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<p>Astaxanthin, a keto-carotenoid renowned for its strong antioxidant capacity, has become an increasingly preferred target for microbial biosynthesis. <i>Saccharomyces cerevisiae</i> is regarded as a promising host for astaxanthin production because of its native mevalonate pathway. However, the limited catalytic efficiency of the key enzymes β-carotene hydroxylase (CrtZ) and β-carotene ketolase (CrtW) remains a major constraint in achieving high yields. In this study, we combined multiple strategies to enhance catalytic performance. First, we performed combinatorial screening of CrtZ and CrtW from diverse sources and identified an enzyme pair that efficiently catalyzed the conversion of β-carotene to astaxanthin. Subsequently, a heterologous ferredoxin-based redox-partner system was introduced and optimized, resulting in a 79.5% increase in astaxanthin production to (63.21 ± 2.74)&#xa0;mg/L. In addition, a dual-compartmentalization strategy targeting both lipid droplets and the endoplasmic reticulum enhanced the spatial proximity between CrtZ/CrtW and the substrate β-carotene while reducing byproduct accumulation, resulting in a 29.9% increase in astaxanthin production to (82.12 ± 2.37)&#xa0;mg/L. Finally, by optimizing induction timing and applying fed-batch fermentation in a 5 L bioreactor, the astaxanthin titer was further elevated to (507.68 ± 27.12)&#xa0;mg/L, representing the highest level reported to date in <i>S. cerevisiae</i>. Collectively, this work establishes an integrated metabolic engineering framework for improving astaxanthin biosynthesis in <i>S. cerevisiae</i>.</p>

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Combinatorial engineering of Saccharomyces cerevisiae for high level production of astaxanthin

  • 期刊论文

  • 发表日期：

    2026年4月15日

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  • Yuting Shi,
  • Yanmei Li,
  • Jiaheng Liu,
  • Dongxu Chen,
  • Xianhao Xu,
  • Zhendong Li,
  • Yanfeng Liu,
  • Guocheng Du,
  • Jianghua Li,
  • Jian Chen,
  • Xueqin Lv,
  • Long Liu

摘要

Astaxanthin, a keto-carotenoid renowned for its strong antioxidant capacity, has become an increasingly preferred target for microbial biosynthesis. Saccharomyces cerevisiae is regarded as a promising host for astaxanthin production because of its native mevalonate pathway. However, the limited catalytic efficiency of the key enzymes β-carotene hydroxylase (CrtZ) and β-carotene ketolase (CrtW) remains a major constraint in achieving high yields. In this study, we combined multiple strategies to enhance catalytic performance. First, we performed combinatorial screening of CrtZ and CrtW from diverse sources and identified an enzyme pair that efficiently catalyzed the conversion of β-carotene to astaxanthin. Subsequently, a heterologous ferredoxin-based redox-partner system was introduced and optimized, resulting in a 79.5% increase in astaxanthin production to (63.21 ± 2.74) mg/L. In addition, a dual-compartmentalization strategy targeting both lipid droplets and the endoplasmic reticulum enhanced the spatial proximity between CrtZ/CrtW and the substrate β-carotene while reducing byproduct accumulation, resulting in a 29.9% increase in astaxanthin production to (82.12 ± 2.37) mg/L. Finally, by optimizing induction timing and applying fed-batch fermentation in a 5 L bioreactor, the astaxanthin titer was further elevated to (507.68 ± 27.12) mg/L, representing the highest level reported to date in S. cerevisiae. Collectively, this work establishes an integrated metabolic engineering framework for improving astaxanthin biosynthesis in S. cerevisiae.