Adam Frankel

Prospective Graduate Students / Postdocs

This faculty member is currently not actively recruiting graduate students or Postdoctoral Fellows, but might consider co-supervision together with another faculty member.

Associate Professor

Research Interests

Biological and Biochemical Mechanisms
Bioactive Molecules
Organic Molecules and Biomolecules
arginine methylation
Chemical Biology
drug discovery
post-translational modifications
Protein Biochemistry

Relevant Degree Programs


Great Supervisor Week Mentions

Each year graduate students are encouraged to give kudos to their supervisors through social media and our website as part of #GreatSupervisorWeek. Below are students who mentioned this supervisor since the initiative was started in 2017.


Thank you so much, Adam, for your friendly supervision during the last years!!

Nelson Gorrin (2019)


Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2020)
Searching for Inhibitors of the Protein Arginine Methyl Transferases: Synthesis and Characterisation of Peptidomimetic Ligands (2016)

Within the last two decades research in the field of epigenetics has increased significantly as targeting the epigenetic enzymes has the potential to alter the transcription of genes. Aberrant regulation of transcription is seen in several disease states, and drugs targeting the epigenetic histone deacetylases and DNA methylases are already marketed for cancer treatment. The Protein Arginine Methyl Transferases (PRMTs) belong to an epigenetic enzyme family that is upregulated in several cancers. However, currently no inhibitors of the PRMTs have been marketed. In this thesis several peptidomimetic strategies were utilised to modify the tryptophan residues in two peptide leads in order to discover new inhibitors of the PRMTs. One of these strategies involved constraining the side chain indole of tryptophan to the peptide backbone, thus producing a seven membered azepinone mimetic, Aia. The peptidomimetic efforts resulted in a structure-activity relationship study from which a constrained peptidomimetic containing two Aias was discovered to be a low micromolar inhibitor of several PRMTs. To characterise the inhibitor the conformation of the inhibitor was examined using solution-phase NMR and was shown to display an interesting turn-structure. The original peptide lead was fluorescently tagged and investigated in a cellular setting, but did not reveal any PRMT-specific localisation.In an effort to study the binding of the discovered inhibitor with the PRMTs, protein expression in E. coli and purification was performed. This resulted in the optimisation of PRMT6 purification in order to obtain highly pure PRMT6 for isothermal titration calorimetry (ITC) studies. Unfortunately these ITC studies were unsuccessful.Furthermore, as the constrained tryptophan mimetic had proven very useful in the peptidomimetic inhibitors of the PRMTs, we attempted to synthesise a lysine/arginine dipeptide mimetic using aziridine chemistry.

View record

The PRMT response to inflammation: substrate methylation and alternative splicing (2016)

Protein arginine N-methyltransferases (PRMTs) are a family of enzymes involved in signaling pathways and gene expression by methylating arginine residues of substrate proteins. PRMT2 has been demonstrated to play a role in the NF-κB signaling pathway. Moreover, our lab recently revealed association using proteomic techniques between PRMT2 and splicing factors including Src-associated in mitosis 68 kDa protein (SAM68) that mediates the alternative splicing of BCL-X involved in the NF-κB mediated inflammatory pathway. I wanted to investigate if the PRMT activity plays a role in response to inflammation under the treatment of inflammatory cytokine tumor necrosis factor-α (TNF-α) or pro-inflammatory bacterial lipopolysaccharide (LPS) in A549 cells. My proteomic experiments revealed that TNF-α and LPS cause similar changes to arginine methylation for proteins primarily involved in mRNA processing, RNA splicing, and nuclear transport, indicating that these two inflammatory stimuli share mutual downstream pathways involving methyltransferase activity. Among the proteins that showed hypermethylation upon treatment relative to control in mass spectrometry analysis, GAP SH3 domain-binding protein 2 (G3BP2) showed consistently in all three replicates on average a 1.5-fold increase in methylation at the R468 site in both TNF-α and LPS-treated cells. G3BP2 binds to IκB-α and prevents NF-κB translocation into the nucleus for subsequent signaling. G3BP2 methylation was necessary for signaling to occur in the Wnt/β-catenin signaling pathway. Methylation of G3BP2 might also have similar role in the inflammatory pathway that demands further study. Moreover, consistent with an inflammatory response, proteins particularly involved in innate immunity and viral response increased upon TNF-α treatment that could be related to the observed change in methylation of proteins involved in RNA processing. Our finding that PRMT2 interacts with SAM68, prompted me to investigate the potential role of PRMT2 in BCL-X alternative splicing. I found that reduced expression of PRMT2 by siRNA caused a decrease in the BCL-X(L)/BCL-X(s) ratio, suggesting that PRMT2 may contribute to BCL-X alternative splicing. This effect was replicated in TNF-α or LPS stimulated cells when PRMT2 expression was reduced by shRNA, and reversed when PRMT2 expression was increased. These results indicate that PRMT2 may play a role during inflammation in alternative splicing regulation.

View record

Oligomerization dependent enzyme kinetics and mechanistic characterization of type I protein arginine n-methytransferases (2013)

Protein arginine N-methyltransferases (PRMTs) constitute a family of post-translationalmodifying enzymes that modulate protein-protein interactions via the addition of methyl groupsto arginine residues in protein substrates (1). PRMTs have been demonstrated to homooligomerizevia a dimerization arm that binds with the outer surface of the S-adenosyl-Lmethionine(AdoMet) binding domain (2-5). In this body of work, I have demonstrated andquantified in vitro the strength of homodimerization for PRMT1 and PRMT6 and demonstratedthat saturating concentrations of S-adenosyl-L-methionine (AdoMet) or S-adenosyl-Lhomocysteine(AdoHcy) respectively strengthen or weaken this interaction. This findingsupports an ordered bisubstrate mechanism in which AdoMet binding promotes formation of thecomplete peptide-substrate binding groove through dimerization, and AdoHcy generationpromotes dissociation of the dimeric complex and turnover of substrate.A kinetic study using HIV Tat peptides revealed oligomerization-dependent kineticpatterns with these substrates. Kinetic experiments were initially performed on HIV Tat peptidewith novel ωN-substitutions to probe their ability to inhibit PRMT1, 4 and 6. It was found thatthese Tat-peptides act as substrate inhibitors for both PRMT1 and PRMT6 and that this substrateinhibition was mitigated as the enzyme concentration increased. A model was proposed thatrepresents activity as the sum of each ordered oligomer in solution, with the monomer beinguniquely susceptible to substrate inhibition.Diverging from strictly oligomerization effects, R1 fibrillarin-like peptide containing asingle arginine was substituted to alter the pKa of the terminal guanidino group to better probethe physicochemical properties that control methyltransfer. Surprisingly, hydroxyl substitutedR1 peptide demonstrated an enhanced catalytic constant with PRMT1. MS and MS² experiments demonstrate that only monomethylation occurs on substituted arginines with PRMT1, and that this addition is asymmetric. PRMT1 D51N, a catalytically compromised mutant, revealed the kcat as rate limiting in the presence of D₂O, and electrostatic potential maps indicate that deprotonation of hydroxyl substituted arginine produces a strong nucleophile capable of enhanced methyltransfer.Altogether, these studies support water mediated, ordered bisubstrate mechanism in which oligomerization modulates activity. Substrate inhibition and active site chemistry were investigated using novel chemically substituted peptide probes that highlight trends beyond what site-directed mutagenesis can reveal alone.

View record

Insights into a heteronomic protein arginine N-methyltransferase complex (2012)

Protein arginine N-methyltransferases (PRMTs) act in signaling pathways and geneexpression by methylating arginine residues within target proteins. PRMT1 is responsible formost cellular arginine methylation activity and can work independently or in collaboration withother PRMTs. In this Ph.D. thesis I demonstrated an interaction between PRMT1 and -2 usingco-immunoprecipitation and bimolecular fluorescence complementation (BiFC). As a result ofthis interaction, PRMT2 stimulated PRMT1 methyltransferase activity, affecting its apparentVmax and Km values in vitro, and increasing the production of methylarginines in cells. Activesite mutations and regional deletions on PRMT1 and -2 were also investigated, whichdemonstrated that complex formation required full-length, active PRMT1. However, theinteraction between PRMT1 and -2 proved insensitive to methylation inhibition in the absence ofthe PRMT2 Src homology 3 (SH3) domain, which suggests that the PRMT2 SH3 domain maymediate this interaction between PRMT1 and -2 in a methylation-dependent fashion.The role of the PRMT2 SH3 domain was investigated through screening for its associatedproteins using GST-pull down assays followed by LC-MS/MS proteomic analysis. The result ofthis study revealed associations of the PRMT2 SH3 domain with at least 29 splicing-relatedproteins, suggesting a potential role of PRMT2 in regulating pre-mRNA processing and splicing.The interaction between PRMT2 and the Src substrate associated in mitosis of 68 kDa (Sam68)possibly through the PRMT2 SH3 domain was demonstrated using co-immunoprecipitation.Additionally, immunofluorescence results present herein imply that the PRMT2 SH3 domaincould affect Sam68 sub-cellular localization in hypomethylated HeLa cells. The biological functions of PRMT2 and the PRMT1/2 heteromeric complex were exploredby pursuing the identity of associated proteins common to both PRMT1 and -2 using massspectrometry proteomics. Approximately 50% of the identified protein hits have reported rolesin controlling gene expression, while other hits are involved in diverse cellular processes such asprotein folding, degradation, and metabolism. Importantly, three novel PRMT2 binders, p53,promyelocytic leukemia protein (PML), and extra eleven nineteen (EEN) were uncovered,suggesting that PRMT2 could participate in regulation of transcription and apoptosis throughPRMT2-protein interactions.

View record

Master's Student Supervision (2010 - 2018)
Evaluation of Ginsenosides in Transactivation and Transrepression of Human Glucocorticoid Receptor Alpha (2016)

Ginsenosides are pharmacologically active compounds in ginseng, a medicinal herb that is highly valued and widely consumed. They are reported to have diverse effects, including neuromodulation, anticancer, and immunomodulation. Glucocorticoid receptor (GR) is a nuclear receptor involved in transcriptional regulation of genes in numerous important physiological processes, such as stress-related homeostasis, gluconeogenesis, bone remodeling, and anti-inflammation. Previous research suggested ginsenosides as agonists of rodent GRα. Studies on human GRα (hGRα) mainly focused on a single ginsenoside and its effect on either hGRα-mediated transactivation or transrepression. However, only a few ginsenosides (compound K, Rh1, Rh2, Re, Rg1) were examined and it is not known whether ginsenosides activate hGRα in an analog-selective manner. In this study, seven protopanaxadiol (PPD)-type ginsenosides (Rb1, Rb2, Rc, Rd, compound K, Rh2, PPD) and five protopanaxatriol (PPT)-type ginsenosides (Re, Rf, Rg1, Rh1, PPT) were investigated to determine whether they act as functional ligands of hGRα for both its transactivation and transrepression activity. In vitro time resolved-fluorescence resonance energy transfer (TR-FRET) competitive ligand-binding assay revealed that ginsenosides can weakly bind to the ligand-binding domain of hGRα. Among the selected ginsenosides, monoglycosylated PPD-type ginsenosides compound K and Rh2 exhibited strongest binding to the receptor. Dual-luciferase reporter gene assays employing firefly luciferase reporter vectors carrying either glucocorticoid response element or NF-κB response element were conducted in human colon adenocarcinoma cells (LS180). None of the ginsenosides increased or attenuated hGRα-mediated transactivation or transrepression activity. Furthermore, hGRα target gene (hTAT and hCBG) expression was studied in human hepatocellular carcinoma cells (HepG2) and quantified by real-time PCR. The data indicated that ginsenoside Rh2 did not influence hGRα target gene expression. In summary, among all PPD-type ginsenosides (Rb1, Rb2, Rc, Rd, compound K, Rh2, PPD) and PPT-type ginsenosides (Re, Rf, Rg1, Rh1, PPT) tested, monoglycosylated PPD-type ginsenosides compound K and Rh2 exhibited stronger binding to hGRα-LBD, while others could only bind weakly. Nevertheless, none of the ginsenosides could modulate hGRα activity or affect target gene expression. Therefore, these ginsenosides are not functional ligands of hGRα in LS180 and HepG2 cells.

View record

Recent Tri-Agency Grants

The following is a selection of grants for which the faculty member was principal investigator or co-investigator. Currently, the list only covers Canadian Tri-Agency grants from years 2013/14-2016/17 and excludes grants from any other agencies.

  • Dynamics of Arginine Methylation in Cellular Processes - Natural Sciences and Engineering Research Council of Canada (NSERC) - Discovery Grants Program - Individual (2015/2016)
  • Dynamics of arginine methylation in cellular processes - Natural Sciences and Engineering Research Council of Canada (NSERC) - Discovery Grants Program - Individual (2014/2015)



If this is your researcher profile you can log in to the Faculty & Staff portal to update your details and provide recruitment preferences.


Get key application advice, hear about the latest research opportunities and keep up with the latest news from UBC's graduate programs.!