Chemical Biology

Megan L. Matthews

Photo: 
First Name: 
Megan L.
Last Name: 
Matthews
Official Title: 
Assistant Professor of Chemistry
Contact Information
Office Location: 
2003 Vagelos
Email: 
megamatt@sas.upenn.edu
Phone: 
215-746-4738
Twitter: 
@MegaMatthewsLab
Admin Support: 
Education: 

B.S., Chemistry, Miami University (2005)

 

Ph.D., Chemistry, The Pennsylvania State University (2011)

 

Merck Helen Hay Whitney Postdoctoral Fellow (2012–2015) and postdoctoral associate (2015–2017), Department of Molecular Medicine, The Scripps Research Institute

Research Interests: 

Research in the Matthews group unites enzymology and chemical biology to develop novel chemical proteomics technologies for the discovery of enzyme cofactors and regulatory post-translational modifications that cannot readily be predicted by gene or protein sequence.

 

Intrinsic nucleophiles abound among the proteinogenic amino acids, but, interestingly, reactive electrophiles are essentially absent. Therefore, the majority of chemical probes target nucleophilic sites to discover enzymes, inhibitors and drug therapies. However, by acquiring them through post-translational modifications, enzymes do indeed exploit diverse classes of protein-bound electrophiles for catalysis and other essential functions. Owing to this mode of acquisition, functional electrophiles are not generally predictable from sequence; thus, their breadth and prevalence remain to be found. Our group is exploring this unknown to understand the functions of reactive modifications that we have found unexpectedly on drug targets implicated in cancer and Alzheimer’s disease. Such discoveries can be uncovered using the ‘reverse-polarity’ chemical probes that we develop. We expect that this largely un-profiled half of the reactive proteome – the covalent ‘electrophilome’ – will be found to rival its 'nucleophilome' counterpart in functional diversity and disease relevance.

Selected Publications: 

The Scripps Research Institute

17.    Matthews ML*, He L, Olson EJ, Horning BD, Correia BE, Yates JR, III, Dawson PE & Cravatt BF*. “Chemoproteomic profiling and discovery of protein electrophiles in human cells.” Nat. Chem. 9, 234–243 (2017).

16.    Horning BD, Suciu RM, Ghadiri D, Ulanovskaya O, Matthews ML, Lum KM, Backus KM, Brown SJ, Rosen H & Cravatt BF. “Chemical proteomic profiling of human methyltransferases.” J. Am. Chem. Soc. 138, 13335–13343 (2016).

15.    Rajagopalan S, Wang C, Yu K, Kuzin AP, Richter F, Lew S, Miklos AE, Matthews ML, Seetharaman J, Su M, Hunt JF, Cravatt BF & Baker D. “Design of activated serine-containing catalytic triads with atomic-level accuracy.” Nat. Chem. Biol. 10, 386-391 (2014).

14.    Chang JW, Niphakis MJ, Lum KM, Cognetta AB, Wang C, Matthews ML, Niessen S, Buczynski MW, Parsons LH & Cravatt BF. “Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates.” Chem. Biol. 19, 579-588 (2012).

The Pennsylvania State University

13.    Srnec M, Wong SD, Matthews ML, Krebs C, Bollinger JM, Jr. & Solomon EI. “Electronic structure of the ferryl intermediate in the a-ketoglutarate dependent non-heme iron halogenase SyrB2: Contributions to H-atom abstraction reactivity.” J. Am. Chem. Soc. 138, 5110-5122 (2016). 

12.    Matthews ML*, Chang WC, Layne AP, Miles LA, Krebs C & Bollinger JM, Jr.* “Direct nitration and azidation of aliphatic carbons by an iron-dependent halogenase.” Nat. Chem. Biol. 10, 209-215 (2014).  

11.    Wong SD, Srnec M, Matthews ML, Liu LV, Kwak Y, Park K, Bell CB, Alp EE, Zhao JY, Yoda Y, Kitao S, Seto M, Krebs C, Bollinger JM, Jr. & Solomon EI. “Elucidation of the Fe(IV)=O intermediate in the catalytic cycle of the halogenase SyrB2.” Nature 499, 320-323 (2013).

10.    Krebs C, Dassama LMK, Matthews ML, Jiang W, Price JC, Korboukh V, Li N & Bollinger JM, Jr. “Novel approaches for the accumulation of oxygenated intermediates to multi-millimolar concentrations.” Coord. Chem. Rev. 257, 234-243 (2013).

9.      Hollenhorst MA, Bumpus SB, Matthews ML, Bollinger JM, Jr. Kelleher NL & Walsh CT. “The nonribosomal peptide synthetase enzyme DdaD tethers N(b)-fumaramoyl-L-2,3-diaminopropionate for Fe(II)/a-ketoglutarate-dependent epoxidation by DdaC during dapdiamide antibiotic biosynthesis.” J. Am. Chem. Soc. 132, 15773-15781 (2010).

8.      Bollinger JM, Jr. & Matthews ML. “Remote enzyme microsurgery.” Science 327, 1337-1338 (2010).

7.      Matthews ML, Neumann CS, Miles LA, Grove TL, Booker SJ, Krebs C, Walsh CT & Bollinger JM, Jr. “Substrate positioning controls the partition between halogenation and hydroxylation in the aliphatic halogenase, SyrB2.” Proc. Natl. Acad. Sci. USA 106, 17723-17728 (2009).

6.      Matthews ML, Krest CM, Barr EW, Vaillancourt FH, Walsh CT, Green MT, Krebs C & Bollinger JM, Jr. “Substrate-triggered formation and remarkable stability of the C–H bond-cleaving chloroferryl intermediate in the aliphatic halogenase, SyrB2.” Biochemistry 48, 4331-4343 (2009).

5.      Bollinger JM, Jr., Diao Y, Matthews ML, Xing G & Krebs C. “Myo-inositol oxygenase: a radical new pathway for O2 and C-H activation at a nonheme diiron cluster.” Dalton Trans. 905-914 (2009).

4.      Krebs C, Matthews ML, Jiang W & Bollinger JM, Jr. “AurF from Streptomyces thioluteus and a possible new family of manganese/iron oxygenases.” Biochemistry 46, 10413-10418 (2007).

3.      Fujimori DG, Barr EW, Matthews ML, Koch GM, Yonce JR, Walsh CT, Bollinger JM, Jr., Krebs C & Riggs-Gelasco PJ. “Spectroscopic evidence for a high-spin Br-Fe(IV)-oxo intermediate in the a-ketoglutarate-dependent halogenase CytC3 from Streptomyces.”  J. Am. Chem. Soc. 129, 13408-13409 (2007).

 

Miami University, 2001–2005

2.      Matthews ML, Periyannan G, Hajdin C, Sidgel TK, Bennett B & Crowder MW. “Probing the reaction mechanism of the D-ala-D-ala dipeptidase, VanX, by using stopped-flow kinetic and rapid-freeze quench EPR studies on the Co(II)-substituted enzyme.” J. Am. Chem. Soc. 128, 13050-13051 (2006).

1.      Breece RM, Costello A, Bennett B, Sigdel TK, Matthews ML, Tierney DL & Crowder MW. “A five-coordinate metal center in Co(II)-substituted VanX.” J. Biol. Chem. 280, 11074-11081 (2005).

Chemistry Biophysics Mini-Symposium

Fri, 2016-12-09 (All day)
Speaker: 
TBA
Location: 
TBA

Hirschmann Visiting Professor - Lecture III (Sam Gellman, Wisconsin)

Thu, 2016-04-07 12:00 - 13:00
Speaker: 

Prof. Sam Gellman

University of Wisconsin, Madison

 

Location: 

Lynch Lecture Hall

 

Lecture II

Hirschmann Visiting Professor - Lecture II (Sam Gellman, Wisconsin)

Wed, 2016-04-06 13:00 - 14:00
Speaker: 

Prof. Sam Gellman

University of Wisconsin, Madison

Location: 

Lynch Lecture Hall

Lecture II

Special Biophysical Chemistry Seminar: Christy Landes, Rice

Wed, 2016-01-20 13:00 - 14:00
Speaker: 

Prof. Christy Landes

Rice University

Location: 
Lynch Lecture Hall
Attached Document: 

Single molecule dynamics at soft interfaces: from basic science to a $100,000,000,000 problem

 

Abstract

Special Seminar: Andrew Lee (Northwestern)

Tue, 2014-07-08 15:30 - 16:30
Speaker: 
Dr. Andrew Lee Northwestern University
Location: 
Lynch Lecture Hall
Attached Document: 
Interaction of Nanoparticle-Oligonucleotide Conjugates with Serum Nucleases

Joachim Frank Sympsoium

Wed, 2014-04-23 08:30 - 15:00
Speaker: 

The Ribosome: Structure and Function

 

Research Symposium Honoring 2014 Franklin Medal Laureate Joachim Frank

Location: 

Smilow Center for Translational Research

Attached Document: 

Speakers

 

Peter B. Moore, Ph.D.

Sterling Professor of Chemistry, Professor of Molecular Biophysics and Biochemistry, Yale University

 

Barry S. Cooperman, Ph.D.

Professor of Chemistry and Biological Chemistry, University of Pennsylvania

 

Christian Spahn, Ph.D.

Director, Institute for Medical Physics and Biophysics, Charité-Universitätsmedizin, Berlin

 

Yifan Cheng, Ph.D.

Research Professor of Biochemistry and Biophysics, University of California San Francisco

Special Biological Seminar: Joshua Rabinowitz, Princeton University

Thu, 2014-03-13 10:30 - 11:30
Speaker: 

Prof. Joshua D. Rabinowitz

Princeton University

Location: 

Lynch Lecture Hall

Attached Document: 

Towards a Comprehensive Understanding of Cellular Metabolism

 

For more information on Prof. Rabinowitz, please visit here.

Special Energy Seminar: L. Robert Baker, Berkeley

Tue, 2013-11-26 22:00
Speaker: 

Dr. L. Robert Baker   
University of California, Berkeley

Location: 

Carolyn Hoff Lynch Lecture Hall
Chemistry Complex
231 South 34th Street

Attached Document: 

Charge Transfer and Chemistry at Catalytic Interfaces

Abstract

Department of Chemistry

231 S. 34 Street, Philadelphia, PA 19104-6323

215.898.8317 voice | 215.573.2112 fax | web@chem.upenn.edu

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