Journal
COMPUTATIONAL BIOLOGY AND CHEMISTRY
Volume 74, Issue -, Pages 94-104Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.compbiolchem.2018.03.006
Keywords
Sirtuin; Metabolism; Homology modeling; Cancer; Docking; Ischemic heart disease
Funding
- Vehicle Racing Commemorative Foundation
- Joint Usage and Joint Research Programs, the Institute of Advanced Medical Sciences, Tokushima University
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Sirtuin4 (Sirt4) is one of the mammalian homologues of Silent information regulator 2 (Sir2), which promotes the longevity of yeast, C. elegans, fruit flies and mice. Sirt4 is localized in the mitochondria, where it contributes to preventing the development of cancers and ischemic heart disease through regulating energy metabolism. The ADP-ribosylation of glutamate dehydrogenase (GDH), which is catalyzed by Sirt4, downregulates the TCA cycle. However, this reaction mechanism is obscure, because the structure of Sirt4 is unknown. We here constructed structural models of Sirt4 by homology modeling and threading, and docked nicotinamide adenine dinucleotide(+) (NAD(+)) to Sirt4. In addition, a partial GDH structure was docked to the Sirt4-NAD(+) complex model. In the ternary complex model of Sirt4-NAD(+)-GDH, the acetylated lysine 171 of GDH is located close to NAD(+). This suggests a possible mechanism underlying the ADP-ribosylation at cysteine 172, which may occur through a transient intermediate with ADP-ribosylation at the acetylated lysine 171. These results may be useful in designing drugs for the treatment of cancers and ischemic heart disease. (C) 2018 Elsevier Ltd. All rights reserved.
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