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Compared to animal blood extraction, it is more advantageous to develop a microbial cell factory to produce heme. However, heme biosynthesis in microorganisms is tightly regulated, and its accumulation is highly cytotoxic. The current review describes the biosynthetic pathway of free heme, its fermentation production using different engineered bacteria constructed by metabolic engineering, and strategies for further improving heme synthesis. Heme synthetic pathway in <jats:italic>Bacillus subtilis<\/jats:italic> was modified utilizing genome-editing technology, resulting in significantly improved heme synthesis and secretion abilities. This technique avoided the use of multiple antibiotics and enhanced the genetic stability of strain. Hence, engineered <jats:italic>B. subtilis<\/jats:italic> could be an attractive cell factory for heme production. Further studies should be performed to enhance the expression of heme synthetic module and optimize the expression of heme exporter and fermentation processes, such as iron supply.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Key points<\/jats:title>\n            <jats:p>\u2022 <jats:italic>Strengthening the heme biosynthetic pathway can significantly increase heme production.<\/jats:italic>\n            <\/jats:p>\n            <jats:p>\u2022 <jats:italic>Heme exporter overexpression helps to promote heme secretion, thereby further promoting excessive heme synthesis.<\/jats:italic>\n            <\/jats:p>\n            <jats:p>\u2022 <jats:italic>Engineered B. subtilis is an attractive alternative for heme production.<\/jats:italic>\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00253-023-12968-5","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T11:02:23Z","timestamp":1704798143000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Recent advances in microbial synthesis of free heme"],"prefix":"10.1007","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1275-8401","authenticated-orcid":false,"given":"Shaomei","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuyu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxuan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyuan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuzhen","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,9]]},"reference":[{"key":"12968_CR1","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.4236\/ojog.2020.10120161","volume":"10","author":"AM Abbas","year":"2020","unstructured":"Abbas AM, Elhalwagy MM, Afifi K, Ibrahim K, Sweed MS (2020) Single vs. double dose iron supplementation for prevention of iron deficiency anemia in twin pregnancy: a randomized controlled clinical trial. 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