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Gregory Ducker

Assistant Professor of Biochemistry

Ducker

B.A. Carleton College

Ph.D. University of California, Berkeley

Research

References

greg.ducker@biochem.utah.edu

Greg Ducker's Lab Page

Greg Ducker's PubMed Literature Search

 

Molecular Biology Program

Biological Chemistry Program

Cancer Metabolism, Mass Spectrometry, Antimetabolites, Chemical Biology, Mitochondria, Tetrahydrofolates

Research

Changes in cellular metabolism underlie many diseases. Research in my group focuses on understanding at a molecular level the fundamental metabolic processes underlying cellular disease physiology- what pathways and processes contribute to disease and how do cells acquire the nutrients to fuel them? One long-term goal of our research is to characterize the metabolic requirements of cancer cells and tumors in vivo in order to identify and validate new therapeutic targets. Our approach is fundamentally biochemical, based on integrating new mass spectrometry technology with CRISPR/Cas9 genetic engineering to be able to precisely quantify metabolic fluxes in vivo. By starting with a fundamentals-based perspective on metabolism, we are able to apply our knowledge across different cell types and disease states providing a unifying framework to understand diverse biological phenomena.

Glycine metabolism in cancer. Glycine may be the simplest amino acid, but it is an essential building block for larger biomolecules such as heme, purines and glutathione. Cancer cells shift their metabolism to favor the production of glycine and stop glycine degradative processes. Inhibiting the biosynthesis of glycine or restricting glycine in the diet attenuates tumor growth. We are interested in understanding the quantitative demand for glycine in tumors in vivo and ways to therapeutically modulate glycine availability in both the tumor cell and the environment.

One-carbon and methionine metabolism. Methionine is an essential amino acid and the functional core for the most important methyl transfer molecule in the body, S-adenosylmethionine (SAM). SAM provides methyl donors for many reactions, including methylation reactions that modify gene expression. Upon the transition from healthy liver tissue to hepatocellular carcinoma, a major metabolic switch occurs between different nutrient sources of one-carbon units for the production of SAM. Our research seeks to ask why this switch occurs and if downregulated metabolic pathways might have tumor suppressor-like properties.

5-formyl-THF in immunity and neurodevelopment. Folate metabolism is required for proper fetal development and disorders of this pathway can result in both gross anatomical abnormalities (microcephaly) as well as more subtle disorders of neurodevelopment (seizures). The folate vitamer 5-formyl-THF is not directly required for any biosynthetic process, but deletion of the enzyme (MTHFS) that metabolizes it is embryonic lethal in mice and results in severe multisystem birth defects in humans. Interestingly, MTHFS is among the most upregulated enzymes upon T-cell activation. Our group is using CRISPR to generate MTHFS mutants cell systems to study the role of 5-formyl-THF in immune activation and neurodevelopment.

References

  1. Rodan L, Qi W, Ducker GS, Demirbas D, Laine R, Yang E, Walker MA, Eichler F, Rabinowitz JD, Anselm I, Berry GT. (2018) 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol. Genet. Metab. DOI: 10.1016/j.ymgme.2018.06.006
  2. Ksionda O, Mues M, Wandler AM, Donker L, Tenhagen M, Jun J, Ducker GS, Matlawska-Wasowska K, Shannon K, Shokat KM, Roose JP. (2018) Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy. PLoS One 13 (5): e0193849.
  3. Morscher RJ, Ducker GS, Li H, Gitai Z, Rabinowitz JD. (2018) Mitochondrial translation requires folate-dependent tRNA methylation.  Nature 553 (7690): 128-132.
  4. Ducker GS, Ghergurovich JM, Mainolfi N, Suri V, Hsin-Jung L, Jeong SK, Friedman A, Manfredi A, Gitai Z, Kim H, Rabinowitz JD. (2017) Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma. Proc. Natl. Acad. Sci. 114 (43): 11404-11409.
  5. Chen L, Ducker GS, Lu W, Teng X, Rabinowitz JD. (2017) An LC-MS chemical derivatization method for the measurement of five different one-carbon states of cellular tetrahydrofolate. Anal. Bioanal. Chem. 409 (25): 5955-5964.
  6. Ducker GS, Rabinowitz JD. (2017) One-carbon metabolism in health and disease. Cell Met. 25 (1): 27-42.
  7. Ducker GS, Chen L, Morscher RJ, Ghergurovich JM, Esposito M, Teng X, Kang Y, Rabinowitz JD. (2016) Reversal of cytosolic flux compensates for loss of mitochondrial folate pathway. Cell Met. 23 (6): 1140-1153.
  8. Ducker GS, Rabinowitz JD. (2015) ZMP: A master regulator of one-carbon metabolism. Mol. Cell. 57 (2): 203-204.
  9. Davies J, Robinson AE, Cowdrey C, Mummaneni P, Ducker GS, Shokat KM, Bollen A, Hann B, Phillips JJ. (2014) Generation of a patient-derived chordoma xenograft and characterization of the phospho-proteome in a recurrent chordoma. J. Neurosurg. 120 (2): 331-336.
  10. Ducker GS, Atreya CE, Simko JP, Hom YK, Matli MR, Benes CH, Hann B, Nakakura EK, Bergsland EK, Donner DB, Settleman J, Shokat KM, Warren RS. (2014) Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors.  Oncogene. 33 (12): 1590-1600.
  11. Pourdehnad M, Truitt ML, Siddiqi IN, Ducker GS, Shokat KM, Ruggero D. (2013) Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Natl. Acad. Sci. 110 (29): 11988-11993.
  12. Atreya CE, Ducker GS, Feldman ME, Warren RS, Bergsland EK, Shokat KM. (2012) Combination of ATP-competitive mammalian target of rapamycin inhibitors with standard chemotherapy for colorectal cancer. Invest. New Drugs. 30 (6): 2219-2225.
  13. Wang BT, Ducker GS, Barczak AJ, Barbeau R, Erle DJ, Shokat KM. (2011) ATP competitive mTOR inhibitor reveals a role for 4E-BP1 in cholesterol biosynthesis and a rapamycin-resistant transcriptional profile. Proc. Natl. Acad. Sci. 108 (37): 15201-15206.
  14. Okuzumi T, Ducker GS, Zhang C, Aizenstein R, Shokat KM. (2010) Synthesis and evaluation of indazole based analog sensitive Akt inhibitors. Mol. Biosyst. 6 (8): 1389-1402.
  15. McCormick SR, McCormick MJ, Grutkoski PS, Ducker GS, Banerji N, Higgins RR, Mendiola JR, Reinartz JJ. (2010) FLT3 mutations at diagnosis and relapse in acute myeloid leukemia: cytogenetic and pathologic correlations, including cuplike blast morphology. Arch. Pathol. Lab. Med. 134 (8): 1143-1151.

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Last Updated: 9/20/18