Mechanistic Multi-Enzyme Engineering for High-Yield Bilirubin Biosynthesis Article Swipe
Rongzhen Zhang
,
Zhentao Jiang
,
Jingxin Rao
,
Chenglin Zhu
,
Yamiao Li
,
Qiang Zhu
,
Mingyue Zheng
,
Wenchi Zhang
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-6554107/v1
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-6554107/v1
Bilirubin biosynthesis has long been limited by low yields and unclear bottlenecks. Here, we report a fully in vitro pathway that coverts heme to bilirubin with the highest reported titer. Through systematically screening and engineering, we identified two hidden challenges: Fe²⁺ causes intermediate degradation, and CO inhibits heme oxygenase activity. Initial yields stalled at 48.1% due to Fe²⁺-induced biliverdin and bilirubin breakdown. We revealed that Fe²⁺ interacts with deprotonated biliverdin and bilirubin, triggering oxidative ring-opening degradation via O₂-mediated radical mechanism. DFT calculations showed Fe²⁺-ligand complexes reduce the HOMO-LUMO gap, enhancing their elector transfer susceptibility. Competitive chelation of Fe2+ and protonation-modulation boosted yield to 80.1%. Furthermore, heme-CO complexes block O2-activation for accessing heme oxygenase. Introducing carbon monoxide dehydrogenase for CO removal and formate dehydrogenase for NADPH-recycling enabled efficient bilirubin synthesis of 1.7 g/L and 95.8% yield—a 20-fold improvement. Our work shows byproducts control is the key to stabilize heme-related pathways and as an advanced tool in synthetic biology.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-6554107/v1
- https://www.researchsquare.com/article/rs-6554107/latest.pdf
- OA Status
- gold
- References
- 4
- Related Works
- 10
- OpenAlex ID
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All OpenAlex metadata
Raw OpenAlex JSON
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- DOI
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https://doi.org/10.21203/rs.3.rs-6554107/v1Digital Object Identifier
- Title
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Mechanistic Multi-Enzyme Engineering for High-Yield Bilirubin BiosynthesisWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-05-29Full publication date if available
- Authors
-
Rongzhen Zhang, Zhentao Jiang, Jingxin Rao, Chenglin Zhu, Yamiao Li, Qiang Zhu, Mingyue Zheng, Wenchi ZhangList of authors in order
- Landing page
-
https://doi.org/10.21203/rs.3.rs-6554107/v1Publisher landing page
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https://www.researchsquare.com/article/rs-6554107/latest.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
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https://www.researchsquare.com/article/rs-6554107/latest.pdfDirect OA link when available
- Concepts
-
Biosynthesis, Yield (engineering), Enzyme, Chemistry, Biochemistry, Bilirubin, Biology, Materials science, Endocrinology, MetallurgyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
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4Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.key | 145 |
| abstract_inverted_index.low | 8 |
| abstract_inverted_index.the | 27, 87, 144 |
| abstract_inverted_index.two | 38 |
| abstract_inverted_index.been | 5 |
| abstract_inverted_index.gap, | 89 |
| abstract_inverted_index.heme | 23, 48, 112 |
| abstract_inverted_index.long | 4 |
| abstract_inverted_index.that | 21, 65 |
| abstract_inverted_index.tool | 154 |
| abstract_inverted_index.with | 26, 68 |
| abstract_inverted_index.work | 139 |
| abstract_inverted_index.48.1% | 55 |
| abstract_inverted_index.95.8% | 134 |
| abstract_inverted_index.Here, | 13 |
| abstract_inverted_index.block | 108 |
| abstract_inverted_index.fully | 17 |
| abstract_inverted_index.shows | 140 |
| abstract_inverted_index.their | 91 |
| abstract_inverted_index.vitro | 19 |
| abstract_inverted_index.yield | 102 |
| abstract_inverted_index.80.1%. | 104 |
| abstract_inverted_index.carbon | 115 |
| abstract_inverted_index.causes | 42 |
| abstract_inverted_index.hidden | 39 |
| abstract_inverted_index.reduce | 86 |
| abstract_inverted_index.report | 15 |
| abstract_inverted_index.showed | 83 |
| abstract_inverted_index.titer. | 30 |
| abstract_inverted_index.yields | 9, 52 |
| abstract_inverted_index.20-fold | 136 |
| abstract_inverted_index.Fe²⁺ | 41, 66 |
| abstract_inverted_index.Initial | 51 |
| abstract_inverted_index.Through | 31 |
| abstract_inverted_index.boosted | 101 |
| abstract_inverted_index.control | 142 |
| abstract_inverted_index.coverts | 22 |
| abstract_inverted_index.elector | 92 |
| abstract_inverted_index.enabled | 126 |
| abstract_inverted_index.formate | 122 |
| abstract_inverted_index.heme-CO | 106 |
| abstract_inverted_index.highest | 28 |
| abstract_inverted_index.limited | 6 |
| abstract_inverted_index.pathway | 20 |
| abstract_inverted_index.radical | 79 |
| abstract_inverted_index.removal | 120 |
| abstract_inverted_index.stalled | 53 |
| abstract_inverted_index.unclear | 11 |
| abstract_inverted_index.advanced | 153 |
| abstract_inverted_index.biology. | 157 |
| abstract_inverted_index.inhibits | 47 |
| abstract_inverted_index.monoxide | 116 |
| abstract_inverted_index.pathways | 149 |
| abstract_inverted_index.reported | 29 |
| abstract_inverted_index.revealed | 64 |
| abstract_inverted_index.transfer | 93 |
| abstract_inverted_index.Bilirubin | 1 |
| abstract_inverted_index.HOMO-LUMO | 88 |
| abstract_inverted_index.accessing | 111 |
| abstract_inverted_index.activity. | 50 |
| abstract_inverted_index.bilirubin | 25, 61, 128 |
| abstract_inverted_index.chelation | 96 |
| abstract_inverted_index.complexes | 85, 107 |
| abstract_inverted_index.efficient | 127 |
| abstract_inverted_index.enhancing | 90 |
| abstract_inverted_index.interacts | 67 |
| abstract_inverted_index.oxidative | 74 |
| abstract_inverted_index.oxygenase | 49 |
| abstract_inverted_index.screening | 33 |
| abstract_inverted_index.stabilize | 147 |
| abstract_inverted_index.synthesis | 129 |
| abstract_inverted_index.synthetic | 156 |
| abstract_inverted_index.yield—a | 135 |
| abstract_inverted_index.bilirubin, | 72 |
| abstract_inverted_index.biliverdin | 59, 70 |
| abstract_inverted_index.breakdown. | 62 |
| abstract_inverted_index.byproducts | 141 |
| abstract_inverted_index.identified | 37 |
| abstract_inverted_index.mechanism. | 80 |
| abstract_inverted_index.oxygenase. | 113 |
| abstract_inverted_index.triggering | 73 |
| abstract_inverted_index.Competitive | 95 |
| abstract_inverted_index.Introducing | 114 |
| abstract_inverted_index.challenges: | 40 |
| abstract_inverted_index.degradation | 76 |
| abstract_inverted_index.Furthermore, | 105 |
| abstract_inverted_index.biosynthesis | 2 |
| abstract_inverted_index.bottlenecks. | 12 |
| abstract_inverted_index.calculations | 82 |
| abstract_inverted_index.degradation, | 44 |
| abstract_inverted_index.deprotonated | 69 |
| abstract_inverted_index.engineering, | 35 |
| abstract_inverted_index.heme-related | 148 |
| abstract_inverted_index.improvement. | 137 |
| abstract_inverted_index.intermediate | 43 |
| abstract_inverted_index.ring-opening | 75 |
| abstract_inverted_index.O₂-mediated | 78 |
| abstract_inverted_index.dehydrogenase | 117, 123 |
| abstract_inverted_index.Fe²⁺-ligand | 84 |
| abstract_inverted_index.systematically | 32 |
| abstract_inverted_index.Fe<sup>2+</sup> | 98 |
| abstract_inverted_index.Fe²⁺-induced | 58 |
| abstract_inverted_index.NADPH-recycling | 125 |
| abstract_inverted_index.susceptibility. | 94 |
| abstract_inverted_index.<italic>via</italic> | 77 |
| abstract_inverted_index.protonation-modulation | 100 |
| abstract_inverted_index.<title>Abstract</title> | 0 |
| abstract_inverted_index.O<sub>2</sub>-activation | 109 |
| cited_by_percentile_year | |
| countries_distinct_count | 2 |
| institutions_distinct_count | 8 |
| citation_normalized_percentile.value | 0.22308039 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |