Biochemistry & Biophysics

Margaret E. Glasner

glasner Assistant Professor of Biochemistry and Biophysics

Phone: (979) 458-0123
Email: margy.glasner@tamu.edu

B.S., B.M. University of Wyoming (1995)
Ph.D. Massachusetts Institute of Technology (2003)
Postdoc. University of California, San Francisco (2003-2008)

Joined Texas A&M Faculty 2008

Evolution of Protein Structure and Function
How do protein sequence and structure mediate protein function? Evolution is the organizing principle of biology and provides the cornerstone of our approach to answering this deceptively simple question. We use large scale bioinformatic analysis to place biochemical data into evolutionary and biological context, and we experimentally test hypotheses derived from these bioinformatic studies to analyze protein structure-function relationships. Our primary focus is determining how structure and function coevolve to preserve function or to evolve new activities. We are applying this knowledge to predicting protein functions, correcting misannotations from genome sequencing projects, and improving protein engineering strategies.

The subject of our current research is the mechanistically diverse enolase superfamily. Enzymes in this superfamily are evolutionarily related and share a set of conserved catalytic residues that perform a common partial reaction (abstracting a proton adjacent to a carboxylate and stabilizing the resulting enolate anion intermediate). Using these conserved residues and additional active site residues, different families in the enolase superfamily not only bind different substrates, but also catalyze diverse overall reactions, including racemization of modified amino acids and dehydration of several different acid sugars. There are over 1000 proteins in the superfamily, and over fifteen different isofunctional families have been identified. About half of the proteins in the superfamily have unknown functions.

Our areas of research include:
  • Determining the extent and variety of ways that homologous, isofunctional proteins are allowed to vary without compromising their function
  • Accurately categorizing superfamily members into isofunctional families, a task made more difficult by the occurrence of catalytically promiscuous proteins
  • Identifying principles of natural evolution that can be applied to improve protein engineering methods

Recent Publications
  1. Sakai A, Fedorov AA, Fedorov EV, Schnoes AM, Glasner ME, Brown S, Rutter ME, Bain K, Chang S, Gheyi T, Sauder JM, Burley SK, Babbitt PC, Almo SC & Gerlt JA (2009) Evolution of Enzymatic Activities in the Enolase Superfamily: Stereochemically Distinct Mechanisms in Two Families of cis,cis-Muconate Lactonizing Enzymes. Biochemistry 48: 2569-70
  2. Sakai A, Fedorov AA, Fedorov EV, Schnoes AM, Glasner ME, Brown S, Rutter ME, Bain K, Chang S, Gheyi T, Sauder JM, Burley SK, Babbitt PC, Almo SC & Gerlt JA (2009) Evolution of enzymatic activities in the enolase superfamily: stereochemically distinct mechanisms in two families of cis,cis-muconate lactonizing enzymes. Biochemistry 48: 1445-53
  3. Pieper U, Chiang R, Seffernick JJ, Brown SD, Glasner ME, Kelly L, Eswar N, Sauder JM, Bonanno JB, Swaminathan S, Burley SK, Zheng X, Chance MR, Almo SC, Gerlt JA, Raushel FM, Jacobson MP, Babbitt PC & Sali A (2009) Target selection and annotation for the structural genomics of the amidohydrolase and enolase superfamilies. J Struct Funct Genomics 10: 107-25
  4. Kalyanaraman C, Imker HJ, Fedorov AA, Fedorov EV, Glasner ME, Babbitt PC, Almo SC, Gerlt JA & Jacobson MP (2008) Discovery of a dipeptide epimerase enzymatic function guided by homology modeling and virtual screening. Structure 16: 1668-77
  5. Rakus JF, Fedorov AA, Fedorov EV, Glasner ME, Hubbard BK, Delli JD, Babbitt PC, Almo SC & Gerlt JA (2008) Evolution of enzymatic activities in the enolase superfamily: L-rhamnonate dehydratase. Biochemistry 47: 9944-54
  6. Rakus JF, Fedorov AA, Fedorov EV, Glasner ME, Vick JE, Babbitt PC, Almo SC & Gerlt JA (2007) Evolution of enzymatic activities in the enolase superfamily: D-Mannonate dehydratase from Novosphingobium aromaticivorans. Biochemistry 46: 12896-908
  7. Song L, Kalyanaraman C, Fedorov AA, Fedorov EV, Glasner ME, Brown S, Imker HJ, Babbitt PC, Almo SC, Jacobson MP & Gerlt JA (2007) Prediction and assignment of function for a divergent N-succinyl amino acid racemase. Nat Chem Biol 3: 486-91
  8. Glasner ME, Gerlt JA & Babbitt PC (2007) Mechanisms of protein evolution and their application to protein engineering. Adv Enzymol Relat Areas Mol Biol 75: 193-239, xii-xiii
  9. Glasner ME, Gerlt JA & Babbitt PC (2006) Evolution of enzyme superfamilies. Curr Opin Chem Biol 10: 492-7
  10. Glasner ME, Fayazmanesh N, Chiang RA, Sakai A, Jacobson MP, Gerlt JA & Babbitt PC (2006) Evolution of structure and function in the o-succinylbenzoate synthase/N-acylamino acid racemase family of the enolase superfamily. J Mol Biol 360: 228-50
  11. Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, Hammond SM, Bartel DP & Schier AF (2005) MicroRNAs regulate brain morphogenesis in zebrafish. Science 308: 833-8
  12. Lim LP, Glasner ME, Yekta S, Burge CB & Bartel DP (2003) Vertebrate microRNA genes. Science 299: 1540
  13. Glasner ME, Bergman NH & Bartel DP (2002) Metal ion requirements for structure and catalysis of an RNA ligase ribozyme. Biochemistry 41: 8103-12
  14. Johnston WK, Unrau PJ, Lawrence MS, Glasner ME & Bartel DP (2001) RNA-catalyzed RNA polymerization: accurate and general RNA-templated primer extension. Science 292: 1319-25
  15. Glasner ME, Yen CC, Ekland EH & Bartel DP (2000) Recognition of nucleoside triphosphates during RNA-catalyzed primer extension. Biochemistry 39: 15556-62
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