By combining transporter engineering with energy and precursor optimization, the study demonstrates an efficient strategy to overcome intracellular bottlenecks that limit vitamin A production.
Vitamin A, also known as retinoids, is an essential fat-soluble vitamin with critical roles in vision, bone health, immune function, and skin maintenance. Retinol, the active form, is widely used in the cosmetics industry for its antioxidant and anti-aging properties. At present, commercial vitamin A is produced mainly through chemical synthesis, a process that involves complex steps, high energy consumption, and elevated costs. Microbial biosynthesis has emerged as a sustainable alternative, using engineered microorganisms such as Escherichia coli and Saccharomyces cerevisiae to convert biomass-derived sugars into retinoids. Despite notable advances, current microbial production levels remain below industrial demand. One major limitation is that large proportions of vitamin A compounds remain trapped inside cells, reducing overall yield. Transport engineering—specifically identifying and optimizing membrane transport proteins—offers a promising solution to enhance secretion and relieve intracellular stress.
A study (DOI:10.1016/j.bidere.2025.100023) published in BioDesign Research on 17 April 2025 by Hongwei Yu & Lidan Ye’s team, Zhejiang University, demonstrates that integrating transporter engineering with energy and precursor optimization provides an effective strategy to achieve high-level, secretory vitamin A biosynthesis in yeast, offering a sustainable alternative to chemical synthesis.
The study applied a systematic transporter- and energy-engineering strategy in Saccharomyces cerevisiae to overcome bottlenecks in vitamin A secretion. Researchers began by screening the full set of endogenous pleiotropic drug resistance (PDR) proteins—three transcription factors (Pdr1p, Pdr3p, Pdr8p) and ten ABC transporters—through individual overexpression under a PGAL1 promoter in a GAL80Δ background, monitoring retinoid titers and secretion profiles in strains producing retinol/retinal (Y03) or retinal/retinoic acid (Y03-784). Molecular docking complemented these experiments to explore substrate preferences. Results showed that Pdr3p, Pdr10p, and Snq2p markedly enhanced retinal and retinol efflux, while Pdr8p, Pdr11p, Pdr12p, Pdr18p, and Aus1p significantly increased retinoic acid yields. In Y03, PDR3 or PDR10 expression raised total retinoids to over 400 mg/L with secretion ratios above 95%. In Y03-784, PDR8 improved retinoic acid from 83.34 to 106.75 mg/L. To further dissect specificity, strains were engineered to produce retinal only by knocking out dehydrogenases, where PDR3/PDR10 co-expression drove retinal to 638.12 mg/L with 98.7% secreted. In retinol-only strains, SNQ2 and PDR10 increased titers from 356.21 to 430.14 mg/L and raised extracellular ratios to over 93%, while promoter balancing of PDR3 and PDR10 delivered 549.79 mg/L retinol and 94.5% secretion. Recognizing ATP demands of transport, the team enhanced energy metabolism: MGM1 synergized with PDR10 to boost retinol from 401.26 to 534.82 mg/L, and Vitreoscilla hemoglobin (Vgb) improved oxygen delivery, raising titers to 406.62 mg/L though at a cost to growth. To relieve precursor limitations, acetyl-CoA flux was reinforced via ACS1/ACSL641P overexpression, MLS1 deletion, and ERG10 up-regulation, culminating in a record 727.30 mg/L retinol from 20 g/L glucose with a 7.62% carbon conversion rate. Together, these results highlight transporter engineering combined with energy and precursor optimization as an effective route to high-level vitamin A biosynthesis.
These findings highlight a powerful metabolic engineering strategy that integrates transporter design, energy regulation, and precursor balancing. The ability to secrete retinoids efficiently not only raises product yields but also reduces cellular stress, potentially lowering downstream processing costs. Industrial production of vitamin A through engineered yeast offers a greener alternative to traditional chemical synthesis, with clear benefits for health supplements, pharmaceuticals, and anti-aging cosmetics. Moreover, improved secretion strategies can be extended to other high-value terpenoids and lipophilic compounds, broadening their use in biotechnology and bio-based manufacturing.
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References
DOI
10.1016/j.bidere.2025.100023
Original Source URL
https://doi.org/10.1016/j.bidere.2025.100023
Funding information
This work was supported by the National Key Research and Development Program of China (Grant No. 2020YFA0908400), the National Natural Science Foundation of China (Grant No. 32171412), and the Fundamental Research Funds for the Central Universities (Grant No. 226-2022-00055).
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