Janet Smith, Ph.D.

Margaret J. Hunter Collegiate Professor, Life Sciences Institute
Professor, Biological Chemistry

3437 Life Sciences Institute
210 Washtenaw Avenue
Ann Arbor, MI 48109-2216

 

(734) 615-9564

Appointments

Life Sciences Institute
Biological Chemistry, Medical School
Biophysics, College of Literature, Science, and the Arts

Areas of Interest

Our group studies protein structure using X-ray crystallography in order to understand protein function. We use the three-dimensional structures of proteins to understand molecular mechanisms of biological processes and to develop hypotheses about function, which we test through experiments in our lab or by collaboration. Two current projects illustrate our approach.

Glutamine amidotransferases are complex enzymes that produce ammonia from the amide group of glutamine, and channel the ammonia through an intra-molecular tunnel to a second active site where it is added to a second substrate. Amidotransferases occur in a variety of pathways for biosynthesis of nitrogenous molecules, including purine and pyrimidine bases, cofactors, aminosugars and amino acids. Our crystal structures of glutamine PRPP amidotransferase (purine pathway), GMP synthetase (guanine pathway), imidazole glycerol phosphate synthase (histidine pathway) and other enzymes show that the chemical steps of glutamine hydrolysis and amination occur independently, but that they are coordinated by the protein through a variety of conformational switches. Our analysis of the structures has shown how each enzyme keeps its glutaminase active site in an inactive state until the second substrate is bound and ready to accept the labile ammonia. Currently challenges are to understand the conformational switches used for cross-talk by the distant active sites and to study new amidotransferases that have been detected in genome sequences.

The replication machinery of alphaviruses and flaviviruses also represents a complex catalytic system. These positive-sense RNA viruses encode enzymes for genome replication, RNA capping, RNA unwinding and polyprotein processing. Specific protein-protein complexes, as yet poorly characterized, coordinate the catalytic activities and specify particular RNA or protein substrates at appropriate times in the viral life cycle. Our structural studies of individual enzymes and enzyme complexes aim to elucidate mechanisms of catalysis and of time-dependent activation and specificity.

Honors & Awards

      2016        Distinguished Faculty Lectureship Award in Biomedical Research, University of Michigan Medical School
      2007        AAAS Fellow, American Association for the Advancement of Science
      2001        Herbert Newby McCoy Award, Purdue University
1998-2008     National Institutes of Health MERIT Award

Published Articles or Reviews

Protein-protein interactions in "cis-AT" polyketide synthases.
Dodge GJ, Maloney FP, Smith JL.
Nat Prod Rep. 2018; 35: 1082-1096.

Molecular Basis for Olefin Rearrangement in the Gephyronic Acid Polyketide Synthase.
Dodge GJ, Ronnow D, Taylor RE, Smith JL.
ACS Chem Biol. 2018; 13: 2699-2707.

Biosynthesis of t-Butyl in Apratoxin A: Functional Analysis and Architecture of a PKS Loading Module.
Skiba MA, Sikkema AP, Moss NA, Lowell AN, Su M, Sturgis RM, Gerwick L, Gerwick WH, Sherman DH, Smith JL.
ACS Chem Biol. 2018; 13: 1640-1650.

PKS-NRPS Enzymology and Structural Biology: Considerations in Protein Production.
Skiba MA, Maloney FP, Dan Q, Fraley AE, Aldrich CC, Smith JL, Brown WC.
Methods Enzymol. 2018; 604: 45-88.

Thiosulfate sulfurtransferase-like domain-containing 1 protein interacts with thioredoxin.
Libiad M, Motl N, Akey DL, Sakamoto N, Fearon ER, Smith JL, Banerjee R.
J Biol Chem. 2018; 293: 2675-2686.

A Mononuclear Iron-Dependent Methyltransferase Catalyzes Initial Steps in Assembly of the Apratoxin A Polyketide Starter Unit.
Skiba MA, Sikkema AP, Moss NA, Tran CL, Sturgis RM, Gerwick L, Gerwick WH, Sherman DH, Smith JL.
ACS Chem Biol. 2017; 12: 3039-3048.

APOBEC3H structure reveals an unusual mechanism of interaction with duplex RNA.
Bohn JA, Thummar K, York A, Raymond A, Brown WC, Bieniasz PD, Hatziioannou T,Smith JL.
Nat Commun. 2017; 8: 1021.

For a list of publications from Pubmed, click HERE

Web Sites