Željko Svedružić

International Spelling: Zeljko M. Svedruzic

Positions: Assistant Professor at University of Rijeka Department of Biomedical Technology and Adjunct Faculty at the Faculty of Medicine

Laboratory: Biomolecular Structure and Function

E-mail: zeljko-at-svedruziclab.com (more, including social networks)

Postal Address: Radmile Matejčić 2, University Campus Trsat, HR-51000 Rijeka, Croatia

Office: 8th floor, room number 823

Phone Number: +385-51-584-575

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Željko M. Svedružić at work in the wet lab

Research

  1. Development of mechanism-based inhibitors of mammalian/human DNA methyltransferases with IC50 values below 50 nM. The most successful inhibitors can be used for control of functional organization of mammalian genome in research laboratories, biotechnology, and ultimately in clinics for treatment of pathogenic mechanisms related to epigenetic processes (i.e. tissue regeneration, oncogenesis, psychiatric and neurological disorders, viral infections, immunological disorders).
  2. Development of novel bivalent mechanism-based inhibitors of membrane-embedded protease γ-secretase. The most successful compounds can be used for treatment and early-diagnosis of Alzheimer’s disease, or for control of different physiological processes that depend on cell-to-cell communication. Paid consultant for pharmaceutical industry, γ-secretase modulators and assays.

Career goals

Development and commercialization of inhibitors and modulators of human DNA methyltransferase Dnmt1 and membrane embedded protease γ-secretase.

Major Accomplishments and Perspective

DNA methyltransferases

Enzymatic mechanism, regulation, and novel drug-design strategies.

Present research work: Development of mechanism-based inhibitors of mammalian/human DNA methyltransferases.

Membrane-embedded protease γ-secretase

Enzymatic mechanism, regulation and novel drug-design and early diagnostic strategies for Alzheimer’s disease.

Present research work: Development of novel bivalent mechanism-based inhibitors of membrane-embedded protease γ-secretase.

Substrate channeling

Substrate channeling in transient protein-protein interactions. Further research work in perspective.

Teaching

  • On ongoing basis: molecular modeling and numerical methods in biomedical sciences, i.e. structure and function of biomolecules, enzyme kinetics, and protein-ligand interactions. Courses taught:
    • Chemoinformatics (undergraduate level, syllabus in Croatian),
    • Physical organic and computational chemistry (master level), and
    • Design of biologically active molecules by computational nethods (master level, syllabus in Croatian).
  • Mentoring individual students in research and thesis preparation.
  • Invited lectures: molecular mechanisms in Alzheimer’s disease or molecular mechanisms in epigenetics.

Expertise

Molecular mechanisms in epigenetics and chromatin organization; molecular mechanisms in Alzheimer’s disease; protein-protein and protein-ligand interactions; assay-development and drug-design based on enzyme structure-function principles; substrate channeling.

Specialty

Enzymology: in vitro, in vivo and in silico approaches for studies of structure and function of biomolecules.

Training

Biochemistry, physical biochemistry (i.e. biophysics), medicinal chemistry, bioorganic chemistry, molecular genetics, biological membranes, medical biochemistry, cell biology.

Work experience

Senior scientist appointments

Postdoctoral research

Education

Publications

Journal papers

  1. Miletić, V., Odorčić, I., Nikolić, and P., Svedružić, Ž. M. In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1. PLoS One 12(4), April 11th (2017). PubMed
  2. Svedružić, Ž. M., Popović, K., and Šendula-Jengić, V. Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer’s disease. Molecular and Cellular Neuroscience 67, July 31st (2015). PDF
  3. Svedružić, Ž. M., Popović, K., and Šendula-Jengić, V. Modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer’s disease. PLoS One 8(1), January 7th (2013). PubMed
  4. Svedružić, Ž. M. Popović, K., Smoljan, I., and Šendula-Jengić, V. Modulation of γ-secretase activity by multiple enzyme-substrate interactions: Implications in pathogenesis of Alzheimer’s disease. PLoS One 7(3), March 30th (2012). PubMed
  5. Svedružić, Ž. M. Mammalian Cytosine DNA methyltransferase Dnmt1: Enzymatic Mechanism, Novel Mechanism-Based Inhibitors, and RNA-directed DNA methylation. Current Medicinal Chemistry 15(1), 92–106 (2008). PDF
  6. Svedružić, Ž. M. and Spivey, H. O. Interaction between Mammalian Glyceraldehyde-3-phosphate Dehydrogenase and L-Lactate Dehydrogenase from Heart and Muscle. Proteins, Structure, Function and Bioinformatics 63(3), 501–511 (2006). PDF
  7. Svedružić, Ž. M., Wang, C., Kosmoski, J. V., and Smerdon, M. J. Accommodation and Repair of a UV Photoproduct in DNA at Different Rotational Settings on the Nucleosome Surface. Journal of Biological Chemistry 280(48), 40051–40057 (2005).
  8. Svedružić, Ž. M. and Reich, N. O. The Mechanism of Allosteric Regulation of Dnmt1’s Processivity. Biochemistry 44(45), 14972–14988 (2005). PDF
  9. Svedružić, Ž. M. and Reich, N. O. DNA Cytosine C5 Methyltransferase Dnmt1: Catalysis Dependent Release of Allosteric Inhibition. Biochemistry 44(27), 9472–9485 (2005).
  10. Svedružić, Ž. M. and Reich, N. O. The Mechanism of Target Base Attack in DNA Cytosine C5 Methylation. Biochemistry 43(36), 11460–11473 (2004).
  11. Lehoux E. A., Svedružić, Ž., and Spivey, H. O. Determination of Specific Radioactivity of [14C] Lactate by Enzymatic Decarboxylation and CO2 Collection. Analytical Biochemistry 253(2), 190–195 (1997).

Conference abstracts

  1. Nikolić P., Miletić V., and Svedružić, Ž. M. DNA Methyltransferase Dnmt1: Regulation of Substrate Selectivity. In 6th OEGMBT Annual Meeting 2014 Abstract Book, edited by Alexandra Khassidov, Walter Glaser, and Christoph Klimek, 129. Vienna, Austria: Austrian Association of Molecular Life Sciences; Biotechnology; Servicebetrieb ÖH-Uni Graz GmbH. (2014).
  2. Svedružić, Ž. M. and Reich N. O. Enzymatic properties of mouse cytosine DNA methyltransferase DNMT1. Abstracts of Papers of the American Chemical Society 223:C75. (2002).

Book chapters

  1. Nikolić, P., Miletić, V., Odorčić, I., and Svedružić, Ž.M. (2016). In Silico Optimization of the First DNA-Independent Mechanism-Based Inhibitor of Mammalian DNA Methyltransferase DNMT1. In: Epi-Informatics, (Boston: Academic Press), pp. 113–153. PDF
  2. Svedružić, Ž. M. Mammalian DNA methyltransferase Dnmt1: Structure and Function. In: Modification of Mammalian DNA: Mechanism, Management, Missions, and Medical Implications. Progress in Molecular Biology and Translational Science 101, 221–254 (Elsevier, 2011). PDF

In preparation

  1. Svedružić, Ž. M., Nikolić, P., Miletić, V., and Odorčić, I. Substrate-lock mechanism controls de novo methylation by mammalian DNA methyltransferase Dnmt1.
  2. Svedružić, Ž. M., Popović, K., and Šendula-Jengić, V. The basic enzymology of modulation of γ-secretase activity: identification of the key pharmacophoric groups.
  3. Svedružić, Ž. M., Svedružić, D., and Spivey, H. O. Allosteric Regulation of Substrate Channeling in Transient Protein-Protein Interactions; the case of NAD(H) dehydrogenases.
  4. Svedružić, Ž. M. A flexible loop and two charged amino acids regulate formation and break-up of transient catalytic complex between protein phosphatase CDC25B and Cdk2/Cycline-A heterodimer.

Miscellaneous

Invited lectures

  1. 248th ACS National Meeting and Exposition. ChemEpInformatics: In the Pursuit of Epidrugs Using Chemoinformatics and Computational Approaches, August 10–14, 2014, San Francisco, CA, USA. DNA methyltransferase Dnmt1: Regulation and novel drug-design strategies
  2. EuroSciCon: Alzheimer’s Drug Discovery and Development, June 25, 2014, London, UK. Modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer’s disease.
  3. Ruder Bošković Institute, May 23, 2013, Zagreb, Croatia. Alzheimerova bolest iz molekularne perspektive: patogeneza, rana dijagnostika i razvoj novih lijekova.
  4. 4th Croatian Congress on Side Effects of Psychopharmacs, March 29–31 2012, Osijek, Croatia. Side effects of antipsychotics: how to avoid them and how can they be useful.

Miscellaneous experience

  1. Conferences: almost 20 years of active participation in professional meetings and conferences.
  2. Teaching: almost 20 years of active direct and indirect mentoring of junior colleagues in research laboratories.

Personal

My sister Draženka works as a Research Scientist at NREL Bioenergy.

My name is pronounced as Zhelko Svedruzhich, with “zh” pronounced as letters “asu” in words like: “treasure”, “pleasure”, “measure”.

My name appears on papers in different forms. Some of them are Svedruzic, ZM, Svedruzic, Z. M., Svedružić, ŽM, and Svedružić, Ž. M. Name will appear with or without Croatian accents depending on the publication.