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| Rabinowitz Lab Webpage | |
| This e-mail address is being protected from spam bots, you need JavaScript enabled to view it | Faculty Assistant: |
| Carl Icahn Lab-241 | This e-mail address is being protected from spam bots, you need JavaScript enabled to view it |
| Phone: 609-258-8985 | Phone: 609-258-7058 |
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
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. [Epub ahead of print]
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 USA 93: 1401-1405. PubMed