Abstract 4494: Structure, dynamics and therapeutic potential of fatty acid synthase
Bibliographic record
Abstract
Abstract De novo lipid synthesis is facilitated by the multifunctional enzyme fatty acid synthase (FASN), a hallmark of cancer associated with chemotherapeutic resistance and poor prognosis. Human FASN (hFASN) is a dynamic protein that undergoes significant conformational changes during catalysis, posing challenges for structural characterization. To date, no structural information is available for full-length hFASN, hindering our understanding of its catalytic mechanism and complicating rational drug design.Here, we report the structure of hFASN resolved using electron cryo-microscopy (cryoEM). The modifying region of hFASN was determined at near-atomic resolution using a recombinant expression system bound to the first-in-class inhibitor Denifanstat, enabling structure-based small molecule discovery. Additionally, we solved the full-length structure of endogenous hFASN from MCF7 cells, revealing an interaction with the small heat shock protein HSP27. In some 2D classes of hFASN from cryoEM data, we found partial unfolding of the modifying region, evidence of potential protein degradation. However, HSP27 knockdown in breast cancer cell lines did not alter overall hFASN levels, indicating that this interaction may be transient or involve additional partners.Mass spectrometry-based post-translational modification analysis further identified dihydroxylation of proline, arginine, and tyrosine residues in hFASN from MCF7 cells, likely reflecting oxidative stress. These modifications may play a role in protein stabilization or regulation under stress conditions, highlighting a potential mechanism for hFASN activity modulation. Together, these findings provide critical structural and regulatory insights, paving the way for targeted therapeutic development. Citation Format: Naimul Hasan, Alexander Keszei, Matthew Waas, Thomas Kislinger, Razq Hakem, Mohammad Mazhab-Jafari. Structure, dynamics and therapeutic potential of fatty acid synthase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4494.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".