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Substrate specificity and mechanism from the structure of Pyrococcus furiosus galactokinase.
J Mol Biol. 2004 Mar 19; 337(2):387-98.JM

Abstract

Galactokinase (GalK) catalyses the first step of the Leloir pathway of galactose metabolism, the ATP-dependent phosphorylation of galactose to galactose-1-phosphate. In man, defects in galactose metabolism can result in disorders with severe clinical consequences, and deficiencies in galactokinase have been linked with the development of cataracts within the first few months of life. The crystal structure of GalK from Pyrococcus furiosus in complex with MgADP and galactose has been determined to 2.9 A resolution to provide insights into the substrate specificity and catalytic mechanism of the enzyme. The structure consists of two domains with the active site in a cleft at the domain interface. Inspection of the substrate binding pocket identifies the amino acid residues involved in galactose and nucleotide binding and points to both structural and mechanistic similarities with other enzymes of the GHMP kinase superfamily to which GalK belongs. Comparison of the sequence of the Gal3p inducer protein, which is related to GalK and which forms part of the transcriptional activation of the GAL gene cluster in the yeast Saccharomyces cerevisiae, has led to an understanding of the molecular basis of galactose and nucleotide recognition. Finally, the structure has enabled us to further our understanding on the functional consequences of mutations in human GalK which cause galactosemia.

Authors+Show Affiliations

Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15003454

Citation

Hartley, Andrew, et al. "Substrate Specificity and Mechanism From the Structure of Pyrococcus Furiosus Galactokinase." Journal of Molecular Biology, vol. 337, no. 2, 2004, pp. 387-98.
Hartley A, Glynn SE, Barynin V, et al. Substrate specificity and mechanism from the structure of Pyrococcus furiosus galactokinase. J Mol Biol. 2004;337(2):387-98.
Hartley, A., Glynn, S. E., Barynin, V., Baker, P. J., Sedelnikova, S. E., Verhees, C., de Geus, D., van der Oost, J., Timson, D. J., Reece, R. J., & Rice, D. W. (2004). Substrate specificity and mechanism from the structure of Pyrococcus furiosus galactokinase. Journal of Molecular Biology, 337(2), 387-98.
Hartley A, et al. Substrate Specificity and Mechanism From the Structure of Pyrococcus Furiosus Galactokinase. J Mol Biol. 2004 Mar 19;337(2):387-98. PubMed PMID: 15003454.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Substrate specificity and mechanism from the structure of Pyrococcus furiosus galactokinase. AU - Hartley,Andrew, AU - Glynn,Steven E, AU - Barynin,Vladimir, AU - Baker,Patrick J, AU - Sedelnikova,Svetlana E, AU - Verhees,Corné, AU - de Geus,Daniel, AU - van der Oost,John, AU - Timson,David J, AU - Reece,Richard J, AU - Rice,David W, PY - 2003/08/15/received PY - 2004/01/16/revised PY - 2004/01/24/accepted PY - 2004/3/9/pubmed PY - 2004/4/24/medline PY - 2004/3/9/entrez SP - 387 EP - 98 JF - Journal of molecular biology JO - J Mol Biol VL - 337 IS - 2 N2 - Galactokinase (GalK) catalyses the first step of the Leloir pathway of galactose metabolism, the ATP-dependent phosphorylation of galactose to galactose-1-phosphate. In man, defects in galactose metabolism can result in disorders with severe clinical consequences, and deficiencies in galactokinase have been linked with the development of cataracts within the first few months of life. The crystal structure of GalK from Pyrococcus furiosus in complex with MgADP and galactose has been determined to 2.9 A resolution to provide insights into the substrate specificity and catalytic mechanism of the enzyme. The structure consists of two domains with the active site in a cleft at the domain interface. Inspection of the substrate binding pocket identifies the amino acid residues involved in galactose and nucleotide binding and points to both structural and mechanistic similarities with other enzymes of the GHMP kinase superfamily to which GalK belongs. Comparison of the sequence of the Gal3p inducer protein, which is related to GalK and which forms part of the transcriptional activation of the GAL gene cluster in the yeast Saccharomyces cerevisiae, has led to an understanding of the molecular basis of galactose and nucleotide recognition. Finally, the structure has enabled us to further our understanding on the functional consequences of mutations in human GalK which cause galactosemia. SN - 0022-2836 UR - https://www.unboundmedicine.com/medline/citation/15003454/Substrate_specificity_and_mechanism_from_the_structure_of_Pyrococcus_furiosus_galactokinase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022283604001147 DB - PRIME DP - Unbound Medicine ER -