Metabolic Engineering for Lactic Acid Production in Yeast

Lactic acid is a versatile platform chemical central to the manufacture of biodegradable plastics and other bio-based materials. Yeast have emerged as attractive production hosts owing to their acid tolerance, robust genetics and established industrial use. Metabolic engineering strategies have focused on redirecting carbon flux from ethanol towards lactic acid, typically through expression of heterologous lactate dehydrogenase (LDH), disruption of competing pyruvate decarboxylase pathways and optimisation of lactate export. Systems biology and synthetic biology tools, including genome-scale modelling, adaptive laboratory evolution (ALE) and dynamic control of pathway enzymes, have been applied to overcome physiological barriers such as product inhibition, redox imbalance and substrate range. Efforts to broaden feedstock scope have led to strains capable of converting methanol or lignocellulosic sugars into lactic acid, while integration of organic acid tolerance mechanisms has improved titres under low-pH conditions. Together, these advances point towards economically viable, sustainable yeast-based bioprocesses for high-purity lactic acid production at scale.

Research from Nature Portfolio

Recent studies have demonstrated that complete abolition of the Crabtree effect in Saccharomyces cerevisiae can substantially enhance flux towards pyruvate-derived chemicals such as lactic acid. By combining rational redesign of pyruvate metabolism with adaptive laboratory evolution, researchers obtained a Crabtree-negative yeast in which ethanol formation is suppressed even under glucose‐rich, aerobic conditions. Integrated systems analyses revealed that a mutation in a mediator complex subunit rewires global transcriptional programmes, favouring respiration and enabling redirection of glycolytic carbon to LDH-catalysed lactate formation. This foundational work establishes a chassis in which ethanol by-product formation is minimised, enhancing theoretical yields and productivity of engineered lactic acid pathways.

Metabolic Engineering for Lactic Acid Production in Yeast publication trend

The graph below shows the total number of articles in metabolic engineering for lactic acid production in yeast across all publications each year (not limited to Nature Index journals).

Technical terms

Crabtree effect: The phenomenon whereby S. cerevisiae produces ethanol under aerobic, glucose-excess conditions, limiting carbon available for other products.

Adaptive laboratory evolution (ALE): A method in which microorganisms are cultured under selective pressure over many generations to enrich beneficial mutations.

Lactate dehydrogenase (LDH): An enzyme that converts pyruvate to lactic acid, regenerating NAD+ from NADH in the process.

Pyruvate branch point: The metabolic node at which pyruvate can be directed towards fermentation, respiration, or biosynthetic pathways.

Titre: The concentration of a desired product in the culture medium, often expressed in grams per litre.

References

1. Engineering the methylotrophic yeast Ogataea polymorpha for lactate production from methanol. Frontiers in Bioengineering and Biotechnology (2023).
2. A highly efficient transcriptome-based biosynthesis of non-ethanol chemicals in Crabtree negative Saccharomyces cerevisiae. Biotechnology for Biofuels and Bioproducts (2023).
3. Global rewiring of cellular metabolism renders Saccharomyces cerevisiae Crabtree negative. Nature Communications (2018).
4. Lactate production yield from engineered yeasts is dependent from the host background, the lactate dehydrogenase source and the lactate export. Microbial Cell Factories (2006).
5. l-Lactic acid production from glucose and xylose with engineered strains of Saccharomyces cerevisiae: aeration and carbon source influence yields and productivities. Microbial Cell Factories (2018).
6. l-Lactic Acid Production Using Engineered Saccharomyces cerevisiae with Improved Organic Acid Tolerance. Journal of Fungi (2021).