|BS||Kent State University||Kent, Ohio||Chemistry|
|PhD||Johns Hopkins School of Medicine||Baltimore, Md.||Biochemistry|
Our laboratory studies the three-dimensional structures of proteins relevant to human disease. A major focus of the lab is characterizing proteins in an enzyme superfamily known as the alpha-D-phosphohexomutases. These enzymes catalyze the production of phosphorylated sugar precursors that are assembled into more complex carbohydrates, such as polysaccharides. Enzymes in this superfamily are found in all organisms, including bacteria, archaea, and eukaryotes. In many bacteria, polysaccharides are critical determinants of infectivity, and so these enzymes are excellent targets for the design of antimicrobial agents. In humans, deficiency in the enzyme phosphoglucomutase 1 (PGM1) has been recently identified as an inherited metabolic disease categorized as both a muscle glycogenosis (type XIV) and a congenital disorder of glycosylation (CDG types I and II).
In studies of the bacterial members of the superfamily, we have conducted detailed structure-function analyses using methods including X-ray crystallography, kinetics, small angle X-ray scattering, and hydrogen deuterium exchange. These studies include enzymes from important human pathogens, including P. aeruginosa, B. anthracis, and S. typhimurium. We have also utilized computational analyses, such as normal mode and co-evolutionary analyses to better understand the relationships between protein structure, conformational flexibility, and sequence relationships in the family. In collaboration with the laboratory of Steven Van Doren, we are characterizing the role of protein dynamics in the mechanism of P. aeruginosa PMM/PGM via NMR. Insights from our recent studies include a key role for phosphorylation of the active site serine in both catalysis and enzyme flexibility. Our recent work on human PGM1 includes biochemical and structural characterization of missense variants associated with disease. A better understanding of the molecular bases of this inherited disease should benefit patient prognosis and therapy.
Xu J, Lee Y, Beamer LJ, Van Doren SR. 2015. Phosphorylation in the catalytic cleft stabilizes and attracts domains of a phosphohexomutase.
Biophys J. 2015 Jan 20;108(2):325-37.
Lee Y, Stiers KM, Kain BN, Beamer LJ. 2014. Compromised catalysis and potential folding defects in in vitro studies of missense mutants associated with hereditary phosphoglucomutase 1 deficiency. J Biol Chem. 2014 Nov 14;289(46):32010-9. Epub 2014 Oct 6.
Beamer LJ. Mutations in hereditary phosphoglucomutase 1 deficiency map to key regions of enzyme structure and function. J Inherit Metab Dis. 2015 Mar;38(2):243-56. Epub 2014 Aug 29.
Lee Y, Villar MT, Artigues A, Beamer LJ. Promotion of enzyme flexibility by dephosphorylation and coupling to the catalytic mechanism of a phosphohexomutase. J Biol Chem. 2014 Feb 21;289(8):4674-82. Epub 2014 Jan 8.
Luebbering EK, Mick J, Singh RK, Tanner JJ, Mehra-Chaudhary R, Beamer LJ. 2014. Conservation of functionally important global motions in an enzyme superfamily across varying quaternary structures. J Mol Biol. 2012 Nov 9;423(5):831-46. Epub 2012 Aug 27.
Lee Y, Mick J, Furdui C, Beamer LJ. 2012. A coevolutionary residue network at the site of a functionally important conformational change in a phosphohexomutase enzyme family. PLoS One. 2012;7(6):e38114. Epub 2012 Jun 7.
Research areas: Structural biology: X-ray crystallography of medically important proteins.
How to apply:
Electronic submission is encouraged, e-mail to email@example.com
Applicants should send CV and names of two references to:
Dr. Lesa J. Beamer
117 Schweitzer Hall
University of Missouri
Columbia, MO 65211