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alliedacademies
Archives of Industrial Biotechnology | Volume 2
May 14-15, 2018 | Montreal, Canada
World Yeast Congress
2 -Hydroxyglutarate (2HG) is an atypical metabolite that
accumulates in neurometabolic diseases as well as in
certain types of cancer. The mechanisms through which
2HG leads to cell transformation or neurodegeneration
remain, however, poorly understood. Compared to the
research on 2HG in mammalian systems, and despite certain
advantages of yeast as a model organism for biomedical
research, only a very limited number of studies reported
on the occurrence and metabolism of 2HG in yeast. An
extensive study performed over the last three years in our
lab, revealed a panoply of new findings on 2HG metabolism
of Saccharomyces cerevisiae. Among those the fact that the
yeast phosphoglycerate dehydrogenases Ser3 and Ser33
convert α-ketoglutarate to D-2HG in addition to their primary
metabolic role, which consists in catalysing the first step of
the serine synthesis way converting 3-phosphoglycerate to
3-phosphohydroxypyruvate. Our results also show, however,
that the two identified D-2HG producing enzymes do not
represent the only sources of this metabolite in yeast Within
our study, the two dehydrogenases Dld2 and Dld3 were both
shown to convert D-2HG to α-ketoglutarate in vitro. Targeted
metabolome analyses and biochemical characterisation led
additionally to the original finding that DLD3 is actually an
FAD-dependent trans-hydogenase that converts D-2HG to
α-ketoglutarate, using pyruvate as a hydrogen acceptor.
Based on our findings, we were for the first time able
to propose a central carbon network of Saccharomyces
cerevisiae integrating the metabolite D-2HG and connecting
its metabolism to the mitochondrial respiratory chain. In
the present research project we aimed to further elucidate
the metabolic network involved in 2HG formation and
degradation in yeast. Using targeted metabolome analysis
and high-throughput growth phenotyping, we analysed the
accumulation of D-2HG in genotyped natural yeast isolates.
The analysis of strains carrying copy number variations of the
gene DLD3 confirmed that it is the main regulator of 2HG,
but also showed evidence for the presence of additional
regulators.
Speaker Biography
Nicole Paczia obtained her doctorate from the University of Bielefeld (Germany) in
2012, and worked as a postdoctoral researcher at the Institute for Bio- and Geosciences
1 (Research center Jülich), before starting as a research associate at the Luxembourg
centre for systems biomedicine (LCSB). In 2016, Dr. Paczia was awarded a CORE Junior
Fellowship by the Luxembourg National Reseach Fund (FNR), which allowed her to
establish a Junior Research group within the group for Enzymology and Metabolism,
headed by Dr. Carole Linster at the LCSB. She has published more than 10 papers in
reputed journals, and holds two patents.
e:
Using natural yeast isolates to understand the function of an orphan metabolite
Nicole Paczia
University of Luxembourg, Luxembourg