Metanis Norman

Senior Lecturer of Chemistry
Bioorganic Chemistry. Chemical Protein Synthesis. Selenoproteins
• Ph.D., 2008, Technion – Israel Institute of Technology
• M.Sc., 2004, Technion – Israel Institute of Technology
• B.A., 2000, Technion – Israel Institute of Technology
Office: 
Philadelphia 320
Phone: 
02 6586 562
Fax: 
02 6585 345
Research Focus: 

Our research group is interested in topics ranging from total chemical synthesis of proteins, the development of chemoselective reactions applied to peptide and protein chemistry, therapeutic peptides and proteins, protein posttranslational modifications as well as protein functions.

We use either recombinant expression technologies or chemical protein synthesis and semi-synthesis to prepare our proteins of interest. Chemical protein synthesis (CPS) allows us to substitute any position in the protein sequence with functionalities that are not constrained to the 20 standard encoded amino acids. Furthermore, it allows the preparation of proteins with specific posttranslational modifications (PTMs) in homogenous forms and excellent yields to help understand the effect of each PTM on the proteins function and structure.

Chemical protein synthesis, a subfield of chemical biology, has matured in the last 30 years on the basis of two major innovations in this field: the solid-phase peptide synthesis (SPPS) pioneered by Bruce Merrifield, and chemical ligation reactions developed by Stephen Kent, most notably the native chemical ligation (NCL) (Figure 1a and b, respectively).We extensively use these two techniques in our research group.

 

 

 

 

 

 

 

 

 

 

Figure 1. The two major methods used in our laboratory; a. solid-phase peptide synthesis (SPPS) and

b. native chemical ligation (NCL) in order to chemically synthesize small to medium size proteins (up to ~100-200 amino acids).

 

One target in our group is to understand the role of selenocysteine (Sec) in selenoproteins. The 21st encoded amino acid Sec is typically found in the active site of selenoproteins. Of the thousands of proteins in the human body, only 25 proteins are selenoproteins. Yet, only few members are well studied. Most selenoproteins are redox selenoenzymes (they catalyze oxidation-reduction reactions). Since sulfur and selenium belong to the same group of elements, they share many properties including electronegativity, atom size, and major oxidation states. However, they also differ in some properties, for example seleno-compounds are easier to oxidize than sulfur containing compounds, and the selenol group has a much lower pKa than thiol (5.2 for the seleno group in Sec compared to 8.3 for the thiol group in Cys).

 

 

 

 

 

 

 

 

Figure 2. Structure and side-chain pKa values of selenocysteine (Sec) and cysteine (Cys).

One major obstacle in studying selenoproteins is the challenge in preparing sufficient amounts of these proteins, especially by recombinant DNA technologies. Chemical protein synthesis allows substituting any atom in a protein sequence, with functionalities that are not restricted to the 20 standard amino acids.

We will study human selenoproteins, in order to shed more light into the importance of selenium in human health and disease.

Furthermore, we will continue to explore the effect of Sec in protein synthesis, modifications, protein folding studies, and more.

 

 

Selected Publications: 

1.    Deri, S.; Reddy Post, S.; Aharon Deri, L.; Mousa, R.; Notis Dardashti, R. and Metanis, N.* .  “Insights into the Deselenization of Selenocysteine into Alanine and Serine” (2015) Chem. Sci., Accepted.
2.    Metanis, N.* and Hilvert D. “Harnessing selenocysteine reactivity for oxidative protein folding” (2015) Chem. Sci., 6, 322-325.
3.    Metanis, N.* and Hilvert D. “Natural and Synthetic Selenoproteins” (2014) Curr. Open. Chem. Biol., 22, 27-34.
4.    Metanis, N.* “Chemical Protein Synthesis (CPS) Meeting 2013”, (2013) ChemBioChem, 14, 1381-1384. (Invited Conference Report).
5.    Metanis N. and Hilvert D. “Strategic Use of Nonnative Diselenide Bridges to Steer Oxidative Protein Folding” (2012) Angew. Chem. Int. Ed., 51, 5585-5588.
·        Selected by referees as Very Important Paper (VIP)
·        Highlighted in Nature Chemistry
·        Highlighted in ChemBioChem
6.    Metanis, N.; Beld, J. and Hilvert, D. “The Chemistry of Selenocysteine” (2011), Patai’s Chemistry of Functional Groups, Ed. Rappoport, Z., DOI: 10.1002/9780470682531.pat0582.
7.    Metanis, N.; Foletti, C.; Beld, J. and Hilvert, D. “Selenoglutathione-Mediated Rescue of Kinetically Trapped Intermediate in Oxidative Protein Folding”, (2011) Isr. J. Chem., 51, 953-959. (Invited article in special issue).
·        Highlighted in ChemBioChem
8.    Metanis, N.; Keinan, E. and Dawson, P.E. “Traceless Ligation of Cysteine Peptides using Selective Deselenization”, (2010) Angew. Chem. Int. Ed., 49, 7049-7053.
9.    Shekhter, T. §; Metanis, N.§; Dawson, P.E. and Keinan, E., “A Residue Outside the Active Site CXXC Motif Regulates the Catalytic Efficiency of Glutaredoxin 3”, (2010) Mol. BioSyst., 6, 241-248. §authors contributed equally
10. Metanis, N.; Keinan, E. and Dawson, P.E. “Synthetic Seleno-Glutaredoxin 3 Analogs are Highly Reducing Oxidoreductase with Enhanced Catalytic Efficiency” (2006) J. Am. Chem. Soc., 128, 16684-16691.
11. Metanis, N.; Keinan, E. and Dawson, P.E. “A Designed Synthetic Analogue of 4-OT is Specific for a Non-Natural Substrate” (2005) J. Am. Chem. Soc., 127, 5862-5868.
12. Metanis, N.; Brik, A.; Dawson, P.E. and Keinan, E. “Electrostatic Interactions Dominate the Catalytic Contribution of Arg39 in 4-Oxalocrotonate Tautomerase”, (2004) J. Am. Chem. Soc., 126, 12726-12727.