Department of biochemistry and Molecular biology
Natalia Krupenko, PhD
Biochemistry and Molecular Biology
1999 Participant of the International School of Structural Biology and Magnetic
Resonance NATO Advance Study Institute, 4th course: "Dynamics, structure
and function in biological macromolecules"
1992-1994 Rockefeller Foundation Postdoctoral Fellow in Population Sciences,
Vanderbilt University, Nashville, TN
1987 Institute of Bioorganic Chemistry, Byelorussion Academy of Sciences, Minsk, USSR
1980 B.S., Byelorussion State University, Minsk, USSR
My research area could be broadly defined as Folate and methyl group metabolism. Methyl transfer reactions are extremely important to cellular biochemistry. Dietary deficiency of labile methyl groups is the only nutrient deficiency known to be carcinogenic in itself. However, only a few types of methyl donors are used in the cell, and S-adenosylmethionine (SAM) is the most common of them. SAM is second only to ATP in the variety of reactions for which it serves a cofactor. The second most commonly used methyl donor is various forms of folates. Methyl groups from the folate pool can be used to re-methylate homocysteine to methionine and, thus, restore the methylating potential of the cell. It is believed that some of the effects of folate deficiency in higher animals results from the disruption of methyl group metabolism. There are more than 120 different SAM-dependent methyltransferases present in small amounts in the cell, each catalyzing the synthesis of an essential product. Activity of these enzymes is regulated by the SAM/SAH ratio. My research is focused on a unique member of the methyltransferase family - glycine N-methyltransferase (GNMT). This enzyme is an abundant protein in mammalian liver cytosol (1-3% of the soluble protein), it is less sensitive to the backfeed inhibition by the product S-adenosylhomocysteine (SAH) than all other methyltransferases, and it does not yield a biologically active compound necessary for cellular metabolism. Besides, GNMT is a major folate-binding protein in mammalian liver cytosol. This protein is believed to function as a regulatory switch in methionine conservation/transsulfuration pathway to maintain SAM/SAH ratio adequate for the cell. Additional gene-regulatory functions have been suggested for this protein. Along with the unique properties, GNMT has a molecular structure drastically different from the structures of other methyltransferases. Therefore, one of the aims of my research is a structure-functional characterization of GNMT including the study of enzyme oligomerization and elucidation of the structures and mechanisms involved in folate binding and inhibition of the enzyme activity. Another point of interest is the study of nuclear localization and transport of GNMT, its binding targets and determination of the possible biological function of GNMT in the nucleus. Studies of tissue expression of the enzyme and its regulation in different physiological and pathological conditions will help to improve our understanding of the role of GNMT in folate and methyl group metabolism.
Recent Publications | Additional Publications
Debroy S, Kramarenko II, Ghose S, Oleinik NV, Krupenko SA, Krupenko NI. A novel tumor suppressor function of glycine N-methyltransferase is independent of its catalytic activity but requires nuclear localization. PLoS One. 2013 Jul 30;8(7):e70062. doi: 10.1371/journal.pone.0070062. Print 2013. PMID: 23936142 [PubMed - in process]
Christensen KE, Deng L, Leung KY, Arning E, Bottiglieri T, Malysheva OV, Caudill MA, Krupenko NI, Greene ND, Jerome-Majewska L, Mackenzie RE, Rozen R. A novel mouse model for genetic variation in 10-formyltetrahydrofolate synthetase exhibits disturbed purine synthesis with impacts on pregnancy and embryonic development. Hum Mol Genet. 2013 May 31. [Epub ahead of print]
Hoeferlin LA, Fekry B, Ogretmen B, Krupenko SA, Krupenko NI. Folate stress induces apoptosis via p53-dependent de novo ceramide synthesis and up-regulation of ceramide synthase 6. J Biol Chem. 2013 May 3;288(18):12880-90. doi: 10.1074/jbc.M113.461798. Epub 2013 Mar 21. PMID: 23519469 [PubMed - indexed for MEDLINE]
Strickland KC, Krupenko NI, Krupenko SA. Molecular mechanisms underlying the potentially adverse effects of folate. Clin Chem Lab Med. 2013 Mar 1;51(3):607-16. doi: 10.1515/cclm-2012-0561.
Hoeferlin LA, Oleinik NV, Krupenko NI, Krupenko SA. Activation of p21-dependent G1/G2 arrest in the absence of DNA damage as an antiapoptotic response to metabolic stress. Genes Cancer. 2011 Sep;2(9):889-99. PubMed PMID: 22593801; PubMed Central PMCID: PMC3352155.
Oleinik NV, Krupenko NI, Krupenko SA. Epigenetic silencing of ALDH1L1, a metabolic regulator of cellular proliferation in cancers. Genes Cancer. 2011 Feb;2(2):130-9. PubMed PMID: 21779486; PubMed Central PMCID: PMC3111244.
Carrasco MP, Enyedy EA, Krupenko NI, Krupenko SA, Nuti E, Tuccinardi T, Santamaria S, Rossello A, Martinelli A, Santos MA. Novel folate-hydroxamate based antimetabolites: synthesis and biological evaluation. Med Chem. 2011 Jul;7(4):265-74. PubMed PMID: 21568878.
Strickland KC, Krupenko NI, Dubard ME, Hu CJ, Tsybovsky Y, Krupenko SA. Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase. Chem Biol Interact. 2011 May 30;191(1-3):129-36. Epub 2011 Jan 14. PubMed PMID: 21238436; PubMed Central PMCID: PMC3103650.
Strickland KC, Holmes RS, Oleinik NV, Krupenko NI, Krupenko SA. Phylogeny and evolution of aldehyde dehydrogenase-homologous folate enzymes. Chem Biol Interact. 2011 May 30;191(1-3):122-8. Epub 2011 Jan 6. PubMed PMID: 21215736; PubMed Central PMCID: PMC3103616.
Oleinik NV, Krupenko NI, Krupenko SA. ALDH1L1 inhibits cell motility via dephosphorylation of cofilin by PP1 and PP2A. Oncogene. 2010 Nov 25;29(47):6233-44. Epub 2010 Aug 23. PubMed PMID: 20729910; PubMed Central PMCID: PMC2992098.
Marques SM, Enyedy EA, Supuran CT, Krupenko NI, Krupenko SA, Santos MA. Pteridine-sulfonamide conjugates as dual inhibitors of carbonic anhydrases and dihydrofolate reductase with potential antitumor activity. Bioorg Med Chem. 2010 Jul 15;18(14):5081-9. Epub 2010 Jun 2. PubMed PMID: 20580561.
Krupenko NI, Dubard ME, Strickland KC, Moxley KM, Oleinik NV, Krupenko SA. ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase. J Biol Chem. 2010 May 24. [Epub ahead of print] PubMed PMID: 20498374.
Strickland KC, Hoeferlin LA, Oleinik NV, Krupenko NI, Krupenko SA. Acyl carrier protein-specific 4'-phosphopantetheinyl transferase activates 10-formyltetrahydrofolate dehydrogenase. J Biol Chem. 2010 Jan 15;285(3):1627-33. Epub 2009 Nov 20. PubMed PMID: 19933275; PubMed Central PMCID: PMC2804320.
Ghose S, Oleinik NV, Krupenko NI, Krupenko SA. 10-formyltetrahydrofolate dehydrogenase-induced c-Jun-NH2-kinase pathways diverge at the c-Jun-NH2-kinase substrate level in cells with different p53 status. Mol Cancer Res. 2009 Jan;7(1):99-107. PubMed PMID: 19147541; PubMed Central PMCID: PMC2632845.
Celtikci B, Leclerc D, Lawrance AK, Deng L, Friedman HC, Krupenko NI, Krupenko SA, Melnyk S, James SJ, Peterson AC, Rozen R. Altered expression of methylenetetrahydrofolate reductase modifies response to methotrexate in mice. Pharmacogenet Genomics. 2008 Jul;18(7):577-89. PubMed PMID: 18551038.