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Title: Structural Studies of the Final Enzyme in the alpha-Aminoadipate Pathway-Saccharopine Dehydrogenase from Saccharomyces cerevisiae

Abstract

The 1.64 Angstroms structure of the apoenzyme form of saccharopine dehydrogenase (SDH) from Saccharomyces cerevisiae shows the enzyme to be composed of two domains with similar dinucleotide binding folds with a deep cleft at the interface. The structure reveals homology to alanine dehydrogense, despite low primary sequence similarity. A model of the ternary complex of SDH, NAD, and saccharopine identifies residues Lys77 and Glu122 as potentially important for substrate binding and/or catalysis, consistent with a proton shuttle mechanism. Furthermore, the model suggests that a conformational change is required for catalysis and that residues Lys99 and Asp281 may be instrumental in mediating this change. Analysis of the crystal structure in the context of other homologous enzymes from pathogenic fungi and human sources sheds light into the suitability of SDH as a target for antimicrobial drug development.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959737
Report Number(s):
BNL-82723-2009-JA
Journal ID: ISSN 0022-2836; JMOBAK; TRN: US201016%%881
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Molecular Biology; Journal Volume: 373
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ALANINES; CATALYSIS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; ENZYMES; FUNGI; OXIDOREDUCTASES; PROTONS; RESIDUES; SACCHAROMYCES CEREVISIAE; SUBSTRATES; TARGETS; national synchrotron light source

Citation Formats

Burk,D., Hwang, J., Kwok, E., Marrone, L., Goodfellow, V., Dmitrienko, G., and Berghuis, A. Structural Studies of the Final Enzyme in the alpha-Aminoadipate Pathway-Saccharopine Dehydrogenase from Saccharomyces cerevisiae. United States: N. p., 2007. Web. doi:10.1016/j.jmb.2007.08.044.
Burk,D., Hwang, J., Kwok, E., Marrone, L., Goodfellow, V., Dmitrienko, G., & Berghuis, A. Structural Studies of the Final Enzyme in the alpha-Aminoadipate Pathway-Saccharopine Dehydrogenase from Saccharomyces cerevisiae. United States. doi:10.1016/j.jmb.2007.08.044.
Burk,D., Hwang, J., Kwok, E., Marrone, L., Goodfellow, V., Dmitrienko, G., and Berghuis, A. Mon . "Structural Studies of the Final Enzyme in the alpha-Aminoadipate Pathway-Saccharopine Dehydrogenase from Saccharomyces cerevisiae". United States. doi:10.1016/j.jmb.2007.08.044.
@article{osti_959737,
title = {Structural Studies of the Final Enzyme in the alpha-Aminoadipate Pathway-Saccharopine Dehydrogenase from Saccharomyces cerevisiae},
author = {Burk,D. and Hwang, J. and Kwok, E. and Marrone, L. and Goodfellow, V. and Dmitrienko, G. and Berghuis, A.},
abstractNote = {The 1.64 Angstroms structure of the apoenzyme form of saccharopine dehydrogenase (SDH) from Saccharomyces cerevisiae shows the enzyme to be composed of two domains with similar dinucleotide binding folds with a deep cleft at the interface. The structure reveals homology to alanine dehydrogense, despite low primary sequence similarity. A model of the ternary complex of SDH, NAD, and saccharopine identifies residues Lys77 and Glu122 as potentially important for substrate binding and/or catalysis, consistent with a proton shuttle mechanism. Furthermore, the model suggests that a conformational change is required for catalysis and that residues Lys99 and Asp281 may be instrumental in mediating this change. Analysis of the crystal structure in the context of other homologous enzymes from pathogenic fungi and human sources sheds light into the suitability of SDH as a target for antimicrobial drug development.},
doi = {10.1016/j.jmb.2007.08.044},
journal = {Journal of Molecular Biology},
number = ,
volume = 373,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
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