Metabolic Engineering for Biobased 3-Hydroxypropionic Acid (3-HP)

Introduction

3-Hydroxypropionic acid (3-HP) is a highly versatile C3 platform chemical with applications in biodegradable plastics, acrylic acid, solvents, and specialty chemicals. Traditionally, 3-HP is synthesized from petroleum-derived acrylic acid through energy-intensive and toxic processes.

However, through metabolic engineering, microbes can be tailored to convert renewable feedstocks like glucose, glycerol, or CO₂ into 3-HP under mild and sustainable conditions. This makes 3-HP a major contender in the bioeconomy, with potential to replace fossil-derived acrylics and support bioplastics, coatings, and superabsorbents industries.

What Products Are Produced?

3-Hydroxypropionic acid (3-HP) – Intermediate for:

• Acrylic acid and acrylamide (superabsorbents, paints)
• 1,3-Propanediol (PDO) – For PTT bioplastics
• Malonic acid, propiolactone – For fine chemicals
• Biodegradable polyesters (poly-3HP)

Pathways and Production Methods

1. Glycerol Route (via Glycerol Dehydration)

• Glycerol → 3-HPA (3-hydroxypropionaldehyde) → 3-HP
• Enzymes involved:
  • Glycerol dehydratase (GDHt)
  • Aldehyde dehydrogenase (AldDH)
• Hosts: Klebsiella pneumoniae, E. coli (engineered for coenzyme B12 recycling)

2. Malonyl-CoA Pathway (from Glucose)

• Glucose → Acetyl-CoA → Malonyl-CoA → 3-HP
• Enzymes:
  • Malonyl-CoA reductase (MCR)
  • Requires tight cofactor and flux balancing
• Hosts: E. coli, Corynebacterium glutamicum, Y. lipolytica

3. β-Alanine Pathway

• Glucose → L-aspartate → β-alanine → 3-HP
• Engineered in E. coli, shows promise for improved yield and ATP efficiency

4. CO₂-Based Routes

• Cupriavidus necator and cyanobacteria engineered to fix CO₂ → 3-HP
• Requires synthetic carbon fixation modules and redox coupling

Catalysts and Key Tools Used

Key Enzymes:

• Glycerol dehydratase (GDHt)
• Malonyl-CoA reductase (MCR)
• Aspartate decarboxylase, β-alanine transaminase
• Aldehyde dehydrogenase (AldDH)

Metabolic Engineering Tools:

• CRISPR/Cas systems for gene knock-in/out
• Dynamic pathway regulation for toxic intermediates
• Adaptive laboratory evolution (ALE) to enhance tolerance
• Synthetic operon design for high-yield flux channeling

Fermentation Techniques:

• Fed-batch with oxygen and pH control
• In situ product removal to reduce toxicity
• Co-substrate feeding (glucose + glycerol) for redox balance

Case Study: Cargill & Novozymes – 3-HP to Acrylic Acid

Highlights

• Developed engineered E. coli for 3-HP production from glucose
• Converted 3-HP to acrylic acid using dehydration catalysts
• Demonstrated cost-competitive biobased route with >70% yield
• Pilot tested in Cargill’s biorefinery for SAP (superabsorbent polymer) applications

Timeline

• 2013 – Cargill and Novozymes announce partnership
• 2016 – Achieve industrial-scale 3-HP titers in 50L fermenters
• 2020 – Acrylic acid derived from 3-HP enters diaper and coating trials
• 2023 – Commercial readiness for biobased acrylic acid validated

Global and Indian Startups Working in This Area

Global

• Cargill (USA) – Leading the 3-HP → acrylic acid value chain
• BASF & Evonik – Exploring malonyl-CoA and CO₂ pathways
• DSM – Focus on PDO and poly-3HP
• Metabolic Explorer (France) – Glycerol-based microbial 3-HP

India

• IIT Bombay & NCL Pune – Malonyl-CoA based synthetic pathways
• CSIR-IICT – Glycerol valorization for platform acid production
• Agnisumukh BioTech – Exploring biodegradable polymers from 3-HP
• Godavari Biorefineries – Trials on glycerol-to-3HP fermentation from sugar feedstock

Market and Demand

The 3-HP market is valued at USD 180 million (2023), projected to grow to USD 650 million by 2030, at a CAGR of ~19.5%, driven by demand in green acrylics and polyesters.

Major End-Use Segments:

• Superabsorbent polymers (SAPs) – Diapers, hygiene products
• Acrylic coatings and adhesives
• Bioplastics (e.g., PTT, poly-3HP)
• Solvents and specialty chemicals

Key Growth Drivers

• Shift to BPA-free and VOC-free coatings
• Demand for biodegradable plastics with heat resistance
• Surplus glycerol from biodiesel as cheap feedstock
• Push for CO₂-to-chemical pathways in carbon capture
• Integration of 3-HP into acrylic acid value chains

Challenges to Address

• 3-HP toxicity to microbial hosts limits yield
• Oxygen sensitivity of glycerol dehydratase in native pathways
• Need for cofactor regeneration (NADPH) in malonyl route
• Downstream dehydration to acrylic acid requires heat/catalysts
• In India: limited industrial offtake for poly-3HP or biobased acrylics

Progress Indicators

• 2010–2012 – First engineered 3-HP pathways from glycerol and glucose
• 2015 – Cargill achieves commercial titers for 3-HP in pilot trials
• 2018 – Indian labs begin β-alanine and malonyl-CoA pathway work
• 2022 – CO₂-to-3HP modules tested in synthetic chassis
• 2024 – Bioacrylics tested in diaper absorbents and paints in Asia

Fermentative 3-HP production via glycerol and glucose is at TRL 7–8 globally, with full industrial pilots underway. In India, it stands at TRL 4–5, with academic proof-of-concept and early bioprocess optimization in progress.

Conclusion

3-Hydroxypropionic acid (3-HP) is a high-value platform chemical at the heart of the green chemicals revolution. With its ability to serve as a precursor to acrylic acid, biodegradable plastics, and specialty solvents, 3-HP offers a compelling case for replacing fossil-based intermediates.

Through metabolic engineering, enzyme optimization, and biorefinery integration, the biological production of 3-HP is reaching industrial maturity. With India’s abundant glycerol and sugar feedstock base, it has the potential to become a bio-manufacturing hub for this crucial molecule in the near future.

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