Joshua Rabinowitz

This email address is being protected from spambots. You need JavaScript enabled to view it.	Rabinowitz Research Lab
(609) 258-8985	Carl Icah Lab, 241
	Lab (609) 258-8985
Faculty Assistant	Marybeth fedele
This email address is being protected from spambots. You need JavaScript enabled to view it.	(609) 258-7058

Research Focus

Towards a Holistic Understanding of Cellular Metabolism

The 20th century saw remarkable progress in understanding key biochemical structures and processes, such as the enzymatic pathway by which glucose is used to generate ATP and the mechanism of replication of genetic material. Until very recently, however, chemical biology focused almost exclusively on understanding biological processes in relative isolation, with minimal attention to the mechanisms by which the complete chemical constituents of cells, or even more dauntingly multi-cellular organisms, function together. With newfound knowledge of the full genetic sequences of multiple organisms, chemical biology is for the first time beginning to investigate the means by which the integrated functioning of the full complement of biological chemicals yields life.

To succeed in developing a complete chemical model of even a simple organism, it is necessary to gain a comprehensive understanding of the molecular constituents involved, including their function, production, consumption, and geometrical organization. These constituents can be broadly divided into large molecule biopolymers such as DNA, RNA, and proteins, and small molecules such metabolic intermediates and membrane lipids. Currently, progress towards a complete understanding of biopolymers is progressing with remarkable speed, largely due to the advent of powerful new analytical tools such as DNA microarrays.

A critical complement to the current holistic studies of cellular large molecules is comparably comprehensive study of the dynamics of the intracellular metabolites. Currently, methods for comprehensive characterization of small molecule concentrations and fluxes in living cells lag behind those for biopolymer expression. The overall goal of our lab is to develop robust means of measuring the concentrations and fluxes of numerous intracellular metabolites in parallel.

Scientific and Biomedical Applications

In our research, beyond developing analytical tools, we apply our metabolite concentration and flux measurement capabilities in three areas:

• Quantitative modeling of the complete metabolic reaction network, using iterative series of computer simulations and experiments;
• Exploration of the linkages between perturbation of the cellular environment (e.g., nutrient deprivation), metabolic response, and gene expression response; and
• Discovery of improved metabolic inhibitors (a large number of important drugs, including some antibiotics, anticancer agents, and cholesterol lowering drugs, function by blocking specific metabolic reactions)

Selected Publications

Xu YF, Zhao X, Glass DS, Absalan F, Perlman DH, Broach JR, Rabinowitz JD. (2012) Regulation of yeast pyruvate kinase by ultrasensitive allostery independent of phosphorylation. Mol Cell. 48: 52-62. Pubmed

Reaves ML, Sinha S, Rabinowitz JD, Kruglyak L, Redfield RJ. (2012) Absence of detectable arsenate in DNA from arsenate-grown GFAJ-1 cells. Science. 337: 470-473. Pubmed

Grady SL, Hwang J, Vastag L, Rabinowitz JD, Shenk T. (2012) Herpes simplex virus 1 infection activates poly(ADP-ribose) polymerase and triggers the degradation of poly(ADP-ribose) glycohydrolase. J Virol.  86: 8259-8268. PubMed

Rabinowitz JD, Vastag L. (2012) Teaching the design principles of metabolism. Nat Chem Biol. 8: 497-501. PubMed

Xu YF, Amador-Noguez D, Reaves ML, Feng XJ, Rabinowitz JD. (2012) Ultrasensitive regulation of anapleurosis via allosteric activation of PEP carboxylase. Nat Chem Biol. 8: 562-568. PubMed

Peterson CN, Levchenko I, Rabinowitz JD, Baker TA, Silhavy TJ. (2012) RpoS proteolysis is controlled directly by ATP levels in Escherichia coli. Genes Dev. 26: 548-553. PubMed

Clasquin MF, Melamud E, Rabinowitz JD. (2012) LC-MS data processing with MAVEN: a metabolomic analysis and visualization engine. Curr Protoc Bioinformatics. Chapter 14: Unit14.11. PubMed

Terry LJ, Vastag L, Rabinowitz JD, Shenk T. (2012) Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection. Proc Natl Acad Sci. 109: 3071-3076. PubMed

Kamphorst JJ, Fan J, Lu W, White E, Rabinowitz JD. (2011) Liquid chromatography-high resolution mass spectrometry analysis of fatty acid metabolism. Anal Chem. 83: 9114-9122. PubMed

Amador-Noguez D, Brasg IA, Feng XJ, Roquet N, Rabinowitz JD. (2011) Metabolome remodeling during the acidogenic-solventogenic transition in Clostridium acetobutylicum. Appl Environ Microbiol.  77: 7984-7997. PubMed

Clasquin MF, Melamud E, Singer A, Gooding JR, Xu X, Dong A, Cui H, Campagna SR, Savchenko A, Yakunin AF, Rabinowitz JD, Caudy AA. (2011) Riboneogenesis in yeast. Cell. 145: 969-980. PubMed

Liu ST, Sharon-Friling R, Ivanova P, Milne SB, Myers DS, Rabinowitz JD, Brown HA, Shenk T. (2011) Synaptic vesicle-like lipidome of human cytomegalovirus virions reveals a role for SNARE machinery in virion egress. Proc Natl Acad Sci. 108: 12869-12874. PubMed

Petti AA, Crutchfield CA, Rabinowitz JD, Botstein D. (2011) Survival of starving yeast is correlated with oxidative stress response and nonrespiratory mitochondrial function. Proc Natl Acad Sci. 108: E1089-10898. PubMed

Reaves ML, Rabinowitz JD. (2011) Characteristic phenotypes associated with ptsN-null mutants in Escherichia coli K-12 are absent in strains with functional ilvG. J Bacteriol. 193: 4576-4581. PubMed

Vastag L, Koyuncu E, Grady SL, Shenk TE, Rabinowitz JD. (2011) Divergent effects of human cytomegalovirus and herpes simplex virus-1 on cellular metabolism. PLoS Pathog. 7: e1002124. PubMed

Clasquin MF, Melamud E, Singer A, Gooding JR, Xu X, Dong A, Cui H, Campagna SR, Savchenko A, Yakunin AF, Rabinowitz JD, Caudy AA. (2011) Riboneogenesis in yeast. Cell. 145: 969-980. PubMed

Vastag L, Jorgensen P, Peshkin L, Wei R, Rabinowitz JD, Kirschner MW. (2011) Remodeling of the metabolome during early frog development. PLoS One. 6: e16881. PubMed

Klosinska MM, Crutchfield CA, Bradley PH, Rabinowitz JD, Broach JR. (2011) Yeast cells can access distinct quiescent states. Genes Dev. 25: 336-349. PubMed

Rabinowitz JD, White E. (2010) Autophagy and metabolism. Science. 330: 1344-1348. PubMed

Reaves ML, Rabinowitz JD. (2010) Metabolomics in systems microbiology. Curr Opin Biotechnol. 22: 17-25. PubMed

Melamud E, Vastag L, Rabinowitz JD. (2010) Metabolomic analysis and visualization engine for LC-MS Data. Anal Chem. 82: 9818-9826. PubMed

Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, Pollina EA, Rabitz HA, Rabinowitz JD, Coller HA. (2010) Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol. 8: e1000514. PubMed

Kwon YK, Higgins MB, Rabinowitz JD. (2010) Antifolate-induced depletion of intracellular glycine and purines inhibits thymineless death in E. coli. ACS Chem Biol. 5: 787-795. PubMed

Crutchfield CA, Lu W, Melamud E, Rabinowitz JD. (2010) Mass spectrometry-based metabolomics of yeast. Methods Enzymol. 470: 393-426. PubMed

Goyal S, Yuan J, Chen T, Rabinowitz JD, Wingreen NS. (2010) Achieving optimal growth through product feedback inhibition in metabolism. PLoS Comput Biol. 6: e1000802. PubMed

Olszewski KL, Mather MW, Morrisey JM, Garcia BA, Vaidya AB, Rabinowitz JD, Llinás M. (2010) Branched tricarboxylic acid metabolism in Plasmodium falciparum. Nature 466: 774-778. PubMed

Amador-Noguez D, Feng XJ, Fan J, Roquet N, Rabitz H, Rabinowitz JD. (2010) Systems-level metabolic flux profiling elucidates a complete, bifurcated TCA cycle in Clostridium acetobutylicum. J Bacteriol. 192: 4452-4461. PubMed

Goodarzi H, Bennett BD, Amini S, Reaves ML, Hottes AK, Rabinowitz JD, Tavazoie S. (2010) Regulatory and metabolic rewiring during laboratory evolution of ethanol tolerance in E. coli. Mol Syst Biol. 6: 378. PubMed

Lu W, Clasquin MF, Melamud E, Amador-Noguez D, Caudy AA, Rabinowitz JD. (2010) Metabolomic analysis via reversed-phase ion-pairing liquid chromatography coupled to a stand alone orbitrap mass spectrometer. Anal Chem. 82: 3212-3221. PubMed

Kuchma SL, Ballok AE, Merritt JH, Hammond JH, Lu W, Rabinowitz JD, O'Toole GA. (2010) c-di-GMP-mediated repression of swarming motility by Pseudomonas aeruginosa: The pilY1 gene and its impact on surface-associated behaviors. J Bacteriol. 192: 2950-2964. PubMed

Monds RD, Newell PD, Wagner JC, Schwartzman JA, Lu W, Rabinowitz JD, O'Toole GA. (2010) Di-adenosine tetraphosphate (Ap4A) metabolism impacts biofilm formation by Pseudomonas fluorescens via modulation of c-di-GMP-dependent pathways. J Bacteriol. 192: 3011-3023. PubMed

Boer VM, Crutchfield CA, Bradley PH, Botstein D, Rabinowitz JD. (2009) Growth-limiting intracellular metabolites in yeast growing under diverse nutrient limitations. Mol Biol Cell. 21: 198-211. PubMed

Kelly RC, Bolitho ME, Higgins DA, Lu W, Ng WL, Jeffrey PD, Rabinowitz JD, Semmelhack MF, Hughson FM, Bassler BL. (2009) The Vibrio cholerae quorum-sensing autoinducer CAI-1: analysis of the biosynthetic enzyme CqsA. Nat Chem Biol. 5: 891-895. PubMed

Yuan J, Doucette CD, Fowler WU, Feng XJ, Piazza M, Rabitz HA, Wingreen NS, Rabinowitz JD. (2009) Metabolomics-driven quantitative analysis of ammonia assimilation in E. coli. Mol Syst Biol. 5: 302. PubMed

Bennett BD, Kimball EH, Gao M, Osterhout R, Van Dien SJ, Rabinowitz JD. (2009) Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli. Nat Chem Biol. 5: 593-599. PubMed

Olszewski KL, Morrisey JM, Wilinski D, Burns JM, Vaidya AB, Rabinowitz JD, Llinás M. (2009) Host-parasite interactions revealed by Plasmodium falciparum metabolomics. Cell Host Microbe. 5: 191-199. PubMed

Bradley PH, Brauer MJ, Rabinowitz JD, Troyanskaya OG. (2009) Coordinated concentration changes of transcripts and metabolites in Saccharomyces cerevisiae. PLoS Comput Biol. 5: e1000270. PubMed

DiMaggio PA Jr, McAllister SR, Floudas CA, Feng XJ, Rabinowitz JD, Rabitz HA. (2008) Biclustering via optimal re-ordering of data matrices in systems biology: rigorous methods and comparative studies. BMC Bioinformatics. 9: 458 PubMed

McAllister SR, Feng XJ, DiMaggio PA Jr, Floudas CA, Rabinowitz JD, Rabitz H. (2008) Descriptor-free molecular discovery in large libraries by adaptive substituent reordering. Bioorg Med Chem Lett. 18: 5967-5970. PubMed

Munger J, Bennett BD, Parikh A, Feng XJ, McArdle J, Rabitz HA, Shenk T, Rabinowitz JD. (2008) Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat Biotechnol. 26: 1179-1186. PubMed

Lu W, Bennett BD, Rabinowitz JD. (2008) Analytical strategies for LC-MS-based targeted metabolomics. J Chromatogr B Analyt Technol Biomed Life Sci. 871: 236-242. PubMed

Kwon YK, Lu W, Melamud E, Khanam N, Bognar A, Rabinowitz JD. (2008) A domino effect in antifolate drug action in Escherichia coli. Nat Chem Biol. 4: 602-608. PubMed

Yuan J, Bennett BD, Rabinowitz JD. (2008) Kinetic flux profiling for quantitation of cellular metabolic fluxes. Nat Protoc. 3: 1328-1340. PubMed

Bennett BD, Yuan J, Kimball EH, Rabinowitz JD. (2008) Absolute quantitation of intracellular metabolite concentrations by an isotope ratio-based approach. Nat Protoc. 3: 1299-1311 PubMed

Waters CM, Lu W, Rabinowitz JD, Bassler BL. (2008) Quorum sensing controls biofilm formation in Vibrio cholerae through modulation of cyclic di-GMP levels and repression of vpsT. J Bacteriol.190: 2527-2536. PubMed

Lu W, Bennett BD, Rabinowitz JD. (2008) Analytical strategies for LC-MS-based targeted metabolomics. J Chromatogr B Analyt Technol Biomed Life Sci. 871: 236-242. PubMed

Rabinowitz JD, Hsiao JJ, Gryncel KR, Kantrowitz ER, Feng XJ, Li G, Rabitz H. (2008) Dissecting enzyme regulation by multiple allosteric effectors: nucleotide regulation of aspartate transcarbamoylase. Biochemistry. 47: 5881-5888. PubMed

Piazza M, Feng XJ, Rabinowitz JD, Rabitz H. (2008) Diverse metabolic model parameters generate similar methionine cycle dynamics. J Theor Biol. 251: 628-639. PubMed

Waters CM, Lu W, Rabinowitz JD, Bassler BL. (2008) Waters CM, Lu W, Rabinowitz JD, Bassler BL. (2008) Quorum sensing controls biofilm formation in Vibrio cholerae through modulation of cyclic di-GMP levels and repression of vpsT. J Bacteriol. 190: 2527-2536. PubMed

Munger J, Bajad SU, Coller HA, Shenk T, Rabinowitz JD (2007). Dynamics of the cellular metabolome during human cytomegalovirus infection. PLoS Pathog 2: e132. PubMed

Rabinowitz JD, Kimball E (2007). Acidic acetonitrile for cellular metabolome extraction from Escherichia coli. Anal Chem 79: 6167-6173. PubMed

Yuan J, Rabinowitz JD (2007). Differentiating metabolites rormed from de novo synthesis versus macromolecule decomposition. J Am Chem Soc 129: 9294-9295. PubMed

Rabinowitz JD (2007). Cellular metabolomics of Escherchia coli. Expert Rev Proteomics 4: 187-198. PubMed

Lu W, Kwon YK, Rabinowitz JD (2007). Isotope ratio-based profiling of microbial folates. J Am Soc Mass Spectrom. PubMed

Xavier KB, Miller ST, Lu W, Kim JH, Rabinowitz J, Pelczer I, Semmelhack MF, Bassler BL (2007) Phosphorylation and processing of the quorum-sensing molecule autoinducer-2 in enteric bacteria. ACS Chem Biol 2: 128-136. PubMed

Bao Q, Lu W, Rabinowitz JD, Shi Y (2007). Calcium blocks formation of apoptosome by preventing nucleotide exchange in Apaf-1. Mol Cell 25: 181-192. PubMed

Hess DC, Lu W, Rabinowitz JD, Botstein D (2006). Ammonium toxicity and potassium limitation in yeast. Ammonium toxicity and potassium limitation in yeast. PLoS Biol 4: e351. PubMed

Brauer MJ, Yuan J, Bennett BD, Lu W, Kimball E, Botstein D, Rabinowitz JD (2006). Conservation of the metabolomic response to starvation across two divergent microbes. Proc Natl Acad Sci 103: 19302-19307. PubMed

Yuan J, Fowler WU, Kimball E, Lu W, Rabinowitz JD (2006). Kinetic flux profiling of nitrogen assimilation in Escherichia coli. Nat Chem Biol 2: 529-530. PubMed

Kimball E, Rabinowitz JD (2006). Identifying decomposition products in extracts of cellular metabolites. Anal Biochem 358: 273-280. PubMed

Rabinowitz JD, Lloyd PM, Munzar P, Myers DJ, Cross S, Damani R, Quintana R, Spyker DA, Soni P, Cassella JV (2006). Ultra-fast absorption of amorphous pure drug aerosols via deep lung inhalation. J Pharm Sci 95: 2438-2451 PubMed

Bajad SU, Lu W, Kimball EH, Yuan J, Peterson C, Rabinowitz JD (2006). Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatography-tandem mass spectrometry. J Chromatogr A 1125: 76-88. PubMed

Lu W, Kimball E, Rabinowitz JD (2006). A high-performance liquid chromatography-tandem mass spectrometry method for quantitation of nitrogen-containing intracellular metabolites. J Am Soc Mass Spectrom 17: 37-50. PubMed

Rabinowitz JD, Wensley M, Lloyd P, Myers D, Shen W, Lu A, Hodges C, Hale R, Mufson D, Zaffaroni A (2004). Fast onset medications through thermally generated aerosols. J Pharmacol Exp Ther 309: 769-775. PubMed

Kasson PM, Rabinowitz JD, Schmitt L, Davis MM and McConnell HM (2000). Kinetics of peptide binding to the class II MHC protein I-Ek. Biochemistry 39: 1048-1058. PubMed

Rabinowitz JD, Vrljic M, Kasson PM, Liang MN, Busch R, Boniface JJ, Davis MM, McConnell HM (1998). Formation of a highly peptide-receptive state of class II MHC. Immunity 9: 699-709. PubMed

Rabinowitz J, Vacchino J, Beeson C and McConnell H (1998). Potentiometric measurement of intracellular redox activity. J Am Chem Soc 120: 2464-2473.

Boniface JJ, Rabinowitz JD, Wulfing C, Hampl J, Reich Z, Altman JD, Kantor RM, Beeson C, McConnell HM, and Davis MM (1998). Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands. Immunity 9: 459-466. PubMed

Rabinowitz JD, Rigler P, Carswell-Crumpton C, Beeson C and McConnell HM (1997). Screening for novel drug effects with a microphysiometer: a potent effect of clofilium unrelated to potassium channel blockade. Life Sci 61: PL87-94. PubMed

Rabinowitz JD, Beeson C, Wulfing C, Tate K, Allen PM, Davis MM, McConnell HM (1996). Altered T cell receptor ligands trigger a subset of early T cell signals. Immunity 5: 125-135. PubMed

Rabinowitz JD, Beeson C, Lyons DS, Davis MM and McConnell HM (1996). Kinetic discrimination in T-cell activation. Proc Natl Acad Sci 93: 1401-1405. PubMed