title: Structural studies of the final enzyme in the alpha-aminoadipate pathway-saccharopine dehydrogenase from Saccharomyces cerevisiae.
abstract: The 1.64 A 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 dehydrogenase, 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.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3A 1A4.
authors.forename: D L
authors.initials: DL
authors.lastname: Burk
authors.forename: J
authors.initials: J
authors.lastname: Hwang
authors.forename: E
authors.initials: E
authors.lastname: Kwok
authors.forename: L
authors.initials: L
authors.lastname: Marrone
authors.forename: V
authors.initials: V
authors.lastname: Goodfellow
authors.forename: G I
authors.initials: GI
authors.lastname: Dmitrienko
authors.forename: A M
authors.initials: AM
authors.lastname: Berghuis
mesh_terms: D050788:Alanine Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism*; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000254:growth & development; D012443:Saccharopine Dehydrogenases / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D009243:NAD; D050788:Alanine Dehydrogenase; D012443:Saccharopine Dehydrogenases; D008239:Lysine; C100169:saccharopine