Nature Metabolism: Synthetic energy metabolism provides a dual engine for cells

A research team led by Professor YU Tao of the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences has proposed a new synthetic energy system that can support yeast cell growth and the production of highly reducible chemicals
.

The study was published Oct.
27 in
the journal Nature Metabolism.

During evolution, cellular metabolism is optimized to self-proliferate rather than producing specific chemicals
.
In contrast, rational design coupled with the metabolic reorganization of modern biotechnology has transformed cells into high-yield factories
.

To produce highly reduced chemicals, such as free fatty acids (FFAs) as biofuels, cells need to expend energy and overcome stoichiometric limitations
in chemical composition between the substrate and the target product.
Therefore, rewiring reduction/energy metabolism becomes an effective solution
.

In this study, the synthetic energy system consists of three modules: the pentose phosphate (PP) cycle, the trans-hydrogenase cycle, and the external respiratory chain
.
The PP cycle is a repetitive decarboxylation cycle in which a large number of reducing agents such as nicotinamide adenine dinucleotide phosphate (NADPH)
are produced.
This allows the trans-hydrogenase cycle to irreversibly convert one NADPH into a nicotinamide adenine dinucleotide (NADH)
in the cytoplasm.
Through the external respiratory chain, cytosolic NADH can produce energy
.

The researchers tested an evolved pyruvate decarboxylase-deficient strain E1B
.
After overexpression of PP cycling and glycolysis blockade, the strain fails to grow
on glucose due to excessive accumulation of NADPH.
The expression of the trans catalase cycle restores normal cell growth
.
In the context of synthetic energy systems, cell growth has not been weakened, but has been improved due to the downregulation of endogenous energy systems, indicating that this system can be an alternative
to better cell growth to provide energy.

As for reducing chemical production, the succinic acid titer reaches about 3.
3 g/L
.
Combined with fine-tuning of the ratio between precursors, cofactors, and energy, the synthetic energy system increased the yield of FFAs to 40% of the maximum theoretical yield, which is currently the highest yield Saccharomyces cerevisiae has been reported and demonstrated the potential
of the system in industrial-scale production.

Professor YU Tao said: "Energy metabolism reprogramming shows that although there is a wide range of regulation of the catabolism of yeasts, it is still possible to reconnect their energy metabolism
.
"