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The dissimilation pathway in <jats:italic>K. phaffii<\/jats:italic> leads to the loss of carbon atoms in the form of CO<jats:sub>2<\/jats:sub>. However, the \u0394FLD strain, engineered to lack formaldehyde dehydrogenase\u2014an essential enzyme in the dissimilation pathway\u2014displayed growth defects when exposed to a methanol-containing medium.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Inhibiting the dissimilation pathway triggers an excessive accumulation of formaldehyde and a decline in the intracellular NAD<jats:sup>+<\/jats:sup>\/NADH ratio. Here, we designed dual-enzyme complex with the alcohol oxidase1\/dihydroxyacetone synthase1 (Aox1\/Das1), enhancing the regeneration of the formaldehyde receptor xylulose-5-phosphate (Xu5P). This strategy mitigated the harmful effects of formaldehyde accumulation and associated toxicity to cells. Concurrently, we elevated the NAD<jats:sup>+<\/jats:sup>\/NADH ratio by overexpressing isocitrate dehydrogenase in the TCA cycle, promoting intracellular redox homeostasis. The OD<jats:sub>600<\/jats:sub> of the optimized combination of the above strategies, strain DF02-1, was 4.28 times higher than that of the control strain DF00 (\u0394<jats:italic>FLD<\/jats:italic>, <jats:italic>HIS4<\/jats:italic><jats:sup>+<\/jats:sup>) under 1% methanol. Subsequently, the heterologous expression of methanol oxidase Mox from <jats:italic>Hansenula polymorpha<\/jats:italic> in strain DF02-1 resulted in the recombinant strain DF02-4, which displayed a growth at an OD<jats:sub>600<\/jats:sub> 4.08 times higher than that the control strain DF00 in medium containing 3% methanol.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The reduction of formaldehyde accumulation, the increase of NAD<jats:sup>+<\/jats:sup>\/NADH ratio, and the enhancement of methanol oxidation effectively improved the efficient utilization of a high methanol concentration by strain \u0394FLD strain lacking formaldehyde dehydrogenase. The modification strategies implemented in this study collectively serve as a foundational framework for advancing the efficient utilization of methanol in <jats:italic>K. phaffii<\/jats:italic>.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12934-024-02475-1","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T02:01:38Z","timestamp":1721181698000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Metabolic engineering of Komagataella phaffii for the efficient utilization of methanol"],"prefix":"10.1186","volume":"23","author":[{"given":"Yuanyuan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruisi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengguang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dexun","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,17]]},"reference":[{"key":"2475_CR1","doi-asserted-by":"crossref","unstructured":"Bertau M, Offermanns H, Plass L, Schmidt F, Wernicke HJ. 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