Department of Chemistry

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Kabirul Islam

Associate Professor

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1307 Chevron Science Center
Chevron Science Center
219 Parkman Avenue

Pittsburgh, PA 15260
412-624-5061

Research Overview

Chemical Approaches towards Understanding Epigenetic Mechanisms in Human Biology and Disease

Organic Synthesis, Bioorganic Chemistry, Small Molecule Therapeutics, Protein Engineering, Structural Biology and ‘Chromatinomics’

Our group, comprised of graduate students, undergraduates and postdoctoral fellows, has built the foundation of a vibrant research program focused on epigenetics. Biochemically, epigenetics is a DNA sequence-independent mechanism that controls the transcriptional potential of a cell by turning genes ‘on’ and ‘off’ and allows cells to access genetic information only when ‘needed’. Cells employ a range of epigenetic mechanisms, most prominent being the covalent chemical modifications on chromatin (DNA and histone complex) such as acetylation and methylation of lysine residues in histones, and cytosine methylation in DNA. We employ a range of small molecules, peptides, proteins, nucleotides and their unnatural analogues towards functional elucidation of chromatin modifications in transcriptional programming and cellular differentiation. With the improved molecular understanding, we plan to employ our methods to edit epigenetic processes for cell fate reprograming as well as correcting aberrant gene expression in human diseases like obesity and cancer. Our interdisciplinary research spans synthetic organic chemistry, protein and oligonucleotide engineering, mechanistic biochemistry, structural and cell biology, proteomics and transcriptomics.

 

Exploring the Functions of Epigenetic Proteins by Unnatural Amino Acid Mutagenesis

In order to respond to fluctuating developmental and environmental cues, cells employ epigenetic machineries for rapid gene regulation by forming transient complexes with essential proteins such as transcription factors. It has remained a significant challenge to characterize these transient interacting partners in cells. We have developed a novel chemoproteomic approach termed ‘interaction-based protein profiling’ (IBPP) by introducing a photo-crosslinkable amino acid (PCAA) into the hydrophobic pocket of epigenetic proteins to crosslink and enrich transient interacting partners that are inaccessible to traditional methods. Applying IBPP, we have uncovered novel BRD4 interactome such as transcription factors, thus providing new mechanistic insights into how BRD4 reprograms gene expression in normal and cancer cells.

Probing the Epigenetic Proteins by Allele-Specific Chemical Genetics

Epigenetic processes are regulated by a wide range of proteins that modify (writers), recognize (readers) and remove (erasers) specific chemical groups (acetyl, methyl, phosphate) in the chromatin landscape with high spatiotemporal control. Interrogating the function of a specific member is of monumental challenge. We are employing allele-specific chemical genetics (also known as analogue-sensitive chemical genetics or ‘bump-hole’ approach) to break the biochemical degeneracy of the homologous proteins through protein-small molecule engineering. We have developed ‘hole-modified’ epigenetic proteins that can be selectively modulated by ‘bumped’ small molecules (activators/inhibitors). We are currently applying these engineered epigenetic machines to reprogram transcriptional activity in human cells to investigate how transcriptional network set by epigenetic regulators control complex biological processes such as the cell cycle, lineage commitment and oncogenesis.

Targeting Metabolic and Epigenetic Proteins for Precision Medicine

Biochemical link between metabolism and epigenetics is becoming increasingly clear. The essential metabolite 2-ketoglutarate (2KG), produced in the tricarboxylic acid (TCA) cycle by isocitrate dehydrogenases 1 (IDH1), serves as cofactor for >40 chromatin demethylases such as Ten-Eleven Translocation (TET), and Fat mass and obesity-associated protein FTO to regulate gene expression. Somatic mutations, overexpression and chromosomal translocation of these proteins drive multiple human conditions particularly cancer and obesity. We have initiated an active research program towards finding chemical inhibitors that selectively target the driver oncogenic mutations in these proteins to develop epigenome-based precision medicine.

Awards

  • Melanoma SPORE Award, UPCI (2015-2016)
  • Winters Foundation Biomedical Research Award (2014)
  • CRDF Award, University of Pittsburgh (2014)
  • Chair's Outstanding Poster Award, Bioorganic Gordon Conference (2011)
  • Visiting Research Fellowship, Starr Cancer Consortium (2010)

Publications

“Examining Interactome Network of BRD1 Bromodomain,” Kuwik, J.; Wagner, S.; Sudhamalla; B.; Islam, K.  RSC Chem. Biol. 2022, 3, 1061-1068
“Allele-Specific Chemical Rescue of of Histone Demethylases Using Abiotic Cofactor,” Scott, V.; Kuwik, J.; Hinkelman, K.; Waldman, M.; Islam, K. ACS. Chem.Biol. 2021
“Catalytic Space Engineering as a Strategy to Activate C−H Oxidation on 5‐Methylcytosine in Mammalian Genome,” Sappa, S.; Dey, D.; Sudhamalla, B.; Islam, K. J. Am. Chem. Soc. 2021, 143, 11891-11896
“Engineering a Methyllysine Reader with Photoactive Amino Acid in Mammalian Cells,” Arora, S.; Sappa, S.; Hinkelman, K.; Islam, K Chem. Commun 2020, 56, 12210-12213
“Engineering Bromodomains with a Photoactive Amino Acid by Engaging Privileged tRNA Synthetases,” Wagner, S.; Sudhamalla, B.; Mannes, P.; Sappa, S.; Kavoosi, S.; Dey, D.; Wang, S.; Islam, K. Chem. Commun. 2020, 56, 3641-3644
“Engineering Methyllysine Writers and Readers for Allele-Specific Regulation of Protein-Protein Interaction,” Arora, A.; Horne, S. W.; Islam, K. J. AM. Chem. Soc 2019, 141 15466-15470
“Synthesis of 5-Dihydroxyboryluridine Phosphoramidite and It's Site-Specific Incorporation into Oligonucleotides for Probing Thymine DNA Glycosylase,” Kavoosi, S.; Dey, D.; Islam, K.  Org. Lett. 2019, 21 6614
“Allele-Specific Inhibition of Histone Demethylases,” Wagner, S.; Breski, M.; Arora A.; Wagn, S.; Scott, V.; Islam, K ChemBioChem 2019, 20 1133-1138
“Site-and Degree-Specific C-H Oxidation on 5-Methylcytosine Homolgues for Probing Active DNA Demethylation,” Kavoosi, S.; Sudhamalla, B.; Dey D.; Shriver, K.; Arora, S.; Sappa, S.; Islam, K Chemical Science 2019, 10 10550-10555
“Probing Ca2+-induced conformational change of calmodulin with gold nanoparticle-decorated single-walled carbon nanotube field-effect transistors,” Shao, W.; Burkert, S. C.; White, D. L.; Scott, V. L.; Ding, J.; Li, Z.; Oyuang, J.; Lapointe, F.; Malenfant, R.L.; Islam, K.; Star, A. Nanoscale 2019, 11 13397-13406
“The Bump-and-Hole Tactic: Expanding the Horizon of Chemical Genetics,”     Islam, K. Cell Chem Biol. 2018, 25, 1171-1184
“Complementary Steric Engineering at the Protein-Ligand Interface for Analogue-Sensitive TET Oxygenases,” Sudhamalla, B.; Wang, S.; Snyder, V.; Kavoosi, S.; Arora, S.; Islam, K. J. Am. Chem. Soc. 2018, 140, 10263-10269
“Site-Specific Azide-Acetyllyisne Photochemistry on Epigenetic Reader Protein BRD4 for Interactome Profiling,” Sudhamalla, B.; Dey, D.; Breski, M.; Nguyen, T.; Islam, K. Chem. Sci. 2017, 8, 4250-4256
“Engineering Biological C-H Functionalization Leads to Allele-Specific Regulation of Histone Demethylases,” Breski, M.; Dey, D.; Obringer, S.; Sudhamalla, B.; Islam, K. J. Am. Chem. Soc. 2016, 138, 13505-13208
“Allele-Specific Chemical Genetics: Concepts, Strategies and Applications,” Islam, K. “.”  2015, 10, 343-363. ACS Chem. Biol. 2015, 10, 343-363
“Defining efficient enzyme-cofactor pairs for bioorthogonal profiling of protein methylation,” Islam, K.; Chen, Y.; Wu, H.; Bothwell, I.; Blum, G.; Zeng, H.; Dong, A.; Zheng, W.; Min, J.; Deng, H.; Luo, M. Proc. Natl. Acad. Sci. USA. 2013, 110, 16778
“Profiling chromatin methylation with engineered posttranslation apparatus within living cells.,” Wang, R.¶; Islam, K.¶; Zheng, W.; Liu, Y.; Tang, H.; Blum, Gil.; Deng, H.; Luo, L. J. Am. Chem. Soc. 2013, 135, 1048
“Se-adenosyl-L-selenomethionine cofactor analogue as a reporter of protein methylation.,” Bothwell, I.; Islam, K.; Cheng, Y.; Zheng, W..; Blum, G.; Deng, H.; Luo, M. J. Am. Chem. Soc. 2012, 134, 14905
“Bioorthogonal profiling of protein methylation using azido derivative of S-adenosyl-L-methionine.,” Islam, K.; Bothwell, I.; Cheng, Y.; Sengelaub, C.; Wang, R.; Deng, H.; Luo, M. J. Am. Chem. Soc. 2012, 134, 5909
“Expanding cofactor repertoire of protein lysine methyltransferase for substrate labeling.,” Islam, K.; Zheng, W.; Yu, H.; Deng, H.; Luo, M. ACS Chem. Biol. 2011, 6, 679
“Myosin V inhibitor based on ‘privileged’ chemical scaffolds.,” Islam, K.; Olivares, A. O.; De La Cruz, E. M.; Kapoor, T. M. Angew. Chem. Int. Ed. Eng. 2010, 49, 8484
“In situ cryo-crystallization of diphenyl ether: C-H…π mediated polymorphic forms.,” Choudhury, A. R.; Islam, K.; Krichner, M. T; Mehta, G.; Guru Row, T. N. J. Am. Chem. Soc. 2004, 126, 12274
“Enantioselective total synthesis of (-)-Epoxyquinols A and B. Novel, convenient access to chiral epoxyquinone building blocks through enzymatic desymmetrization.,” Mehta, G.; Islam, K. Tetrahedron Lett. 2004, 45, 3611
“Total synthesis of the novel NF-κB inhibitor (-)-Cycloepoxydon.,” Mehta, G.; Islam, K. Org. Lett. 2004, 6, 807
“Enantioselective total syntheses of (+) and (-)-ottelione A and (+) and (-)-ottelione B. Absolute configuration of the novel, biologically active natural products.,” Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 6733
“Total Synthesis of epi-Otteliones.,” Mehta, G.; Islam, K. Org. Lett. 2002, 4, 2881
“Total synthesis of (+)-otteliones A and B,” Mehta, G.; Islam, K. Angew. Chem. Int. Ed. Eng. 2002, 41, 2396