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<p>Methanol is a promising C1 feedstock for bioproduction but its cytotoxicity limits applications. Here we enhanced <i>Komagataella phaffii</i> GS115 methanol tolerance to 10–13% (v/v) by overexpressing four genes (phosphatidylethanolamine methyltransferase (<i>PET2</i>), phosphatidylserine synthase (<i>PSA</i>), <i>PAS_chr1-4_017</i>8 (<i>0178</i>) and <i>PAS_chr2-2_0267</i> (<i>0267</i>)) (S33 strain). Our results show that, under high methanol stress, S33 undergoes membrane lipid remodelling-driven metabolic reprogramming, with central carbon flux being redistributed from the pentose phosphate pathway and citric acid cycle towards glycolysis. Within this framework, <i>0178</i> encodes a vacuolar transporter of sulfur-containing amino acids, which we propose supports phospholipid methylation and redox balance. Meanwhile, <i>0267</i> encodes a peroxisomal thiolase-degrading long‑chain fatty acyl‑CoAs, limiting toxic long-chain sphingolipid accumulation, maintaining membrane stability. These genes enable S33 to achieve lipid titre of approximately 40 g l<sup>−1</sup> under non-sterile fed‑batch fermentation conditions. This work positions S33 as a methanol-tolerant <i>K. phaffii</i> chassis for further strain and process development.</p><p></p>

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Membrane remodelling for increased methanol tolerance in Komagataella phaffii

  • 期刊论文

  • 发表日期：

    2026年6月25日

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  • Shuai Wang,
  • Liu Yang,
  • Zhixuan Li,
  • Hui Ye,
  • Fei Teng,
  • Jun Yang,
  • Chunting Ye,
  • Dexun Fan,
  • Shuangyan Han

摘要

Methanol is a promising C1 feedstock for bioproduction but its cytotoxicity limits applications. Here we enhanced Komagataella phaffii GS115 methanol tolerance to 10–13% (v/v) by overexpressing four genes (phosphatidylethanolamine methyltransferase (PET2), phosphatidylserine synthase (PSA), PAS_chr1-4_0178 (0178) and PAS_chr2-2_0267 (0267)) (S33 strain). Our results show that, under high methanol stress, S33 undergoes membrane lipid remodelling-driven metabolic reprogramming, with central carbon flux being redistributed from the pentose phosphate pathway and citric acid cycle towards glycolysis. Within this framework, 0178 encodes a vacuolar transporter of sulfur-containing amino acids, which we propose supports phospholipid methylation and redox balance. Meanwhile, 0267 encodes a peroxisomal thiolase-degrading long‑chain fatty acyl‑CoAs, limiting toxic long-chain sphingolipid accumulation, maintaining membrane stability. These genes enable S33 to achieve lipid titre of approximately 40 g l−1 under non-sterile fed‑batch fermentation conditions. This work positions S33 as a methanol-tolerant K. phaffii chassis for further strain and process development.