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<p><i>Yarrowia lipolytica</i> is a prominent industrial host for erythritol production, yet yields are limited by carbon flux diversion to competing polyols, such as mannitol. Understanding the molecular basis of this competition is essential for rational strain engineering. This study aimed to elucidate the role of YlMDH2 (YALI0_D18964g; hereafter YIMDH2) in temperature-dependent mannitol biosynthesis and assess its potential as a target for enhancing erythritol yield. An integrative multi-omics approach was employed, including time-course transcriptomics, qPCR validation, protein–protein interaction network analysis, and molecular docking. Strains were cultivated under a temperature gradient (30&#xa0;°C, 33&#xa0;°C, 35&#xa0;°C), and docking simulations evaluated substrate specificity. YlMDH2 displayed a transient peak expression pattern rising 2,630 ± 357 TPM at 48&#xa0;h before declining sharply, whereas the thermotolerant reference strain maintained constitutively high expression. Transcript levels were highly temperature-sensitive, maximizing at 33&#xa0;°C (8,386 ± 441 TPM) and decreasing at 35&#xa0;°C (2,041 ± 1,169 TPM), correlating with mannitol accumulation. Molecular docking revealed a preferential binding affinity for D-fructose (–12.1&#xa0;kcal/mol) and D-mannitol (–11.6&#xa0;kcal/mol), while exhibiting significantly lower affinity for erythrose and erythritol, elucidating the substrate bias. Key catalytic residues Gln183, Ser173, Ser171, and Asn178 were identified, and PPI analysis positioned YlMDH2 within a central NADPH cofactor-management module linked to 6-phosphogluconate dehydrogenase. Temperature-dependent upregulation of YlMDH2 drives mannitol formation and competes directly with erythritol synthesis. Targeting YlMDH2 offers a rational strategy to minimize by-product formation and enhance erythritol production in <i>Y. lipolytica</i>.</p>

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Elucidating the role of YlMDH2 in temperature-dependent mannitol biosynthesis in Yarrowia lipolytica via integrative multi-omics and structural analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Muhammad Sarfaraz Iqbal,
  • Shuo Xu,
  • Yui Zhang,
  • Liyun Ji,
  • Khalid J. Alzahrani,
  • Khalaf F. Alsharif,
  • Fuad M. Alzahrani,
  • Abebe Bogale,
  • Hairong Cheng

摘要

Yarrowia lipolytica is a prominent industrial host for erythritol production, yet yields are limited by carbon flux diversion to competing polyols, such as mannitol. Understanding the molecular basis of this competition is essential for rational strain engineering. This study aimed to elucidate the role of YlMDH2 (YALI0_D18964g; hereafter YIMDH2) in temperature-dependent mannitol biosynthesis and assess its potential as a target for enhancing erythritol yield. An integrative multi-omics approach was employed, including time-course transcriptomics, qPCR validation, protein–protein interaction network analysis, and molecular docking. Strains were cultivated under a temperature gradient (30 °C, 33 °C, 35 °C), and docking simulations evaluated substrate specificity. YlMDH2 displayed a transient peak expression pattern rising 2,630 ± 357 TPM at 48 h before declining sharply, whereas the thermotolerant reference strain maintained constitutively high expression. Transcript levels were highly temperature-sensitive, maximizing at 33 °C (8,386 ± 441 TPM) and decreasing at 35 °C (2,041 ± 1,169 TPM), correlating with mannitol accumulation. Molecular docking revealed a preferential binding affinity for D-fructose (–12.1 kcal/mol) and D-mannitol (–11.6 kcal/mol), while exhibiting significantly lower affinity for erythrose and erythritol, elucidating the substrate bias. Key catalytic residues Gln183, Ser173, Ser171, and Asn178 were identified, and PPI analysis positioned YlMDH2 within a central NADPH cofactor-management module linked to 6-phosphogluconate dehydrogenase. Temperature-dependent upregulation of YlMDH2 drives mannitol formation and competes directly with erythritol synthesis. Targeting YlMDH2 offers a rational strategy to minimize by-product formation and enhance erythritol production in Y. lipolytica.