Reference : 3‑Phosphoglycerate Transhydrogenation Instead of Dehydrogenation Alleviates the Redox...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/38509
3‑Phosphoglycerate Transhydrogenation Instead of Dehydrogenation Alleviates the Redox State Dependency of Yeast de Novo L‑Serine Synthesis
English
Paczia, Nicole* mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Becker, Julia* mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Conrotte, Jean-François mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Cifuente, Javier O. [CIC bioGUNE > Structural Biology Unit]
Guerin, Marcelo E. [CIC bioGUNE > Structural Biology Unit > > ; IKERBASQUE, Basque Foundation for Science]
Linster, Carole mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
* These authors have contributed equally to this work.
Jan-2019
Biochemistry
American Chemical Society
Future of Biochemistry: The International Issue
Yes (verified by ORBilu)
International
0006-2960
1520-4995
Washington
DC
[en] PHGDH ; transhydrogenase ; dehydrogenase ; metabolism ; serine biosynthesis ; yeast
[en] The enzymatic mechanism of 3-phosphoglycerate to 3-phosphohydroxypyruvate oxidation, which forms the first step of the main conserved de novo serine synthesis pathway, has been revisited recently in certain microorganisms. While this step is classically considered to be catalyzed by an NAD-dependent dehydrogenase (e.g., PHGDH in mammals), evidence has shown that in Pseudomonas, Escherichia coli, and Saccharomyces cerevisiae, the PHGDH homologues act as transhydrogenases. As such, they use α-ketoglutarate, rather than NAD+, as the final electron acceptor, thereby producing D-2-hydroxyglutarate in addition to 3-phosphohydroxypyruvate during 3-phosphoglycerate oxidation. Here, we provide a detailed biochemical and sequence−structure relationship characterization of the yeast PHGDH homologues, encoded by the paralogous SER3 and SER33 genes, in comparison to the human and other PHGDH enzymes. Using in vitro assays with purified recombinant enzymes as well as in vivo growth phenotyping and metabolome analyses of yeast strains engineered to depend on either Ser3, Ser33, or human PHGDH for serine synthesis, we confirmed that both yeast enzymes act as transhydrogenases, while the human enzyme is a dehydrogenase. In addition, we show that the yeast paralogs differ from the human enzyme in their sensitivity to inhibition by serine as well as hydrated NADH derivatives. Importantly, our in vivo data support the idea that a 3PGA transhydrogenase instead of dehydrogenase activity confers a growth advantage under conditions where the NAD+:NADH ratio is low. The results will help to elucidate why different species evolved different reaction mechanisms to carry out a widely conserved metabolic step in central carbon metabolism.
Luxembourg Centre for Systems Biomedicine (LCSB): Enzymology & Metabolism (Linster Group)
Fonds National de la Recherche - FnR ; MINECO ; Severo Ochoa Excellence Accreditation
Researchers ; Students
http://hdl.handle.net/10993/38509
10.1021/acs.biochem.8b00990
FnR ; FNR11339953 > Nicole Paczia > COMET > Completing the metabolic map around the oncometabolite D-2-hydroxyglutarate > 01/11/2016 > 31/03/2019 > 2016

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