Structural basis for the broad substrate range of the UDP-sugar pyrophosphorylase from Leishmania major
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Structural basis for the broad substrate range of the UDP-sugar pyrophosphorylase from Leishmania major. / Dickmanns, Achim; Damerow, Sebastian; Neumann, Piotr; Schulz, Eike-Christian; Lamerz, Anne-Christin; Routier, Françoise H; Ficner, Ralf.
in: J MOL BIOL, Jahrgang 405, Nr. 2, 14.01.2011, S. 461-78.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Structural basis for the broad substrate range of the UDP-sugar pyrophosphorylase from Leishmania major
AU - Dickmanns, Achim
AU - Damerow, Sebastian
AU - Neumann, Piotr
AU - Schulz, Eike-Christian
AU - Lamerz, Anne-Christin
AU - Routier, Françoise H
AU - Ficner, Ralf
N1 - Copyright © 2010 Elsevier Ltd. All rights reserved.
PY - 2011/1/14
Y1 - 2011/1/14
N2 - Nucleotide sugars and the enzymes that are responsible for their synthesis are indispensable for the production of complex carbohydrates and, thus, for elaboration of a protective cellular coat for many organisms such as the protozoan parasite Leishmania. These activated sugars are synthesized de novo or derived from salvaged monosaccharides. In addition to UDP-glucose (UDP-Glc) pyrophosphorylase, which catalyzes the formation of UDP-Glc from substrates UTP and glucose-1-phosphate, Leishmania major and plants express a UDP-sugar pyrophosphorylase (USP) that exhibits broad substrate specificity in vitro. The enzyme, likely involved in monosaccharide salvage, preferentially generates UDP-Glc and UDP-galactose, but it may also activate other hexose- or pentose-1-phosphates such as galacturonic acid-1-phosphate or arabinose-1-phosphate. In order to gain insight into structural features governing the differences in substrate specificity, we determined the crystal structure of the L. major USP in the APO-, UTP-, and UDP-sugar-bound conformations. The overall tripartite structure of USP exhibits a significant structural homology to other nucleotidyldiphosphate-glucose pyrophosphorylases. The obtained USP structures reveal the structural rearrangements occurring during the stepwise binding process of the substrates. Moreover, the different product complexes explain the broad substrate specificity of USP, which is enabled by structural changes in the sugar binding region of the active site.
AB - Nucleotide sugars and the enzymes that are responsible for their synthesis are indispensable for the production of complex carbohydrates and, thus, for elaboration of a protective cellular coat for many organisms such as the protozoan parasite Leishmania. These activated sugars are synthesized de novo or derived from salvaged monosaccharides. In addition to UDP-glucose (UDP-Glc) pyrophosphorylase, which catalyzes the formation of UDP-Glc from substrates UTP and glucose-1-phosphate, Leishmania major and plants express a UDP-sugar pyrophosphorylase (USP) that exhibits broad substrate specificity in vitro. The enzyme, likely involved in monosaccharide salvage, preferentially generates UDP-Glc and UDP-galactose, but it may also activate other hexose- or pentose-1-phosphates such as galacturonic acid-1-phosphate or arabinose-1-phosphate. In order to gain insight into structural features governing the differences in substrate specificity, we determined the crystal structure of the L. major USP in the APO-, UTP-, and UDP-sugar-bound conformations. The overall tripartite structure of USP exhibits a significant structural homology to other nucleotidyldiphosphate-glucose pyrophosphorylases. The obtained USP structures reveal the structural rearrangements occurring during the stepwise binding process of the substrates. Moreover, the different product complexes explain the broad substrate specificity of USP, which is enabled by structural changes in the sugar binding region of the active site.
KW - Amino Acid Sequence
KW - Catalysis
KW - Crystallography, X-Ray
KW - Glucosephosphates/metabolism
KW - Leishmania major/enzymology
KW - Models, Molecular
KW - Molecular Sequence Data
KW - Protein Conformation
KW - Sequence Homology, Amino Acid
KW - Substrate Specificity
KW - Sugar Phosphates/metabolism
KW - UTP-Glucose-1-Phosphate Uridylyltransferase/chemistry
KW - Uridine Diphosphate Sugars/metabolism
U2 - 10.1016/j.jmb.2010.10.057
DO - 10.1016/j.jmb.2010.10.057
M3 - SCORING: Journal article
C2 - 21073876
VL - 405
SP - 461
EP - 478
JO - J MOL BIOL
JF - J MOL BIOL
SN - 0022-2836
IS - 2
ER -