami1, Verne Schirch1, and Martin K. Safo1

1 Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23219, USA
2 Dipartimento di Scienze Biochimiche "A. Rossi Fanelli," Università La Sapienza, 00185 Roma, Italy
3 Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan

(RECEIVED May 23, 2007; FINAL REVISION June 26, 2007; ACCEPTED June 26, 2007)

Pyridoxal kinase catalyzes the transfer of a phosphate group from ATP to the 5' alcohol of pyridoxine, pyridoxamine, and pyridoxal. In this work, kinetic studies were conducted to examine monovalent cation dependence of human pyridoxal kinase kinetic parameters. The results show that hPLK affinity for ATP and PL is increased manyfold in the presence of K+ when compared to Na+; however, the maximal activity of the Na+ form of the enzyme is more than double the activity in the presence of K+. Other monovalent cations, Li+, Cs+, and Rb+ do not show significant activity. We have determined the crystal structure of hPLK in the unliganded form, and in complex with MgATP to 2.0 and 2.2 Å resolution, respectively. Overall, the two structures show similar open conformation, and likely represent the catalytically idle state. The crystal structure of the MgATP complex also reveals Mg2+ and Na+ acting in tandem to anchor the ATP at the active site. Interestingly, the active site of hPLK acts as a sink to bind several molecules of MPD. The features of monovalent and divalent metal cation binding, active site structure, and vitamin B6 specificity are discussed in terms of the kinetic and structural studies, and are compared with those of the sheep and Escherichia coli enzymes.

Keywords: pyridoxal kinase; ribokinase; pyridoxal 5'-phosphate; X-ray crystallography; MgATP; cations; vitamin B6; phosphorylation; enzyme activity


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