Gabriel S Brandt Associate Professor of Chemistry
Biography
Professor Brandt is a chemist who rejoices particularly in the splendor of biological molecules. His graduate work involved incorporating unnatural amino acids into human ion channels expressed in the eggs of carnivorous frogs. After post-doctoral research on the X-ray crystallography of various proteins, he currently has a three-fold focus. One project in his lab addresses the biochemistry of proteins involved in the virulence mechanism of the malaria parasite Plasmodium falciparum. The other seeks to control biochemical pathways inside living cells, through methods both modern (developing molecules that enter cells and respond to light pulses once they're inside) and traditional (examining how a potential anti-cancer compound binds to its target enzyme). A third project is a collaboration with Prof. Fields (Biology) to try to understand how warming ocean waters affect the structure of metabolic proteins of corals.
Education
B.A. Reed College
Ph.D. Caltech
Research
My lab is generally interested in the atomic and molecular scale of natural processes. Specifically, we're undertaking three projects. The first has to do with understanding the virulence mechanisms of the malaria parasite P. falciparum. In the second project, we'll try to develop chemical tools for using light to control biochemical processes as they occur in cells in real time. In the third project, we attempt to crystallize proteins from marine organisms, so that we can use X-ray diffraction to identify their atomic structure.
- Molecular mechanisms of virulence in P. falciparum
Globally, most malaria infections are caused by P. vivax, but most deaths result from infection by P. falciparum. Malaria parasites remain within a patient's circulating red blood cells for up to 48 hours, undergoing several cycles of asexual reproduction. The virulence of P. falciparum is thought to be related to its ability to alter the red blood cell surface during this process. These infected erythrocytes adhere to the walls of blood vessels, potentially leading to life-threatening symptoms. We'd like to know more about how the parasite remodels the surface of its host cell. A very large number of P. falciparum proteins are exported into the red blood cell. One family comprises 20 Ser/Thr protein kinases, enzymes that can modify other proteins in a cell. Our goal is to study the biochemistry of the members of this family.
- Controlling biochemical processes in cells
Modern biochemistry is increasingly focused on trying to do experiments in a cell rather than a test tube. I'm interested in developing chemical tools that can ultimately be used inside cells. One way to exert control over a molecule inside a cell is by using light, so one goal of our lab is to design, synthesize and test photoactive molecules. Inside a cell, these molecules can be stimulated to change structure with pulses of light. A more traditional way of manipulating cellular pathways is to use inhibitors of specific enzymes. Our lab has recently begun examining how a promising anti-cancer drug binds to its target enzyme. The compound has been shown to be highly effective against solid tumors, but it's prone to serious side effects. Our goal is to learn precisely how it binds, so that we can try to develop versions that preserve its efficacy while diminishing side effects.
- Protein structure in a warming ocean
Proteins are dynamic molecules. After their birth, as chains of amino acids spooling out of the ribosome, they twitch themselves into a defined shape. Once they have achieved this shape, they continue to move, as all quantum mechanical objects do, vibrating, flexing, swaying, rotating. So, the very idea of a protein's structure encompasses a range of possibilities. My colleague in Biology, Prof. Peter Fields, has long been interested in the effects of temperature on the structures of proteins. Recently, we have begun a collaboration to examine some of the proteins shared by reef-building coral and their symbiotic algae. As seawater warms, this symbiosis breaks down, and the coral expel their photosynthetic algal partners, resulting in coral bleaching. Coral bleaching is undoubtedly a complex phenomenon, but the role of increased water temperature is clear. My lab is interested in crystallizing proteins, in order to shoot X-rays through them and establish their atomic structures. In collaboration with the Fields group, we have begun to collect structural information on variants of metabolic proteins from coral and their symbionts that have been shown to have different degrees of thermostability. In this way, we hope to begin to understand the relationship of structure to temperature sensitivity.
Grants & Awards
2013 - present:
Brandt GS. Improving specificity of a drug that targets cancer metabolism. Commonwealth Universal Research Enhancement Grant : Pennsylvania Department of Health (6/20 - 6/24)
Brandt GS. Preventing parasites from remodeling: screening for inhibitors of kinases secreted from a malaria parasite. American Philosophical Society: Franklin Research Grant. (04/14 - 01/15)
Publications
2017-present:
(Undergraduate student coauthor are in bold.)
Perez AM, Wolfe JA, Schermerhorn JT, Qian Y, Cela BA, Kalinowski CR, Largoza GE, Fields PA, Brandt GS. Thermal stability and structure of glyceraldehyde-3-phosphate dehydrogenase from the coral Acropora millepora. Royal Society of Chemistry Advances. 11 10364 [2021] link
Brandt GS, Novak WR. SARS‐CoV‐2 virtual biochemistry labs on bioinformatics and drug design. Biochemistry and Molecular Biology Education. 49 26 [2021] link
Hosseinzade A, Sadeghi O, Naghdipour Biregani A, Soukhtehzari S, Brandt GS, Esmaillzadeh A. Immunomodulatory effects of flavonoids: possible induction of T CD4+ regulatory cells through suppression of mTOR pathway signaling activity. Frontiers in Immunology 10 51 [2019] link
Novak WRP, West KHJ, Kirkman LMD, Brandt GS. Re-refinement of P. falciparum orotidine 5'- monophosphate decarboxylase provides a clearer picture of an important malarial drug target. Acta Crystallographica F74 664 [2018] link
Brandt GS. Secondary structure. in Wells RD, Bond JS, Klinman J, Masters BSS (eds). Molecular Life Sciences. Springer, New York, NY. [2018] link
Lin BC, Harris DR, Kirkman LM, Perez AM, Qian Y, Schermerhorn JT, Hong MY, Winston DS, Xu L, Lieber AM, Hamilton M, Brandt GS. The anthraquinone emodin inhibits the non-exported FIKK kinase from Plasmodium falciparum. Bioorganic Chemistry 75 217 [2017] link
Lin BC, Harris DR, Kirkman LM, Perez AM, Qian Y, Schermerhorn JT, Hong MY, Winston DS, Xu L, Brandt GS. FIKK kinase, a Ser/Thr kinase important to malaria parasites, is inhibited by tyrosine kinase inhibitors. ACS Omega 2 6605 [2017] link
2000 - 2016:
Liu CF, Brandt GS, Hoang QQ, Naumova N, Lazarevic V, Hwang ES, Dekker J, Glimcher LH, Ringe D, Petsko GA. Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites. Proceedings of the National Academy of Sciences. 113 E6572-81. [2016]
Naffin-Olivos JL, Georgieva M, Goldfarb N, Madan-Lala R, Dong L, Bizzell E, Valinetz E, Brandt GS, Yu S, Shabashvili DE, Ringe D, Dunn BM, Petsko GA, Rengarajan J. Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2. PLoS Pathogens 10 e1004132 [2014]
Brandt GS and Bailey S. Dematin, a human erythrocyte cytoskeletal protein, is a substrate for a recombinant secreted kinase from Plasmodium falciparum. Molecular & Biochemical Parasitology 191 20 [2013]
Brandt GS, Kneen MK, Petsko GA, Ringe D and McLeish MJ. Active site engineering of benzaldehyde lyase shows that a point mutation can confer both new reactivity and susceptibility to mechanism-based inhibition. Journal of the American Chemical Society 132 438 [2010]
Brandt GS, Kneen M, Chakraborty S, Baykal A, Nemeria N, Yep A, Ruby D, Petsko GA, Kenyon GL, McLeish M, Jordan F, Ringe D. Snapshot of a reaction intermediate: analysis of benzoylformate decarboxylase in complex with a benzoylphosphonate inhibitor. Biochemistry 48 3247 [2009]
Chakraborty S, Nemeria N, Balakrishnan A, Brandt GS, Kneen MM, Yep A, McLeish MJ, Kenyon GL, Petsko GA, Ringe D, Jordan F. Diphosphate-bound covalent intermediates derived from a chromophoric substrate analogue on benzoylformate decarboxylase. Biochemistry 48 981 [2009]
Brandt GS, Nemeria N, Chakraborty S, Yep A, McLeish MJ, Kenyon GL, Jordan F, Petsko GA, Ringe D. Probing the active center of benzaldehyde lyase with substitutions and the pseudo-substrate analog benzoylphosphonic acid methyl ester. Biochemistry 47 7734 [2008]
Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher LH, Korsmeyer SJ. Proapoptotic BAX and BAK modulate unfolded protein response by a direct interaction with IRE1a. Science 312 572 [2006]
Rothman DM, Petersson EJ, Vázquez ME, Brandt GS, Dougherty DA, Imperiali B. Caged phosphoproteins. Journal of the American Chemical Society 127 846 [2005]
Petersson EJ, Brandt GS, Zacharias NM, Dougherty DA, Lester HA. Caged amino acids in ion channels. Methods in Enzymology 360 258 [2003]
Beene DL, Brandt GS, Zhong W, Zacharias NM, Lester HA, Dougherty DA. Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine. Biochemistry 41 10262 [2002]
Tong YH, Brandt GS, Li M, Shapovalov G, Slimko E, Karschin A, Dougherty DA, Lester HA. Tyrosine decaging leads to substantial membrane trafficking during modulation of an inward rectifier potassium channel. Journal of General Physiology 117 103 [2001]
Philipson KD, Gallivan JP, Brandt GS, Dougherty DA, Lester HA. Incorporation of caged cysteine and caged tyrosine into a transmembrane segment of the nicotinic ACh receptor. American Journal of Physiology -Cellular Physiology 281 C195 [2001]
Courses Taught
CHM 111 - General Chemistry I: Picturing the Atomic World, Lecture & Lab
CHM 112 - General Chemistry II: Reactions in the Atomic World, Lecture & Lab
CHM 351 - Introductory Biochemistry: Chemistry of Life, Lecture & Lab
CHM 451 - Advanced Biochemistry: Biochemical and Biophysical Techniques