Investigating the essential roles of Ubiquitin-like molecules and the Ubiquitin Proteasome System

Huib Ovaa

Education

  • 1997 - 2001: Ph.D Leiden University, synthetic organic chemistry, Prof. Dr. J.H. van Boom
  • 1993 - 1997: M.Sc. Leiden University, organic chemistry

Research Appointments

  • 1 Okt 2010 - present: C.S.O. and founding member of the biotech company UbiQ B.V.
  • 1 Dic 2009 - present: Tenured Principal Investigator NKI, Division of Cell Biology.
  • 1 Jan 2005 - present: Assistant Professor, Leiden University, Department of Chemistry.
  • 1 July 2004 – 1 Dec 2009: Principal Investigator NKI, Division of Cellular Biochemistry.
  • 1 July 2004 – 1 Jan 2005: Guest Researcher, Leiden University.
  • 1 Apr 2003 – 1 July 2004: Instructor in Pathology, Harvard Medical School.
  • 15 Oct 2001 – 31 March 2003: Postdoctoral fellow with Prof. Dr. H.L. Ploegh at Harvard Medical School.
Huib Ovaa

Research Interests

Research in the lab is centered on one central theme: chemical biology of Ub-mediated proteolysis and antigen presentation, and is currently divided into four subtopics: 1. Ubiquitin chemistry; 2. Activity and inhibition of deubiquitinating enzymes; 3. Proteasome activity; and 4. MHC class I antigen presentation. The basis for all projects can be found in organic synthesis.

All approaches taken in the lab start with organic synthesis, which we use to develop novel enabling research tools. The lab frequently uses high throughput small molecule screening approaches but has also ample experience with molecular and cell biology and we generally embrace any technique required to achieve our goals. My lab is fully equipped for chemical synthesis (mass spectrometer, parallel synhtesizers, NMR machine, 5 HPLCs etc. and is housed within the division of Cell Biology at the Netherlands Cancer Institute. Within this ITN network we will develop novel ubiquitin-based chemical Technologies building on our recent inventions on chemical ubiquitination and we will assist other ITN network members with chemical approaches and assay development.

Selected Publications

1. Albers HM, Hendrickx LJ, van Tol RJ, Hausmann J, Perrakis A, Ovaa H. (2011). Structure-based design of novel boronic acid-based inhibitors of autotaxin. J Med Chem, 54(13), 4619-4626. (IF 4.8)

2. Paul P, van den Hoorn T, Jongsma ML, Bakker MJ, Hengeveld R, Janssen L, Cresswell P, Egan DA, van Ham M, Ten Brinke A, Ovaa H, Beijersbergen RL, Kuijl C, Neefjes J. (2011). A Genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation. Cell. 145(2), 268-283. (IF 30)

3. Hausmann J, Kamtekar S, Christodoulou E, Day JE, Wu T, Fulkerson Z, Albers HM, van Meeteren LA, Houben AJ, van Zeijl L, Jansen S, Andries M, Hall T, Pegg LE, Benson TE, Kasiem M, Harlos K, Kooi CW, Smyth SS, Ovaa H, Bollen M, Morris AJ, Moolenaar WH, Perrakis A. (2011). Structural basis of substrate discrimination and integrin binding by autotaxin. Nat Struct Mol Biol. 18(2), 198-204. (IF 14)

4. El Oualid R, Merkx R, Ekkebus R, Hameed DS, Smit JJ, de Jong A, Hilkmann H, Sixma TK, Ovaa H. Chemical Synthesis of Ubiquitin, Ubiquitin-based Probes and Diubiquitin. Angewandte Chemie, 49 (52), 10149-10153 (IF 11.8)

5. Cavalli S, Houben AJ, Albers HM, van Tilburg EW, de Ru A, Aoki J, van Veelen P, Moolenaar WH, Ovaa H. (2010). Development of an Activity-Based Probe for Autotaxin. Chembiochem. 11 (16), 2311-2317 (IF 3.8)

6. Hoppes R, Ekkebus R, Schumacher TN, Ovaa H. 2010 Technologies for MHC class I immunoproteomics. (2010). J. Proteomics. 73, 1945 (IF 3.9)

7. Shanmugham, A., Fish, A., Luna-Vargas MPA., Faesen AC., El Oualid F., Sixma TK., Ovaa H. (2010). Non-hydrolyzalbe ubiquitin isopeptide isosteres as deubiquinating enzyme probes. JACS 132, 8834. (IF 8.6)

8. Albers HM, van Meeteren LA, Egan DA, van Tilburg EW, Moolenaar WH, Ovaa H. (2010) Discovery and Optimization of Boronic Acid Based Inhibitors of Autotaxin. J Med Chem. 53(13), 4958-4967 (IF 4.8)

9. Albers HM, Dong A, van Meeteren LA, Egan DA, Sunkara M, van Tilburg EW, Schuurman K, van Tellingen O, Morris AJ, Smyth SS, Moolenaar WH, Ovaa H. (2010). Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation. Proc Natl Acad Sci U S A. 2010, 107, 7257. (IF 9.4)

10. Rodenko B, Toebes M, Celie P, Perrakis A, Schumacher T, Ovaa H. (2009). MHC class I complexes loaded by a periodate trigger. JACS 131, 12305. (IF 8.6) Cit. 3*

11. Ovaa H, van Leeuwen F. (2008). Chemical Biology Approaches to Probe the Proteome. Chembiochem. (IF 3.8)

12. Shanmugham A, Ovaa H. (2008). DUBs and disease: activity assays for inhibitor development. Curr Opin Drug Discov Devel 11, 688-696. (IF 4.9)

13. Berkers CR, de Jong A, Ovaa H,1 Rodenko B. (2008). Transpeptidation and reverse proteolysis and their consequences for immunity. Int J Biochem Cell Biol. 41, 66-71. (IF 4.887) 1corresponding author

14. Bakker AH, Hoppes R, Linnemann C, Toebes M, Rodenko B, Berkers CR, Hadrup SR, van Esch WJ, Heemskerk MH, Ovaa H,2 Schumacher TN.2 (2008). Conditional MHC class I ligands and peptide exchange technology for the human MHC gene products HLA-A1, -A3, -A11, and -B7. Proc Natl Acad Sci U S A 105, 3825-3830. (IF 9.4), 2co-correspondence

15. Ovaa H. (2007). Active-site directed probes to report enzymatic action in the ubiquitin proteasome system. Nat Rev Cancer 7, 613-620. (IF 29.5)

16. Berkers CR, van Leeuwen FW, Groothuis TA, Peperzak V, van Tilburg EW, Borst J, Neefjes JJ, Ovaa H. (2007). Profiling proteasome activity in tissue with fluorescent probes. Mol Pharm 4, 739-748. (IF 4.5)

17. Toebes M, Coccoris M, Bins A, Rodenko B, Gomez R, Nieuwkoop NJ, van de Kasteele W, Rimmelzwaan GF, Haanen JB, Ovaa H,2 Schumacher TN.2 (2006). Design and use of conditional MHC class I ligands. Nature Medicine 12, 246-251. (IF 27.1), 2co-correspondence

18. Rodenko B, Toebes M, Hadrup SR, van Esch WJ, Molenaar AM, Schumacher TN, Ovaa H. (2006). Generation of peptide-MHC class I complexes through UV-mediated ligand exchange. Nature Protocols 1, 1120-1132. (IF 6.3)

19. Groll M, Berkers CR, Ploegh HL, Ovaa H. (2006). Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 14, 451-456. (IF 5.9)

20. Borodovsky A, Ovaa H,3 Meester WJ, Venanzi ES, Bogyo MS, Hekking BG, Ploegh HL, Kessler BM, Overkleeft HS. (2005). Small-molecule inhibitors and probes for ubiquitin- and ubiquitin-like-specific proteases. Chembiochem 6, 287-291. (IF 3.8) 3shared first authorship.

21. Berkers CR, Ovaa H. (2005). Immunotherapeutic potential for ceramide-based activators of iNKT cells. Trends Pharmacol Sci 26, 252-257. (IF 9.1)

22. Berkers CR, Verdoes M, Lichtman E, Fiebiger E, Kessler BM, Anderson KC, Ploegh HL, Ovaa H,1 Galardy PJ. (2005). Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib. Nature Methods 2, 357-362. (IF 16.9), 1corresponding author

23. Ovaa H, Kessler BM, Rolen U, Galardy PJ, Ploegh HL, Masucci MG. (2004). Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Proc Natl Acad Sci U S A 101, 2253-2258. (IF 9.4)

24. Hemelaar J, Borodovsky A, Kessler BM, Reverter D, Cook J, Kolli N, Gan-Erdene T, Wilkinson KD, Gill G, Lima CD, Ploegh HL, Ovaa H. (2004). Specific and covalent targeting of conjugating and deconjugating enzymes of ubiquitin-like proteins. Mol Cell Biol 24, 84-95. (IF6.0) *

25. Hemelaar J, Galardy PJ, Borodovsky A, Kessler BM, Ploegh HL, Ovaa H. (2004). Chemistry-based functional proteomics: mechanism-based activity-profiling tools for ubiquitin and ubiquitin-like specific proteases. J Proteome Res 3, 268-276. (IF 5.1)

26. Ovaa H, van Swieten PF, Kessler BM, Leeuwenburgh MA, Fiebiger E, van den Nieuwendijk AM, Galardy PJ, van der Marel GA, Ploegh HL, Overkleeft HS. (2003). Chemistry in living cells: detection of active proteasomes by a two-step labeling strategy. Angewandte Chemie Int Ed Engl 42, 3626-3629. (IF11.8)

27. Ovaa H, Van der Marel GA, Van Boom JH, Blechert S. (2002). Ruthenium catalyzed ring rearrangement: rapid entry to branched oxa- and azacycles. Tetrahedron 2002, 58(37), 7503-7518. 58, 7503-7518. (IF2.6)

28. Borodovsky A, Ovaa H,3 Kolli N, Gan-Erdene T, Wilkinson KD, Ploegh HL, Kessler BM. (2002). Chemistry-based functional proteomics reveals novel members of the deubiquitinating enzyme family. Chem Biol 9, 1149-1159. (IF6.5), 3shared first authorship Cit.

29. Ovaa H, Stragies R, Van der Marel GA, Van Boom JH, Blechert S. (2000). Asymmetric synthesis of indolizidine alkaloids by ring-closing ring-opening metathesis. Chem. Commun. 1501-1502. (IF 5.5)

30. Ovaa H, Codée JDC, Lastdrager B, Overkleeft HS, Van der Marel GA, Van Boom JH. (1999). A versatile approach to the synthesis of highly functionalised carbocycles. Tetrahedron Lett. 40, 5063-5066. (IF2.7)

31. Ovaa H, Leeuwenburgh MA, Overkleeft HS, Van der Marel GA, Van Boom J. (1998). An expeditious route to the synthesis of highly functionalized chiral oxepines from monosaccharides. Tetrahedron Lett. 39, 3025-3028. (IF 2.7)

32. Ovaa H, Codée JDC, Lastdrager B, Overkleeft HS, Van der Marel GA, Van Boom JH. (1998). A stereoselective and efficient route to (3S, 4R, 5S)-(+)-4,5-dihydroxycyclopent-1-en-3-ylamine: the side chain of the hypermodified nucleoside Q. Tetrahedron Lett 39, 7987-7990. (IF 2.7)

Awards and achievements

2011 ERC starting grant

2010 Amsterdam Inventor Award

2009 NVBMB award, Netherlands Society for biochemistry and molecular biology

2008 Dana Farber Cancer Institute career development award

2008 Top 25 EURYI competition 2007 (award not made because of lack of funds)

2005 VIDI-grant, awarded by the Netherlands Foundation for Scientific Research (NWO)

2004 AVL-fellowship, awarded by the Netherlands Cancer Institute (NKI-AVL)

2003 VENI-grant, awarded by the Netherlands Foundation for Scientific Research (NWO)

2003 Dana Farber/Harvard Cancer Center SPORE career development award (NCI, USA)

2002 C.J. Kok prize, Leiden University, best Ph.D. thesis 2001

2001 TALENT-fellowship (NWO)

2001 Ph.D. awarded cum laude

1998 Stipend (NWO) to carry out PhD research in Berlin

Amino Acid Sequence

A) Amino acid sequence of Ub containing the set of dipeptide building blocks used in our Fmoc-SPPS of Ub; L8T9, I13T14, L56S57, and S65T66 were replaced by the corresponding pseudoproline dipeptide (I), A46G47 and D52G53 were replaced by their corresponding dimethoxybenzyl dipeptide (II).

B) Liquid chromatography profile of commercial Ub and C) crude synthetic Ub. D) MS analysis of crude synthetic Ub, calcd 8565 Da, found: 8565 Da; the deconvoluted spectrum is shown on the right. Angewandte Chemie International Edition, Volume 49, Issue 52, pages 10149-10153. DOI: 10.1002/anie.201005995. Download

Partner

NKI-AVL

Additional information

Laboratory web page: Ovalaab

Collaborators

David Komander (LMB, Cambridge, UK)

Ronald T. Hay (University of Dundee, UK)

Projects

Probe molecules and assay reagents to study action in Ub and UBL systems and role of DUBs; synthetic approaches.

Proteasome activation to treat neurodegeneration.