|BS||Chemistry||Kent State University||Kent, Ohio|
|PhD||Biochemistry||Johns Hopkins School of Medicine||Baltimore, Md.|
Structural biology: X-ray crystallography of metabolic enzymes; biophysical studies of disease-related missense variants
Our laboratory uses structural biology and other biophysical methods to characterize enzyme function. A primary technique employed by the laboratory is X-ray crystallography, which provides atomic resolution information on the three-dimensional structures of macromolecules. Our overall focus is characterizing enzymes in various metabolic pathways, in organisms ranging from bacteria to plants to humans. In addition to crystallography, we use methods such as enzyme kinetics, small angle X-ray scattering, and hydrogen deuterium exchange, as well as various bioinformatic and computational approaches.
An ongoing effort in the lab is an NSF-funded project in collaboration with plant scientist Melissa Mitchum from the University of Georgia. The project involves studies of a soybean enzyme involved in folate metabolism. Amino acid variants in this enzyme, serine hydroxymethyltransferase 8 (SHMT8), are associated with resistance to the devastating pathogen soybean cyst nematode (SCN). Our initial structural and biochemical studies showed that these amino acid variants impair the binding of folate to SHMT8. Current goals include developing new ways to engineer SCN resistance to help combat this critical agricultural pathogen.
Another recent project involves using structural biology to understand the consequences of mutations that cause inherited disease in humans. In particular, we are studying amino acid variants responsible for a deficiency in the enzyme phosphoglucomutase 1 (PGM1). We have found that different mutations have profoundly different effects on enzyme structure and activity. A better understanding of the molecular bases of this inherited disease should benefit patient prognosis and therapy.
Notable Honors and Service
- Session chair, 2018 annual meeting of the American Crystallographic Association
- Editor, Acta Crystallographica F: Structural Biology and Crystallization Communications, 2009-2017
- Chair, BIOMAC Special Interest Group American Crystallographic Association
- Program Director, Annual meeting of the American Crystallographic Association, 2004
Beamer LJ. (2021) Enzyme dysfunction at atomic resolution: disease-associated variants of human phosphoglucomutase-1. Biochimie 183: 44-48.
Stiers KM, Hansen RP, Daghlas BA, Mason KN, Zhu JS, Jakeman DL, Beamer LJ. (2020). A missense variant remote from the active site impairs stability of human phosphoglucomutase 1. J Inherit Metab Dis. 2020 Feb 14. doi: 10.1002/jimd.12222. Epub ahead of print. [PubMed]
Korasick DA, Kandoth PK, Tanner JJ, Mitchum MG, Beamer LJ. (2020). Impaired folate binding of serine hydroxymethyltransferase 8 from soybean underlies resistance to the soybean cyst nematode. J Biol Chem. 2020 Feb 2. doi: 10.1074/jbc.RA119.012256. Epub ahead of print. [PubMed]
Zhu JS, Stiers KM, Soleimani E, Groves BR, Beamer LJ, Jakeman DL. (2019). Inhibitory Evaluation of αPMM/PGM from Pseudomonas aeruginosa: Chemical Synthesis, Enzyme Kinetics, and Protein Crystallographic Study. J Org Chem. 84(15):9627-9636. doi: 10.1021/acs.joc.9b01305. [PubMed]
Stiers KM, Graham AC, Zhu JS, Jakeman DL, Nix JC, Beamer LJ. (2019). Structural and dynamical description of the enzymatic reaction of a phosphohexomutase. Struct Dyn. 6(2):024703. doi: 10.1063/1.5092803. eCollection 2019 Mar. [PubMed]
Radenkovic S, Bird MJ, Emmerzaal TL, Wong SY, Felgueira C, Stiers KM, Sabbagh L, Himmelreich N, Poschet G, Windmolders P, Verheijen J, Witters P, Altassan R, Honzik T, Eminoglu TF, James PM, Edmondson AC, Hertecant J, Kozicz T, Thiel C, Vermeersch P, Cassiman D, Beamer L, Morava E, Ghesquière B. (2019). The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG. Am J Hum Genet. 104(5):835-846. doi: 10.1016/j.ajhg.2019.03.003. [PubMed]
Stiers KM, Beamer LJ. (2018). A Hotspot for Disease-Associated Variants of Human PGM1 Is Associated with Impaired Ligand Binding and Loop Dynamics. Structure. 26(10):1337-1345.e3. doi: 10.1016/j.str.2018.07.005. [PubMed]
Xu J, Sarma AVS, Wei Y, Beamer LJ, Van Doren SR. (2017). Multiple Ligand-Bound States of a Phosphohexomutase Revealed by Principal Component Analysis of NMR Peak Shifts. Sci Rep. 7(1):5343. doi: 10.1038/s41598-017-05557-w. [PubMed]