Janet Smith, Ph.D.

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

Ofc: 3437 LSI
210 Washtenaw Avenue
Ann Arbor, MI 48109-2216

 

(734) 615-9564

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

2018   Elected Fellow, American Crystallographic Association
2016   Distinguished Faculty Lectureship Award in Biomedical Research, University of Michigan Medical School
2007   Elected 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

Recent Publications

Flexibility in nucleic acid binding is central to APOBEC3H antiviral activity.
Bohn JA, DaSilva J, Kharytonchyk S, Mercedes M, Vosters J, Telesnitsky A, Hatziioannou T, Smith JL.
J Virol. 2019, in press.

Fungal indole alkaloid biogenesis through evolution of a bifunctional reductase/Diels-Alderase.
Dan Q, Newmister SA, Klas KR, Fraley AE, McAfoos TJ, Somoza AD, Sunderhaus JD, Ye Y, Shende VV, Yu F, Sanders JN, Brown WC, Zhao L, Paton RS, Houk KN, Smith JL, Sherman DH, Williams RM.
Nat Chem. 2019; in press.

Structural basis for selectivity in flavin-dependent monooxygenase-catalyzed oxidative dearomatization.
Benítez AR, Tweedy S, Baker Dockrey SA, Lukowski AL, Wymore T, Khare D, Brooks CL 3rd, Palfey BA, Smith JL, Narayan ARH.
ACS Catal. 2019; 9: 3633-40.

Structural and dynamical rationale for fatty acid unsaturation in Escherichia coli.
Dodge GJ, Patel A, Jaremko KL, McCammon JA, Smith JL, Burkart MD.
Proc Natl Acad Sci U S A. 2019; 116: 6775-83.

Structural Basis of Polyketide Synthase O-Methylation.
Skiba MA, Bivins MM, Schultz JR, Bernard SM, Fiers WD, Dan Q, Kulkarni S, Wipf P, Gerwick WH, Sherman DH, Aldrich CC, Smith JL.
ACS Chem Biol. 2018; 13: 3221-8.

Ketoreductase Domain Dysfunction Expands Chemodiversity: Malyngamide Biosynthesis in the Cyanobacterium Okeania hirsuta.
Moss NA, Leão T, Rankin MR, McCullough TM, Qu P, Korobeynikov A, Smith JL, Gerwick L, Gerwick WH.
ACS Chem Biol. 2018; 13: 3385-95.

Protein-protein interactions in "cis-AT" polyketide synthases.
Dodge GJ, Maloney FP, Smith JL.
Nat Prod Rep. 2018; 35: 1082-96.

For a list of publications from MyNCBI, click HERE

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