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Faculty Profile

Emmanuel S. Burgos, Ph.D.

Dr. Emmanuel S. Burgos

Research Assistant Professor, Department of Biochemistry

 

Professional Interests

 

I have been deciphering enzyme mechanisms for more than 12 years using synthetic and enzyme-assisted chemistry toward designing small molecule inhibitors of therapeutic targets. I am fully trained in rational drug design with extensive knowledge, both theoretical and practical, in analytical chemistry, synthetic chemistry, enzymology and biochemistry. My expertise is internationally recognized as highlighted by my publication record and sustained participation in numerous research projects.

Nicotinamide and NAD Metabolism

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first reversible step in NAD biosynthesis and nicotinamide (NAM) salvage (Figure 1; red). The enzyme is designed for efficient capture of nicotinamide by energetic coupling of ATP hydrolysis to assist in extraordinary NAM binding affinity[12,13] and formation of nicotinamide mononucleotide (NMN). NAMPT provides the mechanism to replenish the NAD pool in human metabolism. In addition to its role in redox biochemistry, NAD fuels the sirtuins (SIRTs) to regulate transcription factors involved in pathways linked to inflammation, diabetes and lifespan (Figure 1; blue).

NAMPT-mediated lifespan expansion has caused a focus on the catalytic mechanism, regulation and inhibition of NAMPT. Structural, mechanistic and inhibitor design all contribute to a developing but yet incomplete story of NAMPT function. Although the first generation of NAMPT inhibitors has entered clinical trials, disappointing outcomes suggest more powerful and specific inhibitors will be needed.

Understanding the ATP-linked mechanism of NAMPT and the catalytic site machinery may permit the design of improved NAMPT inhibitors as more efficient drugs against cancer[10]. Design of such inhibitors may be achieved by rational design using the Kinetic Isotope Effect tool (KIE)[6].

The Use of Enzyme Biocatalysts for Efficient Synthesis of Valuable Chemical Probes

Enzymes are powerful tools in synthetic chemistry as they promote stereospecific reactions. Like previous chemical biologists, we have taken advantage of these efficient biocatalysts. We recently harvested the enzymatic activity of NAD-nucleosidase mutants for efficient gram-scale production of O-acetyl-ADP-ribose, by-product of the sirtuin-catalyzed reactions. Our in-line production (Figure 2A) allows for preparation of this pure metabolite in a 99% yield (Figure 2D)[4].

Recently, kinases were also used to generated a triphosphorylated derivative of Immucillin-A (Figure 3). This compound is a potent inhibitor of the newly described C–P lyase nucleosidase PhnI[5].

We are currently using our chemoenzymatic approach to generate novel isozyme-specific inhibitors of protein methyltransferases.

Development of in vitro Assays to Decipher Enzymes Mechanisms and Identify Novel Therapeutics

Our recent efforts led to the development of highly sensitive coupled assays based onto the detection of ATP and its derivatives (e.g. adenosine, adenine, S-adenosyl-L-homocysteine) by Photinus pyralis luciferase. These assays are well suited for the detection of a broad variety of activities, including slow enzymes such as protein methyltransferases (Figure 4)[9]. With these analytical platforms we provided the first most quantitative analysis for the Protein Arginine MethylTransferase (PRMT5) reaction mechanism (Figure 5)[1].

 

Selected Publications

References

[1Emmanuel S. Burgos, Carola Wilczek, Takashi Onikubo, Jeffrey B. Bonanno, Janina Jansong, Ulf Reimer, and David Shechter. 2015. “Histone H2A and H4 N-terminal tails are positioned by the MEP50 WD repeat protein for efficient methylation by the PRMT5 arginine methyltransferase.” J. Biol. Chem., 290(15):9674-89. PMID: 25713080 doi: 10.1074/jbc.M115.636894

[2] Keisha Thomas, Scott A. Cameron, Steven C. Almo, Emmanuel S. Burgos, Shivali A. Gulab, and Vern L. Schramm. 2015. “Active site and remote contributions to catalysis in methylthioadenosine nucleosidases.” Biochemistry, 54(15):2520-29 PMID: 25806409 doi: 10.1021/bi501487w

[3] Takashi Onikubo, Joshua J. Nicklay, Li Xing, Christopher Warren, Brandon Anson, Wei-Lin Wang, Emmanuel S. Burgos, Sophie E. Ruff, Jeffrey Shabanowitz, R. Holland Cheng, Donald F. Hunt, and David Shechter. 2015. “Developmentally Regulated Post-translational Modification of Nucleoplasmin Controls Histone Sequestration and Deposition.” Cell Rep., 10(10): 1735-48. PMID: 25772360 doi: 10.1016/j.celrep.2015.02.038

[4] Brett M. Hirsch, Emmanuel S. Burgos, and Vern L. Schramm. 2014. “Transition-state analysis of 2-O-acetyl-ADP-ribose hydrolysis by human macrodomain 1.” ACS Chem. Biol., 9(10):2255-62. PMID: 25051211 doi: 10.1021/cb500485w

[5] Siddhesh S. Kamat, Emmanuel S. Burgos, and Frank M. Raushel. 2013. “Potent inhibition of the C–P lyase nucleosidase PhnI by Immucillin-A triphosphate.” Biochemistry, 52(42):7366-8. PMID: 24111876 doi: 10.1021/bi4013287

[6Emmanuel S. Burgos, Mathew J. Vetticatt , and Vern L. Schramm. 2013. “Recycling nicotinamide. The transition-state structure of human nicotinamide phosphoribosyltransferase.” J. Am. Chem. Soc., 135(9):3485-93. PMID: 23373462 doi: 10.1021/ja310180

[7] Shaun B. Reeksting, Ingrid B. Müller, Pieter B. Burger, Emmanuel S. Burgos, Laurent Salmon, Abraham I. Louw, Lyn-Marie Birkholtz, and Carsten Wrenger. 2013. “Exploring inhibition of Pdx1, a component of the PLP synthase complex of the human malaria parasite Plasmodium falciparum.” Biochem J., 449(1):175-87. PMID: 23039077 doi: 10.1042/BJ20120925

[8] Keisha Thomas, Antti M. Haapalainen, Emmanuel S. Burgos, Gary B. Evans, Peter C. Tyler, Shivali Gulab, Rong Guan, and Vern L. Schramm. 2012. “Femtomolar inhibitors bind to 5′-methylthioadenosine nucleosidases with favorable enthalpy and entropy.” Biochemistry, 51(38):7541-50. PMID: 22931458 doi: 10.1021/bi3009938

[9Emmanuel S. Burgos, Shivali A. Gulab, María B. Cassera, and Vern L. Schramm. 2012. “Luciferase-based assay for adenosine: application to S-adenosyl-L-homocysteine hydrolase.” Anal. Chem., 84(8):3593-98. PMID: 22416759 doi: 10.1021/ac203297z

[10Emmanuel S. Burgos. 2011. “NAMPT in regulated NAD biosynthesis and its pivotal role in human metabolism.” Curr. Med. Chem., 18(13):1947-61. PMID: 21517777

[11] María B. Cassera, Meng-Chiao Ho, Emilio F. Merino, Emmanuel S. Burgos, Agnes Rinaldo-Matthis, Steven C. Almo, and Vern L. Schramm. 2011. “A high-affinity adenosine kinase from Anopheles gambiae.” Biochemistry, 50(11):1885-93. PMID: 21247194 doi: 10.1021/bi101921w

[12Emmanuel S. Burgos, Meng-Chiao Ho, Steven C. Almo, and Vern L. Schramm. 2009. “A phosphoenzyme mimic, overlapping catalytic sites and reaction coordinate motion for human NAMPT.” Proc. Natl. Acad. Sci., 106(33):13748-53. PMID: 19666527 doi: 10.1073/pnas.0903898106

[13Emmanuel S. Burgos, and Vern L. Schramm. 2008. “Weak coupling of ATP hydrolysis to the chemical equilibrium of human nicotinamide phosphoribosyltransferase.” Biochemistry, 47(42):11086-96. PMID: 18823127 doi: 10.1021/bi801198m

Patents

Emmanuel S. Burgos, and Vern L. Schramm. August 1, 2013. “Luciferase-linked methods for detecting adenosine and uses thereof.” WO2013112358 A1.

 

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Contact

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Forchheimer Building, Room 304
Bronx, NY 10461

Tel: 718.430.4128
Fax: 718.430.8565
emmanuel.burgos@einstein.yu.edu

 
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