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Engineering a Yeast-Based Platform for Production of Novel Monoterpene Indole Alkaloid Analogs- [electronic resource]
Engineering a Yeast-Based Platform for Production of Novel Monoterpene Indole Alkaloid Analogs- [electronic resource]
상세정보
- 자료유형
- 학위논문
- Control Number
- 0016933141
- International Standard Book Number
- 9798379682231
- Dewey Decimal Classification Number
- 660
- Main Entry-Personal Name
- Misa, Joshua Russell.
- Publication, Distribution, etc. (Imprint
- [S.l.] : University of California, Los Angeles., 2023
- Publication, Distribution, etc. (Imprint
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Physical Description
- 1 online resource(119 p.)
- General Note
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- General Note
- Advisor: Tang, Yi.
- Dissertation Note
- Thesis (Ph.D.)--University of California, Los Angeles, 2023.
- Restrictions on Access Note
- This item must not be sold to any third party vendors.
- Summary, Etc.
- 요약In addition to satisfying nutritional needs, humans have been consuming plants for medicinal and recreational purposes for millennia. The medicinal and recreational properties of plants are attributed to compounds that are not a product of the plant's core metabolism, but are rather secondary metabolites, also known as natural products. Monoterpene indole alkaloids (MIAs) are an expansive class of bioactive plant natural products, many of which have been named on the World Health Organization's List of Essential Medicines. Among MIAs' divergent structural complexity are psychoactive MIAs such as ibogaine and mitragynine which also hold therapeutic potential. However, low production from native plant hosts necessitates a more reliable source of these compounds to meet global demands in medicine and research. The recent explosion of synthetic biology toolsets and genomics data has enabled reconstitution of plant biosynthetic pathways to build complex MIA structures in alternative hosts.In this dissertation, we report on the development of a yeast-based platform for high-titer production of the universal MIA precursor, strictosidine. Our fed-batch platform produces ∼50 mg/L strictosidine, starting from the commodity chemicals geraniol and tryptamine, and is the highest titer reported to date. Next, we describe approaches to further optimize this platform and leverage it to produce strictosidine analogs. Bioprospecting homologs of pathway genes reveal the variants from Catharanthus roseus have the highest activity in yeast. Finally, we utilized our strictosidine platform to access bioactive MIAs such as heteroyohimbine and corynantheidine type MIAs. We also demonstrate our ability to access novel analogs of these compounds with our platform, which potentially have improved or divergent bioactivity from their native forms.
- Subject Added Entry-Topical Term
- Chemical engineering.
- Subject Added Entry-Topical Term
- Plant sciences.
- Subject Added Entry-Topical Term
- Biochemistry.
- Index Term-Uncontrolled
- Metabolic engineering
- Index Term-Uncontrolled
- Monoterpene indole alkaloids
- Index Term-Uncontrolled
- Strain engineering
- Index Term-Uncontrolled
- Strictosidine
- Index Term-Uncontrolled
- Synthetic biology
- Index Term-Uncontrolled
- Yeast
- Added Entry-Corporate Name
- University of California, Los Angeles Chemical Engineering 0294
- Host Item Entry
- Dissertations Abstracts International. 84-12B.
- Host Item Entry
- Dissertation Abstract International
- Electronic Location and Access
- 로그인을 한후 보실 수 있는 자료입니다.
- Control Number
- joongbu:642227
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■1001 ▼aMisa, Joshua Russell.
■24510▼aEngineering a Yeast-Based Platform for Production of Novel Monoterpene Indole Alkaloid Analogs▼h[electronic resource]
■260 ▼a[S.l.]▼bUniversity of California, Los Angeles. ▼c2023
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2023
■300 ▼a1 online resource(119 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 84-12, Section: B.
■500 ▼aAdvisor: Tang, Yi.
■5021 ▼aThesis (Ph.D.)--University of California, Los Angeles, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aIn addition to satisfying nutritional needs, humans have been consuming plants for medicinal and recreational purposes for millennia. The medicinal and recreational properties of plants are attributed to compounds that are not a product of the plant's core metabolism, but are rather secondary metabolites, also known as natural products. Monoterpene indole alkaloids (MIAs) are an expansive class of bioactive plant natural products, many of which have been named on the World Health Organization's List of Essential Medicines. Among MIAs' divergent structural complexity are psychoactive MIAs such as ibogaine and mitragynine which also hold therapeutic potential. However, low production from native plant hosts necessitates a more reliable source of these compounds to meet global demands in medicine and research. The recent explosion of synthetic biology toolsets and genomics data has enabled reconstitution of plant biosynthetic pathways to build complex MIA structures in alternative hosts.In this dissertation, we report on the development of a yeast-based platform for high-titer production of the universal MIA precursor, strictosidine. Our fed-batch platform produces ∼50 mg/L strictosidine, starting from the commodity chemicals geraniol and tryptamine, and is the highest titer reported to date. Next, we describe approaches to further optimize this platform and leverage it to produce strictosidine analogs. Bioprospecting homologs of pathway genes reveal the variants from Catharanthus roseus have the highest activity in yeast. Finally, we utilized our strictosidine platform to access bioactive MIAs such as heteroyohimbine and corynantheidine type MIAs. We also demonstrate our ability to access novel analogs of these compounds with our platform, which potentially have improved or divergent bioactivity from their native forms.
■590 ▼aSchool code: 0031.
■650 4▼aChemical engineering.
■650 4▼aPlant sciences.
■650 4▼aBiochemistry.
■653 ▼aMetabolic engineering
■653 ▼aMonoterpene indole alkaloids
■653 ▼aStrain engineering
■653 ▼aStrictosidine
■653 ▼aSynthetic biology
■653 ▼aYeast
■690 ▼a0542
■690 ▼a0487
■690 ▼a0479
■71020▼aUniversity of California, Los Angeles▼bChemical Engineering 0294.
■7730 ▼tDissertations Abstracts International▼g84-12B.
■773 ▼tDissertation Abstract International
■790 ▼a0031
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16933141▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
