Saturday, February 22, 2025
No menu items!
HomeNatureSnapshots of acyl carrier protein shuttling in human fatty acid synthase

Snapshots of acyl carrier protein shuttling in human fatty acid synthase

  • Paiva, P. et al. Animal fatty acid synthase: a chemical nanofactory. Chem. Rev. 121, 9502–9553 (2021).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Ameer, F., Scandiuzzi, L., Hasnain, S., Kalbacher, H. & Zaidi, N. De novo lipogenesis in health and disease. Metabolism 63, 895–902 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Batchuluun, B., Pinkosky, S. L. & Steinberg, G. R. Lipogenesis inhibitors: therapeutic opportunities and challenges. Nat. Rev. Drug Discov. 21, 283–305 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Ferraro, G. B. et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat. Cancer 2, 414–428 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Falchook, G. et al. First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine 34, 100797 (2021).

    Article 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Loomba, R. et al. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology 161, 1475–1486 (2021).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Kelly, K. L. et al. De novo lipogenesis is essential for platelet production in humans. Nat. Metab. 2, 1163–1178 (2020).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Bowers, M. et al. FASN-dependent lipid metabolism links neurogenic stem/progenitor cell activity to learning and memory deficits. Cell Stem Cell 27, 98–109.e111 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Grininger, M. Enzymology of assembly line synthesis by modular polyketide synthases. Nat. Chem. Biol. 19, 401–415 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lin, Z., Li, F., Krug, P. J. & Schmidt, E. W. The polyketide to fatty acid transition in the evolution of animal lipid metabolism. Nat. Commun. 15, 236 (2024).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jenke-Kodama, H., Sandmann, A., Müller, R. & Dittmann, E. Evolutionary implications of bacterial polyketide synthases. Mol. Biol. Evol. 22, 2027–2039 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nivina, A., Yuet, K. P., Hsu, J. & Khosla, C. Evolution and diversity of assembly-line polyketide synthases. Chem. Rev. 119, 12524–12547 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fischer, M. & Grininger, M. Strategies in megasynthase engineering — fatty acid synthases (FAS) as model proteins. Beilstein J. Org. Chem. 13, 1204–1211 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rittner, A., Paithankar, K. S., Drexler, D. J., Himmler, A. & Grininger, M. Probing the modularity of megasynthases by rational engineering of a fatty acid synthase type I. Protein Sci. 28, 414–428 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rittner, A. et al. Chemoenzymatic synthesis of fluorinated polyketides. Nat. Chem. 14, 1000–1006 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Buyachuihan, L., Reiners, S., Zhao, Y. & Grininger, M. The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds. Commun. Chem. 7, 187 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maier, T., Jenni, S. & Ban, N. Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science 311, 1258–1262 (2006).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Maier, T., Leibundgut, M. & Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321, 1315–1322 (2008).

    Article 
    ADS 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Leibundgut, M., Jenni, S., Frick, C. & Ban, N. Structural basis for substrate delivery by acyl carrier protein in the yeast fatty acid synthase. Science 316, 288–290 (2007).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Singh, K. et al. Reconstruction of a fatty acid synthesis cycle from acyl carrier protein and cofactor structural snapshots. Cell 186, 5054–5067.e16 (2023).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Witkowski, A., Joshi, A. K. & Smith, S. Characterization of the β-carbon processing reactions of the mammalian cytosolic fatty acid synthase: role of the central core. Biochemistry 43, 10458–10466 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Witkowski, A., Joshi, A. K. & Smith, S. Mechanism of the β-ketoacyl synthase reaction catalyzed by the animal fatty acid synthase. Biochemistry 41, 10877–10887 (2002).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Rittner, A., Paithankar, K. S., Huu, K. V. & Grininger, M. Characterization of the polyspecific transferase of murine type I fatty acid synthase (FAS) and implications for polyketide synthase (PKS) engineering. ACS Chem. Biol. 13, 723–732 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rangan, V. S., Joshi, A. K. & Smith, S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry 40, 10792–10799 (2001).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Brink, J. et al. Quaternary structure of human fatty acid synthase by electron cryomicroscopy. Proc. Natl Acad. Sci. USA 99, 138–143 (2002).

    Article 
    ADS 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Buyachuihan, L., Stegemann, F. & Grininger, M. How acyl carrier proteins (ACPs) direct fatty acid and polyketide biosynthesis. Angew. Chem. Int. Edn https://doi.org/10.1002/anie.202312476 (2023).

    Article 

    Google Scholar
     

  • Rittner, A., Paithankar, K. S., Himmler, A. & Grininger, M. Type I fatty acid synthase trapped in the octanoyl‐bound state. Protein Sci. 29, 589–605 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brignole, E. J., Smith, S. & Asturias, F. J. Conformational flexibility of metazoan fatty acid synthase enables catalysis. Nat. Struct. Mol. Biol. 16, 190–197 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hasan, S. M. N., Lou, J. W., Keszei, A. F. A., Dai, D. L. & Mazhab-Jafari, M. T. Atomic model for core modifying region of human fatty acid synthase in complex with denifanstat. Nat. Commun. 14, 3460 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hardwicke, M. A. et al. A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site. Nat. Chem. Biol. 10, 774–779 (2014).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Klaus, M. et al. Solution structure and conformational flexibility of a polyketide synthase module. JACS Au 1, 2162–2171 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Bunkoczi, G. et al. Mechanism and substrate recognition of human holo ACP synthase. Chem. Biol. 14, 1243–1253 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Izzo, L. T. et al. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis. Sci. Adv. 9, eadf0115 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Chan, D. I. & Vogel, H. J. Current understanding of fatty acid biosynthesis and the acyl carrier protein. Biochem. J. 430, 1–19 (2010).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Nguyen, C. et al. Trapping the dynamic acyl carrier protein in fatty acid biosynthesis. Nature 505, 427–431 (2014).

    Article 
    ADS 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Bagde, S. R., Mathews, I. I., Fromme, J. C. & Kim, C.-Y. Modular polyketide synthase contains two reaction chambers that operate asynchronously. Science 374, 723–729 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cogan, D. P. et al. Mapping the catalytic conformations of an assembly-line polyketide synthase module. Science 374, 729–734 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Monod, J., Wyman, J. & Changeux, J.-P. On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12, 88–118 (1965).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Wang, J. et al. Structural basis for the biosynthesis of lovastatin. Nat. Commun. 12, 867 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Suloway, C. et al. Automated molecular microscopy: the new Leginon system. J. Struct. Biol. 151, 41–60 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7, e42166 (2018).

    Article 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).

    Article 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Bepler, T. et al. Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs. Nat. Methods 16, 1153–1160 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Sanchez-Garcia, R. et al. DeepEMhancer: a deep learning solution for cryo-EM volume post-processing. Commun. Biol. 4, 874 (2021).

    Article 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Tan, Y. Z. et al. Addressing preferred specimen orientation in single-particle cryo-EM through tilting. Nat. Methods 14, 793–796 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D Struct. Biol. 75, 861–877 (2019).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Varadi, M. et al. AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50, D439–D444 (2021).

    Article 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Trefely, S., Ashwell, P. & Snyder, N. W. FluxFix: automatic isotopologue normalization for metabolic tracer analysis. BMC Bioinformatics 17, 485 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • RELATED ARTICLES

    Most Popular

    Recent Comments