Bachelor of Chemistry, Unlisted School (2015)
Master of Science, Indian Institute of Science Education and Research (2015)
Doctor of Philosophy, Cornell University (2021)
Bachelor of Science, Indian Institute of Science Education and Research (2015)
Master of Science, Cornell University (2017)
Doctor of Philosophy, Cornell University, Chemistry and Chemical Biology (2021)
Dual BS-MS, Indian Institute of Science Education and Research (IISER) - Kolkata, Chemistry (2015)
Longzhi Tan, Postdoctoral Faculty Sponsor
Bibudha Parasar, Lin Han, Pamela V Chang. "United States Patent 17/231, 432 Compositions and methods for profiling of gut-microbiota associated bile salt hydrolase (BSH) activity"
Deconvoluting host-gut microbiota co-metabolism.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
2022; 36 Suppl 1
The metagenome of the gut microbiome encodes tremendous potential for the biosynthesis and transformation of small-molecule metabolites through the activity of many enzymes expressed by the intestinal bacteria. The metabolic activity of this gut bioreactor provides numerous important functions for the host, including breaking down indigestible components of our diet, biosynthesizing essential vitamins and nutrients, and regulating the development of our immune system. Accordingly, elucidating the metabolic potential of the multitude of potential enzymatic reactions is critical for understanding how the activities of the gut microbiota contribute to human health and physiology. Therefore, there is a critical need for new technologies that can determine the enzymatic activities of the gut microbiome because these activities cannot be directly determined by existing metagenomic approaches used to profile microbial taxonomy by genetic content. Activity-based probes, which are mechanism-based covalent tags for enzyme active sites, represent a powerful chemical approach for directly identifying and profiling enzymatic activities. Here, we have developed activity-based probes for a class of cysteine proteases known as bile salt hydrolases (BSHs), which are master regulators of gut microbial transformation of host-derived, or primary, bile acids into a large and diverse group of secondary bile acids. These important metabolites regulate myriad host biological processes, including lipid metabolism, energy metabolism, and immune homeostasis. In addition, changes in bile acid levels are known to accompany different physiological states. However, the role of BSH activity in these processes remains poorly understood due to the lack of adequate tools to address its function. To address this critical gap in knowledge, we have applied our chemical approach to profile BSH activity in gut microbiomes using healthy and diseased samples.
View details for DOI 10.1096/fasebj.2022.36.S1.0I178
View details for PubMedID 35553122
BSH-TRAP: Bile salt hydrolase tagging and retrieval with activity-based probes.
Methods in enzymology
2022; 664: 85-102
Bile acids are important molecules that participate in digestion and regulate many host physiological processes, including metabolism and inflammation. Primary bile acids are biosynthesized from cholesterol in the liver, where they are conjugated to glycine and taurine before secretion into the intestines. A small fraction of these molecules remain in the gut, where they are modified by a microbial enzyme, bile salt hydrolase (BSH), which deconjugates the glycine and taurine groups. This deconjugation precedes all subsequent biotransformation in the intestines, including regioselective dehydroxylation and epimerization reactions, to produce numerous secondary bile acids. Thus, BSH is considered the gatekeeper enzyme of secondary bile acid metabolism, and, as a result, it controls the overall bile acid composition in the host. Despite the critical role that BSH plays in bile acid metabolism, there exist few tools to probe its activity in complex biological mixtures. In this chapter, we describe a chemoproteomic approach termed BSH-TRAP (bile salt hydrolase tagging and retrieval with activity-based probes) that enables visualization and identification of BSH activity in bacteria. Here, we describe application of BSH-TRAP to cultured bacterial strains and the gut microbes derived from mice. We envision that BSH-TRAP could be used to profile changes in BSH activity and identify novel BSH enzymes in complex biological samples, such as the gut microbiome.
View details for DOI 10.1016/bs.mie.2021.12.002
View details for PubMedID 35331380
Engineered Th17 Cell Differentiation Using a Photoactivatable Immune Modulator
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2020; 142 (42): 18103-18108
T helper 17 (Th17) cells, an important subset of CD4+ T cells, help to eliminate extracellular infectious pathogens that have invaded our tissues. Despite the critical roles of Th17 cells in immunity, how the immune system regulates the production and maintenance of this cell type remains poorly understood. In particular, the plasticity of these cells or their dynamic ability to trans-differentiate into other CD4+ T cell subsets remains mostly uncharacterized. Here, we report a synthetic immunology approach using a photoactivatable immune modulator (PIM) to increase Th17 cell differentiation on demand with spatial and temporal precision to help elucidate this important and dynamic process. In this chemical strategy, we developed a latent agonist that upon photochemical activation releases a small-molecule ligand that targets the aryl hydrocarbon receptor (AhR) and ultimately induces Th17 cell differentiation. We used this chemical tool to control AhR activation with spatiotemporal precision within cells and to modulate Th17 cell differentiation on demand using UV light illumination. We envision that this approach will enable an understanding of the dynamic functions and behaviors of Th17 cells in vivo during immune responses and in mouse models of inflammatory disease.
View details for DOI 10.1021/jacs.0c07485
View details for Web of Science ID 000580559000034
View details for PubMedID 32975936
Integrated Regulation of HuR by Translation Repression and Protein Degradation Determines Pulsatile Expression of p53 Under DNA Damage
2019; 15: 342-+
Expression of tumor suppressor p53 is regulated at multiple levels, disruption of which often leads to cancer. We have adopted an approach combining computational systems modeling with experimental validation to elucidate the translation regulatory network that controls p53 expression post DNA damage. The RNA-binding protein HuR activates p53 mRNA translation in response to UVC-induced DNA damage in breast carcinoma cells. p53 and HuR levels show pulsatile change post UV irradiation. The computed model fitted with the observed pulse of p53 and HuR only when hypothetical regulators of synthesis and degradation of HuR were incorporated. miR-125b, a UV-responsive microRNA, was found to represses the translation of HuR mRNA. Furthermore, UV irradiation triggered proteasomal degradation of HuR mediated by an E3-ubiquitin ligase tripartite motif-containing 21 (TRIM21). The integrated action of miR-125b and TRIM21 constitutes an intricate control system that regulates pulsatile expression of HuR and p53 and determines cell viability in response to DNA damage.
View details for DOI 10.1016/j.isci.2019.05.002
View details for Web of Science ID 000470104600030
View details for PubMedID 31103853
View details for PubMedCentralID PMC6548907
Chemoproteomic Profiling of Gut Microbiota-Associated Bile Salt Hydrolase Activity
ACS CENTRAL SCIENCE
2019; 5 (5): 867-873
The metagenome of the gut microbiome encodes tremendous potential for biosynthesizing and transforming small-molecule metabolites through the activities of enzymes expressed by intestinal bacteria. Accordingly, elucidating this metabolic network is critical for understanding how the gut microbiota contributes to health and disease. Bile acids, which are first biosynthesized in the liver, are modified in the gut by enzymes expressed by commensal bacteria into secondary bile acids, which regulate myriad host processes, including lipid metabolism, glucose metabolism, and immune homeostasis. The gateway reaction of secondary bile acid biosynthesis is mediated by bile salt hydrolases (BSHs), bacterial cysteine hydrolases whose action precedes other bile acid modifications within the gut. To assess how changes in bile acid metabolism mediated by certain intestinal microbiota impact gut physiology and pathobiology, methods are needed to directly examine the activities of BSHs because they are master regulators of intestinal bile acid metabolism. Here, we developed chemoproteomic tools to profile changes in gut microbiome-associated BSH activity. We showed that these probes can label active BSHs in model microorganisms, including relevant gut anaerobes, and in mouse gut microbiomes. Using these tools, we identified altered BSH activities in a murine model of inflammatory bowel disease, in this case, colitis induced by dextran sodium sulfate, leading to changes in bile acid metabolism that could impact host metabolism and immunity. Importantly, our findings reveal that alterations in BSH enzymatic activities within the gut microbiome do not correlate with changes in gene abundance as determined by metagenomic sequencing, highlighting the utility of chemoproteomic approaches for interrogating the metabolic activities of the gut microbiota.
View details for DOI 10.1021/acscentsci.9b00147
View details for Web of Science ID 000468624100018
View details for PubMedID 31139722
View details for PubMedCentralID PMC6535767
Chemical optogenetic modulation of inflammation and immunity
2017; 8 (2): 1450-1453
The immune system is an essential component of host defense against pathogens and is largely mediated by inflammatory molecules produced by immune cells, such as macrophages. These inflammatory mediators are regulated at the transcriptional level by chromatin-modifying enzymes including histone deacetylases (HDACs). Here we describe a strategy to regulate inflammation and immunity with photocontrolled HDAC inhibitors, which can be selectively delivered to target cells by UV irradiation to minimize off-target effects. We strategically photocaged the active moiety of an HDAC inhibitor and showed that mild UV irradiation leads to the selective release of the inhibitor in a spatiotemporal manner. This methodology was used to decrease the amount of pro-inflammatory mediators produced by a subpopulation of macrophages. Our approach could ultimately be used to control inflammation in vivo as a therapeutic for inflammatory diseases, while minimizing off-target effects to healthy tissues.
View details for DOI 10.1039/c6sc03702j
View details for Web of Science ID 000395428300073
View details for PubMedID 28451285
View details for PubMedCentralID PMC5390787
BSH-TRAP: Bile salt hydrolase tagging and retrieval with activity-based probes
CHEMICAL MICROBIOLOGY, PT A
2022; 664: 85-102
View details for Web of Science ID 000890950200005
- Finding the Sweet Spot for Breast Cancer Detection ACS CENTRAL SCIENCE 2020; 6 (12): 2123-2125
- Microwave assisted cross-coupling reactions using palladium nanoparticles in aqueous media SYNTHETIC COMMUNICATIONS 2019; 49 (6): 859-868
- Bipyridine Facilitates Regioselective Dimerization of Alkynes in the Absence of Transition Metal CHEMISTRYSELECT 2017; 2 (18): 5032-5037
Transcript degradation and noise of small RNA-controlled genes in a switch activated network in Escherichia coli
NUCLEIC ACIDS RESEARCH
2016; 44 (14): 6707-6720
Post-transcriptional regulatory processes may change transcript levels and affect cell-to-cell variability or noise. We study small-RNA downregulation to elucidate its effects on noise in the iron homeostasis network of Escherichia coli In this network, the small-RNA RyhB undergoes stoichiometric degradation with the transcripts of target genes in response to iron stress. Using single-molecule fluorescence in situ hybridization, we measured transcript numbers of the RyhB-regulated genes sodB and fumA in individual cells as a function of iron deprivation. We observed a monotonic increase of noise with iron stress but no evidence of theoretically predicted, enhanced stoichiometric fluctuations in transcript numbers, nor of bistable behavior in transcript distributions. Direct detection of RyhB in individual cells shows that its noise is much smaller than that of these two targets, when RyhB production is significant. A generalized two-state model of bursty transcription that neglects RyhB fluctuations describes quantitatively the dependence of noise and transcript distributions on iron deprivation, enabling extraction of in vivo RyhB-mediated transcript degradation rates. The transcripts' threshold-linear behavior indicates that the effective in vivo interaction strength between RyhB and its two target transcripts is comparable. Strikingly, the bacterial cell response exhibits Fur-dependent, switch-like activation instead of a graded response to iron deprivation.
View details for DOI 10.1093/nar/gkw273
View details for Web of Science ID 000382999900020
View details for PubMedID 27085802
View details for PubMedCentralID PMC5001584
Chiral carbon dots derived from guanosine 5 '-monophosphate form supramolecular hydrogels
2016; 52 (74): 11159-11162
Guanosine 5'-monophosphate, (5'-GMP), is a self-assembling natural nucleotide that has unique potential to form ordered supramolecular structures. We herein describe an intriguing property of Na2(5'-GMP) to form blue emitting chiral carbon dots (G-dots) that exhibit excitation dependent down-conversion and up-conversion fluorescence signature and self-assemble to form fluorescent hydrogels.
View details for DOI 10.1039/c6cc05947c
View details for Web of Science ID 000384202000029
View details for PubMedID 27560935
- A copper based catalyst for poly-urethane synthesis from discarded motherboard RSC ADVANCES 2016; 6 (79): 75749-75756
- MICRO-OPTOMECHANICAL MOVEMENTS (MOMs) WITH SOFT OXOMETALATES (SOMs): CONTROLLED MOTION OF SINGLE SOFT OXOMETALATE PEAPODS USING EXOTIC OPTICAL POTENTIALS JOURNAL OF MOLECULAR AND ENGINEERING MATERIALS 2014; 2 (1)
Ligand mediated iron catalyzed dimerization of terminal aryl alkynes: scope and limitations
ORGANIC & BIOMOLECULAR CHEMISTRY
2014; 12 (11): 1812-1822
Regioselective dimerization of terminal aryl alkynes to produce conjugated enynes has been achieved using FeCl3 and KO(t)Bu in the presence of either DMEDA or dppe. The reaction proceeds smoothly in toluene at 145 °C for 2 h to give the corresponding head-to-head dimers in good to excellent yields (54 to 99%) with high E-selectivity (67 : 33 to 83 : 17 E/Z). Both strongly electron-donating and electron-withdrawing groups are compatible with this procedure. The bidentate phosphine (dppe) ligand exhibits better catalytic activity than the bidentate amine (DMEDA). The aliphatic acetylene fails to react under this catalytic system which suggests that potassium tertiary butoxide activates the conjugated system of aryl acetylene through cation-pi interaction and pi-pi interaction. A radical inhibitor (galvinoxyl or TEMPO) completely suppresses the reaction. Employing FeCl2 as a catalyst instead of FeCl3, only phenyl acetylene afforded the corresponding head to head dimer in good yield. Mechanistic pathways for both FeCl3 catalyzed dimerization of aryl alkynes and FeCl2 catalyzed dimerization of phenyl acetylene have been proposed.
View details for DOI 10.1039/c3ob42365d
View details for Web of Science ID 000332225500018
View details for PubMedID 24514585
pH dependent multifunctional and multiply-configurable logic gate systems based on small molecule G-quadruplex DNA recognition
2013; 49 (18): 1817-1819
A variety of logic operations such as XNOR, NOR, AND, NAND, NOT have been designed with pH as an external modulator by choosing thiazole orange (TO) and a c-kit2 promoter quadruplex as two inputs and fluorescence signals of pyridyl bis-indole amide (PBIA) and TO as two outputs.
View details for DOI 10.1039/c3cc38888c
View details for Web of Science ID 000314650100010
View details for PubMedID 23358682
- Reduction of organic azides to amines using reusable Fe3O4 nanoparticles in aqueous medium CATALYSIS SCIENCE & TECHNOLOGY 2013; 3 (3): 584-588