Seek simplicity and distrust it.
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 two-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 synthesize photosensitive molecules with the goal of controlling, via a pulse of light, specific biochemical pathways inside living cells.
Reed College, BA
My lab is generally interested in the atomic and molecular scale of natural processes. Specifically, we're undertaking two 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.
1. 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.
2. Controlling biochemical processes with light
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. These will be small molecules, like pharmaceuticals, that are themselves dynamic. One way to exert control over a molecule inside a cell is by using light. Although some wavelengths of light can penetrate surprisingly far into an organism, this technique is designed to work in experimental cell cultures, which are essentially transparent. Our goal is to design, synthesize and test photoactive molecules. We'll start out with compounds based on known inhibitors of a well-studied protein kinase called Src. One version of a dynamic Src inhibitor will acquire the ability to block the enzyme only after being irradiated with light. Another version will block the enzyme, but then disintegrate when hit by photons. Using what we learn from these proof-of-principle experiments, we hope to create molecules that can be used to turn biochemical pathways on or off in cultured cells.
Grants & Awards
2013 - present:
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)
2000 - present:
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 
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 
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 
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 
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 
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 
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 
Rothman DM, Petersson EJ, Vázquez ME, Brandt GS, Dougherty DA, Imperiali B. Caged phosphoproteins. Journal of the American Chemical Society 127 846 
Petersson EJ, Brandt GS, Zacharias NM, Dougherty DA, Lester HA. Caged amino acids in ion channels. Methods in Enzymology 360 258 
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 
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 
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 
CHM111: General Chemistry
CHM471: Advanced Biochemistry