About

Ronen Marmorstein, Ph.D., is the George W. Raiziss Professor and an Investigator at the Abramson Family Cancer Research Institute at the University of Pennsylvania Perelman School of Medicine. He is a faculty member in the Department of Biochemistry and Biophysics. His research focuses on the molecular mechanisms of protein post- and co-translational acetylation, acetyl-CoA metabolism, gene expression, epigenetic regulation, and MAPK signaling. Dr. Marmorstein's laboratory employs biochemical, biophysical, and structural techniques such as X-ray crystallography and cryo-electron microscopy to elucidate the structure and function of macromolecules involved in age-associated diseases, including cancer, metabolic, and neurodegenerative disorders. His work includes studying the regulation of protein acetyltransferases, the molecular links between metabolism and epigenetics, and developing small-molecule probes for therapeutic applications. He has a background in chemistry and genetics from the University of California, Davis, and holds a Ph.D. in Chemistry from the University of Chicago. Dr. Marmorstein's research aims to understand the molecular basis of disease-related protein regulation and to develop targeted inhibitors for potential therapeutic use.

Research topics

• Computational biology
• Biology
• Bioinformatics
• Cancer research
• Genetics
• Medicine

Selected publications

• Snapshots of acyl carrier protein shuttling in human fatty acid synthase

  Nature · 2025-02-20 · 12 citations

  articleOpen accessSenior author

  The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis1. FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections2,3. The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP+ plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP–DH and ACP–ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics. Using cryo-electron microscopy, the structures of mammalian fatty acid synthase reveal how the acyl carrier protein dynamically shuttles intermediates between selected active sites.

  PublisherDOI

• Molecular basis of influenza ribonucleoprotein complex assembly and processive RNA synthesis

  Science · 2025-05-15 · 17 citations

  articleOpen access

  Influenza viruses replicate and transcribe their genome in the context of a conserved ribonucleoprotein (RNP) complex. By integrating cryo-electron microscopy single-particle analysis and cryo-electron tomography, we define the influenza RNP as a right-handed, antiparallel double helix with the viral RNA encapsidated in the minor groove. Individual nucleoprotein subunits are connected by a flexible tail loop that inserts into a conserved pocket in its neighbor. We visualize the viral polymerase in RNP at different functional states, revealing how it accesses the RNA template while maintaining the double-helical architecture of RNP by strand sliding. Targeting the tail loop binding interface, we identify lead compounds as potential anti-influenza inhibitors. These findings elucidate the molecular determinants underpinning influenza virus replication and highlight a promising target for antiviral development.

  PublisherOA PDFDOI

• Cryo-EM Structure of the Cyclase Domain and Evaluation of Substrate Channeling in a Bifunctional Class II Terpene Synthase

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-20

  preprintOpen access

  (PvCPS) is a bifunctional class II terpene synthase containing a prenyltransferase that produces geranylgeranyl diphosphate (GGPP) and a class II cyclase that utilizes GGPP as a substrate to generate the bicyclic diterpene copalyl diphosphate. The various stereoisomers of copalyl diphosphate establish the greater family of labdane natural products, many of which have environmental and medicinal impact. Understanding structure-function relationships in class II diterpene synthases is crucial for guiding protein engineering campaigns aimed at the generation of diverse bicyclic diterpene scaffolds. However, only a limited number of structures are available for class II cyclases from bacteria, plants, and humans, and no structures are available for a class II cyclase from a fungus. Further, bifunctional class II terpene synthases have not been investigated with regard to substrate channeling between the prenyltransferase and the cyclase. Here, we report the 2.9 Å-resolution cryo-EM structure of the 63-kD class II cyclase domain from PvCPS. Comparisons with bacterial and plant copalyl diphosphate synthases reveal conserved residues that likely guide the formation of the bicyclic labdane core, but divergent catalytic dyads that mediate the final deprotonation step of catalysis. Substrate competition experiments reveal preferential GGPP transit from the PvCPS prenyltransferase to the cyclase, even when prepared as separate constructs. These results are consistent with a model in which transient prenyltransferase-cyclase association facilitates substrate channeling due to active site proximity.

  PublisherOA PDFDOI

• Molecular targets of bempedoic acid and related decoy fatty acids

  Trends in Endocrinology and Metabolism · 2025-05-09 · 4 citations

  reviewOpen access
  PublisherOA PDFDOI

• Cryo-EM Structure of the Cyclase Domain and Evaluation of Substrate Channeling in a Bifunctional Class II Terpene Synthase

  Biochemistry · 2025-10-17

  articleOpen access

  (PvCPS) is a bifunctional class II terpene synthase containing a prenyltransferase that produces geranylgeranyl diphosphate (GGPP) and a class II cyclase that utilizes GGPP as a substrate to generate the bicyclic diterpene copalyl diphosphate. Various stereoisomers of copalyl diphosphate establish the greater family of labdane natural products, many of which have environmental and medicinal impact. Understanding structure-function relationships in class II diterpene synthases is crucial for guiding protein engineering campaigns aimed at the generation of diverse bicyclic diterpene scaffolds. However, only a limited number of structures are available for class II cyclases from bacteria, plants, and humans, and no structures are available for a class II cyclase from a fungus. Further, bifunctional class II terpene synthases have not been investigated with regard to substrate channeling between the prenyltransferase and the cyclase. Here, we report the 2.9 Å-resolution cryo-EM structure of the 63-kD class II cyclase domain from PvCPS. Comparisons with bacterial and plant copalyl diphosphate synthases reveal conserved residues that likely guide the formation of the bicyclic labdane core but divergent catalytic dyads that mediate the final deprotonation step of catalysis. Substrate competition experiments reveal preferential GGPP transit from the PvCPS prenyltransferase to the cyclase, even when the enzymes are prepared as separate constructs. These results are consistent with a model in which transient prenyltransferase-cyclase association facilitates substrate channeling due to active-site proximity.

  PublisherDOI

• Erratum to: The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases [Journal of Lipid Research 66/1 (2025) 100711]

  Journal of Lipid Research · 2025-10-30

  erratumOpen access
  PublisherDOI

• Engineering substrate channeling in a bifunctional terpene synthase

  Proceedings of the National Academy of Sciences · 2024-10-04 · 14 citations

  articleOpen access

  (PaFS) is a bifunctional terpene synthase. It contains a prenyltransferase (PT) domain that generates geranylgeranyl diphosphate (GGPP) from dimethylallyl diphosphate and three equivalents of isopentenyl diphosphate, and a cyclase domain that converts GGPP into fusicoccadiene, a precursor of the diterpene glycoside Fusicoccin A. The two catalytic domains are connected by a flexible 69-residue linker. The PT domain mediates oligomerization to form predominantly octamers, with cyclase domains randomly splayed out around the PT core. Surprisingly, despite the random positioning of cyclase domains, substrate channeling is operative in catalysis since most of the GGPP generated by the PT remains on the enzyme for cyclization. Here, we demonstrate that covalent linkage of the PT and cyclase domains is not required for GGPP channeling, although covalent linkage may improve channeling efficiency. Moreover, GGPP competition experiments with other diterpene cyclases indicate that the PaFS PT and cyclase domains are preferential partners regardless of whether they are covalently linked or not. The cryoelectron microscopy structure of the 600-kD "linkerless" construct, in which the 69-residue linker is spliced out and replaced with the tripeptide PTQ, reveals that cyclase pairs associate with all four sides of the PT octamer and exhibit fascinating quaternary structural flexibility. These results suggest that optimal substrate channeling is achieved when a cyclase domain associates with the side of the PT octamer, regardless of whether the two domains are covalently linked and regardless of whether this interaction is transient or locked in place.

  PublisherDOI

• Figure S9 from Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma

  2024-05-15

  preprintOpen access

  <p>Figure S9</p>

  PublisherDOI

• Figure S3 from Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma

  2024-05-15

  preprintOpen access

  <p>Figure S3</p>

  PublisherDOI

• Supplementary Data Text from Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma

  2024-05-15

  preprintOpen access

  <p>Supplementary Data Text</p>

  PublisherDOI

Recent grants

• Predoctoral Training at the Chemistry-Biology Interface

  NIH · $3.2M · 2005–2021

• Training Program in Basic Cancer Research

  NIH · $18.5M · 1976–2027

• Targeting HSP70 for MelanomaTherapy

  NIH · $69.3M · 2008–2025

• Predoctoral Training at the Chemistry-Biology Interface

  NIH · $2.0M · 2020–2030

• NIH Grant P01CA025874

  NIH · $61.1M · 2016

Frequent coauthors

• Philip A. Cole

  115 shared

• Marc A. Holbert

  GlaxoSmithKline (United States)

  71 shared

• Leah Gottlieb

  Leiden University Medical Center

  66 shared

• M. Daniel Ricketts

  Johnson & Johnson (United States)

  61 shared

• Sunbin Deng

  Cancer Research Institute

  60 shared

• Katrina Meeth

  57 shared

• Xuepeng Wei

  54 shared

• Sarah M. Gardner

  54 shared

Labs

• Ronen Marmorstein LaboratoryPI

Awards & honors

• George W. Raiziss Professor