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Insight into Acetyl-Coenzyme A Regulation Through the Molecular Mechanism of ATP-Citrate Lyase / Gleb Bazilevsky.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Bazilevsky, Gleb, author.
- Language:
- English
- Subjects (All):
- Biochemistry.
- Biophysics.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Local Subjects:
- Biochemistry.
- Biophysics.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (110 pages)
- Contained In:
- Dissertations Abstracts International 81-05B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- The metabolite acetyl-CoA is necessary in almost all organic life. Cytosolic acetyl-CoA is crucial for lipid synthesis, cholesterol synthesis, and gene regulation. It is also a major factor in metabolic disorders, including diabetes, heart disease, and cancer. In metazoans, the predominant source of cytosolic acetyl-CoA is the essential enzyme ATP-citrate lyase (ACLY). This enzyme is a prime pharmacological target. However, the molecular mechanisms of ACLY activity and regulation are unclear. This work uses a suite of biochemical and biophysical approaches to elucidate ACLY quaternary structure and the mechanisms of acetyl-CoA synthesis. We demonstrate that ACLY forms a tetramer through the previously-uncharacterized ACLY C-terminus. The C-terminus, in the context of the tetramer, interacts with the rest of the protein to bind the reaction substrates. This is a new model for ACLY substrate binding and enzyme activity. We also explore the direct interaction of ACLY with protein acetyltransferases as a means of gene regulation. These findings have implications for our basic understanding of protein biology, evolution, and the rational design of life-saving ACLY therapies.
- Notes:
- Source: Dissertations Abstracts International, Volume: 81-05, Section: B.
- Advisors: Marmorstein, Ronen; Committee members: Roger Greenberg; Joseph Baur; Benjamin Black; Shelley Berger.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2019.
- Local Notes:
- School code: 0175
- ISBN:
- 9781088341513
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
- This item must not be sold to any third party vendors.
- This item must not be added to any third party search indexes.
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