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School of Pharmacy

team: Medicinal Chemistry Faculty

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Gaurav Bhardwaj

Education

B.Tech in Biotechnology, GGS Indraprastha University, Delhi
PhD in Integrative Biosciences, Pennsylvania State University
Postdoctoral work at the University of California, Davis, and University of Washington, Seattle.

Biography

Gaurav received his doctoral degree in Integrative Biosciences from the Pennsylvania State University. During graduate school, he developed computational methods for studying evolution of highly divergent protein families. He did his postdoc with Dr. Kit Lam at University of California, Davis and Dr. David Baker at University of Washington, Seattle. His postdoctoral work focused on computational design of hyperstable constrained peptides and macrocycles with atomic-level accuracy.

Research Interests

  • Computational peptide design for enhanced cell permeability, oral bioavailability, and blood-brain barrier traversal
  • High-throughput design of targeted peptide therapeutics

Taking Students: Yes

Selected Publications

Accurate de novo design of high-affinity protein-binding macrocycles using deep learning. Rettie SA, Juergens D, Adebomi V, Bueso YF, Zhao Q, Leveille AN, Liu A, Bera AK, Wilms JA, Üffing A, Kang A, Brackenbrough E, Lamb M, Gerben SR, Murray A, Levine PM, Schneider M, Vasireddy V, Ovchinnikov S, Weiergräber OH, Willbold D, Kritzer JA, Mougous JD, Baker D, DiMaio F, Bhardwaj G. Nat Chem Biol. 2025 Jun 20. doi: 10.1038/s41589-025-01929-w. Online ahead of print.

Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase. Craven TW, Nolan MD, Bailey J, Olatunji S, Bann SJ, Bowen K, Ostrovitsa N, Da Costa TM, Ballantine RD, Weichert D, Levine PM, Stewart LJ, Bhardwaj G, Geoghegan JA, Cochrane SA, Scanlan EM, Caffrey M, Baker D.ACS Chem Biol. 2024 May 7. doi: 10.1021/acschembio.4c00076. Online ahead of print.

Expansive discovery of chemically diverse structured macrocyclic oligoamides.Salveson PJ, Moyer AP, Said MY, Gӧkçe G, Li X, Kang A, Nguyen H, Bera AK, Levine PM, Bhardwaj G, Baker D.Science. 2024 Apr 26;384(6694):420-428. doi: 10.1126/science.adk1687. Epub 2024 Apr 25.

A Tag-Free Platform for Synthesis and Screening of Cyclic Peptide Libraries.Bruce A, Adebomi V, Czabala P, Palmer J, McFadden WM, Lorson ZC, Slack RL, Bhardwaj G, Sarafianos SG, Raj M.Angew Chem Int Ed Engl. 2024 Mar 26:e202320045. doi: 10.1002/anie.202320045. Online ahead of print.

Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor. Muratspahić E, Deibler K, Han J, Tomašević N, Jadhav KB, Olivé-Marti AL, Hochrainer N, Hellinger R, Koehbach J, Fay JF, Rahman MH, Hegazy L, Craven TW, Varga BR, Bhardwaj G, Appourchaux K, Majumdar S, Muttenthaler M, Hosseinzadeh P, Craik DJ, Spetea M, Che T, Baker D, Gruber CW.Nat Commun. 2023 Dec 6;14(1):8064.

Cell-permeable chameleonic peptides: Exploiting conformational dynamics in de novo cyclic peptide design. Ramelot TA, Palmer J, Montelione GT, Bhardwaj G. Curr Opin Struct Biol. 2023 Jun;80:102603. doi: 10.1016/j.sbi.2023.102603. Epub 2023 May 12.

Cyclic peptide structure prediction and design using AlphaFold. Rettie SA, Campbell KV, Bera AK, Kang A, Kozlov S, De La Cruz J, Adebomi V, Zhou G, DiMaio F, Ovchinnikov S, Bhardwaj G.bioRxiv. 2023 Feb 26:2023.02.25.529956. doi: 10.1101/2023.02.25.529956. Preprint.

Accurate de novo design of membrane-traversing macrocycles. Bhardwaj G, O’Connor J, Rettie S, Huang YH, Ramelot TA, Mulligan VK, Alpkilic GG, Palmer J, Bera AK, Bick MJ, Di Piazza M, Li X, Hosseinzadeh P, Craven TW, Tejero R, Lauko A, Choi R, Glynn C, Dong L, Griffin R, van Voorhis WC, Rodriguez J, Stewart L, Montelione GT, Craik D, Baker D. Cell. 2022 Sep 15;185(19):3520-3532.e26. doi: 10.1016/j.cell.2022.07.019. Epub 2022 Aug 29.

Comprehensive computational design of ordered peptide macrocycles. Hosseinzadeh P, Bhardwaj G, Mulligan VK, Shortridge MD, Craven TW, Pardo-Avila F, Rettie SA, Kim DE, Silva DA, Ibrahim YM, Webb IK, Cort JR, Adkins JN, Varani G, Baker D. Science. 2017 Dec 15;358(6369):1461-1466. doi: 10.1126/science.aap7577.

A Novel Galectin-1 Inhibitor Discovered through One-Bead Two-Compound Library Potentiates the Antitumor Effects of Paclitaxel in vivo.  Shih TC, Liu R, Fung G, Bhardwaj G, Ghosh PM, Lam KS. Mol Cancer Ther. 2017 Jul;16(7):1212-1223. doi: 10.1158/1535-7163.MCT-16-0690. Epub 2017 Apr 10.

Accurate de novo design of hyperstable constrained peptides. Bhardwaj G, Mulligan VK, Bahl CD, Gilmore JM, Harvey PJ, Cheneval O, Buchko GW, Pulavarti SV, Kaas Q, Eletsky A, Huang PS, Johnsen WA, Greisen PJ, Rocklin GJ, Song Y, Linsky TW, Watkins A, Rettie SA, Xu X, Carter LP, Bonneau R, Olson JM, Coutsias E, Correnti CE, Szyperski T, Craik DJ, Baker D. Nature. 2016 Oct 20;538(7625):329-335. doi: 10.1038/nature19791. Epub 2016 Sep 14.

Protection of the Furin Cleavage Site in Low-Toxicity Immunotoxins Based on Pseudomonas Exotoxin A. Kaplan G, Lee F, Onda M, Kolyvas E, Bhardwaj G, Baker D, Pastan I. Toxins (Basel). 2016 Jul 25;8(8). pii: E217. doi: 10.3390/toxins8080217.

Covalent Chemical Ligation Strategy for Mono- and Polyclonal Immunoglobulins at Their Nucleotide Binding Sites. Lac D, Feng C, Bhardwaj G, Le H, Tran J, Xing L, Fung G, Liu R, Cheng H, Lam KS. Bioconjug Chem. 2016 Jan 20;27(1):159-69. doi: 10.1021/acs.bioconjchem.5b00574. Epub 2015 Dec 17.

Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor. Guo W, Liu R, Bhardwaj G, Yang JC, Changou C, Ma AH, Mazloom A, Chintapalli S, Xiao K, Xiao W, Kumaresan P, Sanchez E, Yeh CT, Evans CP, Patterson R, Lam KS, Kung HJ. Cell Death Dis. 2014 Sep 4;5:e1409. doi: 10.1038/cddis.2014.343.

PHYRN: a robust method for phylogenetic analysis of highly divergent sequences. Bhardwaj G, Ko KD, Hong Y, Zhang Z, Ho NL, Chintapalli SV, Kline LA, Gotlin M, Hartranft DN, Patterson ME, Dave F, Smith EJ, Holmes EC, Patterson RL, van Rossum DB. PLoS One. 2012;7(4):e34261. doi: 10.1371/journal.pone.0034261. Epub 2012 Apr 13.

Additional Publications

Libin Xu

Education

  • Postdoctoral training, Vanderbilt University
  • Ph.D. in Organic Chemistry, University of Illinois at Chicago
  • B.Sc. in Chemistry, Nankai University

Courses Taught

  • MEDCH/PCEUT 327
  • MEDCH 562
  • MEDCH 529
  • MEDCH 541
  • MEDCH 582
  • MEDCH 500

Research Interests

  • Mechanisms and products of lipid oxidation
  • Cholesterol biosynthesis disorders, in particular, Smith-Lemli-Opitz syndrome
  • Effect of drugs on lipid metabolism
  • Metabolomics and Lipidomics using ion mobility-mass spectrometry
  • Lipid metabolism in neurodevelopment
  • Mechanisms of antibiotic resistance

Taking Students: Yes

Biography

Dr. Xu was trained as an organic chemist early in his career, but during his postdoctoral training at Vanderbilt University, his research expanded to chemistry and biology of lipid peroxidation underlying human diseases, as well as mass spectrometry-based lipidomics.

The Xu lab is interested in the consequences of unusual lipid metabolism and oxidation processes on the nervous system, which could result from genetic mutations or small molecule interference. The lab aims to develop interventions that could ameliorate or reverse the adverse effects of the disrupted lipid homeostasis and oxidized lipids. The Xu lab is also interested in elucidating the contribution of altered lipid metabolism to antibiotic resistance in bacterial pathogens using mass spectrometry and molecular biology methodologies, aiming to develop strategies to re-sensitize the resistant bacteria. On the analytical chemistry side, the Xu Lab develops novel methodologies for the analysis of lipids, metabolites, drugs, and drug metabolites using ion mobility-mass spectrometry to meet the needs of our biological problems.

Dr. Xu is the recipient of the NIH Pathway to Independence Award from NICHD in 2012 and the Young Investigator Award from the Society for Free Radical Biology and Medicine in 2011. He is also the inaugural recipient, together with Prof. Brian Werth, of the School of Pharmacy Faculty Innovation Fund in 2016. He received this award again, with Dr. Edward Kelly, in 2020.

Recent Publications

Examining the Nephrotoxicity Induced by Benzalkonium Chlorides in 2D and 3D-Cultured Human Proximal Tubule Epithelial Cells Brzoska M, Seguin RP, Yang J, Kelly E, Xu L. J Pharmacol Exp Ther. 2025 Mar, Volume 392, Issue 3, DOI: 10.1016/j.jpet.2024.101674

Respective Roles of CYP4F2 and CYP2D6 in the Formation of Even- and Odd-Carbon Carboxylic Acid Metabolites of Benzalkonium Chloride in Human Hepatocytes  Zhu L, Seguin RP, Xu L. J Pharmacol Exp Ther. 2025 Mar, Volume 392, Issue 3, DOI: 10.1016/j.jpet.2024.101708

Interaction of Benzalkonium Chlorides with CYP168A1 of Pseudomonas aeruginosa Seguin RP, Kandel SE, Lampe JN, Xu L. J Pharmacol Exp Ther. 2025 Mar, Volume 392, Issue 3, DOI: 10.1016/j.jpet.2025.103508

A Multidimensional Database for Biomonitoring of Quaternary Ammonium Compounds and Their Phase I Metabolites in Human Feces Nguyen R, Liu X, Liem L, Lin YS, Xu L. J Pharmacol Exp Ther. 2025 Mar, Volume 392, Issue 3, DOI: 10.1016/j.jpet.2024.101672

PubChemLite Plus Collision Cross Section (CCS) Values for Enhanced Interpretation of Nontarget Environmental Data. Elapavalore A, Ross DH, Grouès V, Aurich D, Krinsky AM, Kim S, Thiessen PA, Zhang J, Dodds JN, Baker ES, Bolton EE, Xu L, Schymanski EL. Environ Sci Technol Lett. 2025 Jan 24;12(2):166-174.

Simulated exposures of oritavancin in in vitro pharmacodynamic models select for methicillin-resistant Staphylococcus aureus with reduced susceptibility to oritavancin but minimal cross-resistance or seesaw effect with other antimicrobials. Werth BJ, Zhang R, Barreras Beltran IA, Penewit K, Waalkes A, Holmes EA, Salipante SJ, Xu L. J Antimicrob Chemother. 2025 Feb 12:dkaf042.

Growth of Staphylococcus aureus in the presence of oleic acid shifts the glycolipid fatty acid profile and increases resistance to antimicrobial peptides. Raskovic D, Alvarado G, Hines KM, Xu L, Gatto C, Wilkinson BJ, Pokorny A. Biochim Biophys Acta Biomembr. 2025 Jan;1867(1):184395.

Empirically establishing drug exposure records directly from untargeted metabolomics data. Zhao HN, Kvitne KE, … Xu L, Knight R, Tsunoda SM, Dorrestein PC. bioRxiv [Preprint]. 2024 Oct 26:2024.10.07.617109.

Molecular basis of cell membrane adaptation in daptomycin-resistant Enterococcus faecalis. Nguyen AH, Tran TT, Panesso D, Hood KS, Polamraju V, Zhang R, Khan A, Miller WR, Mileykovskaya E, Shamoo Y, Xu L, Vitrac H, Arias CA. JCI Insight. 2024 Nov 22;9(22):e173836.

Oral exposure to benzalkonium chlorides in male and female mice reveals alteration of the gut microbiome and bile acid profile. Lopez VA, Lim JJ, Seguin RP, Dempsey JL, Kunzman G, Cui JY, Xu L. Toxicol Sci. 2024 Dec 1;202(2):265-277.

Acetyl-CoA carboxylase inhibition increases retinal pigment epithelial cell fatty acid flux and restricts apolipoprotein efflux. Hass DT, Pandey K, Engel A, Horton N, Haydinger CD, Robbings BM, Lim RR, Sadilek M, Zhang Q, Gulette GA, Li A, Xu L, Miller JML, Chao JR, Hurley JB. J Biol Chem. 2024 Oct;300(10):107772.

Several common methods of making vesicles (except an emulsion method) capture intended lipid ratios. Weakly HMJ, Wilson KJ, Goetz GJ, Pruitt EL, Li A, Xu L, Keller SL. Biophys J. 2024 Oct 1;123(19):3452-3462.

Erratum: How do different lipid peroxidation mechanisms contribute to ferroptosis? Do Q, Xu L. Cell Rep Phys Sci. 2024 May 15;5(5):101932.

Membrane Lipids Augment Cell Envelope Stress Signaling via the MadRS System to Defend Against Antimicrobial Peptides and Antibiotics in Enterococcus faecalis. Miller WR, Nguyen A, Singh KV, Rizvi S, Khan A, Erickson SG, Egge SL, Cruz M, Dinh AQ, Diaz L, Thornton PC, Zhang R, Xu L, Garsin DA, Shamoo Y, Arias CA. J Infect Dis. 2024 Apr 5:jiae173.

Development and Application of a Multidimensional Database for the Detection of Quaternary Ammonium Compounds and Their Phase I Hepatic Metabolites in Humans. Nguyen R, Seguin RP, Ross DH, Chen P, Richardson S, Liem J, Lin YS, Xu L. Environ Sci Technol. 2024 Apr 9;58(14):6236-6249.

How do different lipid peroxidation mechanisms contribute to ferroptosis? Do Q, Xu L. Cell Rep Phys Sci. 2023 Dec 20;4(12):101683.

Interaction and Transport of Benzalkonium Chlorides by the Organic Cation and Multidrug and Toxin Extrusion Transporters. Vieira LS, Seguin RP, Xu L, Wang J. Drug Metab Dispos. 2024 Mar 13;52(4):312-321.

Cholic acid increases plasma cholesterol in Smith-Lemli-Opitz syndrome: A pilot study. Elias ER, Orth LE, Li A, Xu L, Jones SM, Rizzo WB. Mol Genet Metab Rep. 2023 Nov 28;38:101030.

Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome. Li A, Tomita H, Xu L. bioRxiv. 2023 Nov 21:2023.11.21.568116.

Elucidating the impact of bacterial lipases, human serum albumin, and FASII inhibition on the utilization of exogenous fatty acids by Staphylococcus aureus. Pruitt EL, Zhang R, Ross DH, Ashford NK, Chen X, Alonzo F 3rd, Bush MF, Werth BJ, Xu L. mSphere. 2023 Dec 20;8(6):e0036823.

High-throughput analysis of lipidomic phenotypes of methicillin-resistant Staphylococcus aureus by coupling in situ 96-well cultivation and HILIC-ion mobility-mass spectrometry. Zhang R, Ashford NK, Li A, Ross DH, Werth BJ, Xu L. Anal Bioanal Chem. 2023 Oct;415(25):6191-6199.

Tracking the Metabolic Fate of Exogenous Arachidonic Acid in Ferroptosis Using Dual-Isotope Labeling Lipidomics Reimers N, Do Q, Zhang R, Guo A, Ostrander R, Shoji A, Vuong C, Xu L bioRxiv 2023.05.28.542640;

Quaternary Ammonium Compounds: A Chemical Class of Emerging Concern. Arnold WA, Blum A, Branyan J, Bruton TA, Carignan CC, Cortopassi G, Datta S, DeWitt J, Doherty AC, Halden RU, Harari H, Hartmann EM, Hrubec TC, Iyer S, Kwiatkowski CF, LaPier J, Li D, Li L, Muñiz Ortiz JG, Salamova A, Schettler T, Seguin RP, Soehl A, Sutton R, Xu L, Zheng G. Environ Sci Technol. 2023 May 23;57(20):7645-7665.

Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis. Do Q, Zhang R, Hooper G, Xu L. JACS Au. 2023 Mar 4;3(4):1100-1117.

7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome. Tomita H, Hines KM, Herron JM, Li A, Baggett DW, Xu L. Elife. 2022 Sep 16;11:e67141.

High-Throughput Measurement and Machine Learning-Based Prediction of Collision Cross Sections for Drugs and Drug Metabolites. Ross DH, Seguin RP, Krinsky AM, Xu L. J Am Soc Mass Spectrom. 2022 Jun 1;33(6):1061-1072.

Emergence of dalbavancin, vancomycin, and daptomycin non-susceptible Staphylococcus aureus in a patient treated with dalbavancin: Case report and isolate characterization. Zhang R, Polenakovik H, Barreras Beltran IA, Waalkes A, Salipante SJ, Xu L, Werth BJ. Clin Infect Dis. 2022 May 1:ciac341.

CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids. Lo M, Sharir A, Paul MD, Torosyan H, Agnew C, Li A, Neben C, Marangoni P, Xu L, Raleigh DR, Jura N, Klein OD. Nat Commun. 2022 May 3;13(1):2407.

Evolution of Enterococcus faecium in Response to a Combination of Daptomycin and Fosfomycin Reveals Distinct and Diverse Adaptive Strategies. Supandy A, Mehta HH, Tran TT, Miller WR, Zhang R, Xu L, Arias CA, Shamoo Y. Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0233321.

Temporal changes in the brain lipidome during neurodevelopment of Smith-Lemli-Opitz syndrome mice. Li A, Hines KM, Ross DH, MacDonald JW, Xu L. Analyst. 2022 Apr 11;147(8):1611-1621.

Discovery of coordinately regulated pathways that provide innate protection against interbacterial antagonism. Ting SY, LaCourse KD, Ledvina HE, Zhang R, Radey MC, Kulasekara HD, Somavanshi R, Bertolli SK, Gallagher LA, Kim J, Penewit KM, Salipante SJ, Xu L, Peterson SB, Mougous JD. Elife. 2022 Feb 17;11:e74658.

Rheem Totah

Education

  • B.S. (Honors), 1995, Birzeit University, Palestine
  • Masters (Honors), 2000, University of Kansas
  • Ph.D. (Honors), 2002, University of Kansas

Research Interests

  • Prescription drug negative side effects in the heart, skeletal muscle and bone; associated chemical mechanisms for this toxicity
  • Drug-endogenous substrate interactions
  • Pharmacogenetics

Taking Students: Yes

Biography

Dr. Totah obtained her bachelor’s degree in chemistry from Birzeit University in Palestine and her master’s and PhD in medicinal chemistry from the University of Kansas. Dr. Totah is currently a professor in the Department of Medicinal Chemistry. Her research is in the area of prescription drug negative side effects especially in the heart, skeletal muscle and bone. She focuses on researching the chemical mechanisms for this toxicity. Her research is important in guiding research towards medicines with fewer side effects and safer use. Research in the Totah lab is broadly centered on drug-endogenous substrate interactions.

Recent Publications

A Rapid and Reliable Absorbance Assay to Identify Drug-Drug Interactions with Thiopurine Drugs. Russell DA, Stafford C, Totah RA. Metabolites. 2024 Dec 19;14(12):715. doi: 10.3390/metabo14120715. PMID: 39728496

Liver CYP4A autophagic-lysosomal degradation (ALD): A major role for the autophagic receptor SQSTM1/p62 through an uncommon target interaction site. He L, Kwon D, Trnka MJ, Liu Y, Yang J, Li K, Totah RA, Johnson EF, Burlingame AL, Correia MA. bioRxiv [Preprint]. 2024 Oct 14:2024.10.14.618315. doi: 10.1101/2024.10.14.618315. PMID: 39464120 Preprint.

A Rapid and Reliable Absorbance Assay to Identify Drug-Drug Interactions with Thiopurine Drugs. Russell DA, Stafford C, Totah RA. Metabolites. 2024 Dec 19;14(12):715.

Editorial: Cytochromes P450, their modulators and metabolites in cardiovascular function and disease. Adebesin AM, Roman RJ, Campbell WB, Seubert JM, Totah RA. Front Pharmacol. 2024 Dec 3;15:1531166.

Liver CYP4A autophagic-lysosomal degradation (ALD): A major role for the autophagic receptor SQSTM1/p62 through an uncommon target interaction site. He L, Kwon D, Trnka MJ, Liu Y, Yang J, Li K, Totah RA, Johnson EF, Burlingame AL, Correia MA. bioRxiv [Preprint]. 2024 Oct 14:2024.10.14.618315.

A Case to Support the Continued Use of Rifampin in Clinical Drug-Drug Interaction Studies. Bercu JP, Ponting DJ, Ripp SL, Dobo KL, Totah RA, Bolleddula J. Clin Pharmacol Ther. 2024 Jul;116(1):34-37.

Investigating the association between CYP2J2 inhibitors and QT prolongation: a literature review. Wiley AM, Yang J, Madhani R, Nath A, Totah RA. Drug Metab Rev. 2024 Mar 20:1-19.

The methyltransferases METTL7A and METTL7B confer resistance to thiol-based histone deacetylase inhibitors. Robey RW, Fitzsimmons CM, Guiblet WM, Frye WJE, González Dalmasy JM, Wang L, Russell DA, Huff LM, Perciaccante AJ, Ali-Rahmani F, Lipsey CC, Wade HM, Mitchell AV, Maligireddy SS, Terrero D, Butcher D, Edmondson EF, Jenkins LM, Nikitina T, Zhurkin VB, Tiwari AK, Piscopio AD, Totah RA, Bates SE, Arda HE, Gottesman MM, Batista PJ. Mol Cancer Ther. 2023 Dec 28.

Cardioprotective mechanisms of cytochrome P450 derived oxylipins from ω-3 and ω-6 PUFAs. Cho C, Aliwarga T, Wiley AM, Totah RA. Adv Pharmacol. 2023;97:201-227.

METTL7A (TMT1A) and METTL7B (TMT1B) are responsible for alkyl S-thiol methyl transferase activity in liver. Russell DA, Chau MK, Shi Y, Levasseur IN, Maldonato BJ, Totah RA. Drug Metab Dispos. 2023 May 3:DMD-AR-2023-001268.

Effects of Pregnancy on Plasma Sphingolipids Using a Metabolomic and Quantitative Analysis Approach. Enthoven LF, Shi Y, Fay E, Kim A, Moreni S, Mao J, Isoherranen N, Totah RA, Hebert MF. Metabolites. 2023 Sep 21;13(9):1026.

CYP2D6 Activity Is Correlated with Changes in Plasma Concentrations of Taurocholic Acid during Pregnancy and Postpartum in CYP2D6 Extensive Metabolizers. Czuba LC, Malhotra K, Enthoven L, Fay EE, Moreni SL, Mao J, Shi Y, Huang W, Totah RA, Isoherranen N, Hebert MF. Drug Metab Dispos. 2023 Nov;51(11):1474-1482.

Cardioprotective mechanisms of cytochrome P450 derived oxylipins from ω-3 and ω-6 PUFAs. Cho C, Aliwarga T, Wiley AM, Totah RA. Adv Pharmacol. 2023;97:201-227.

METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver. Russell DA, Chau MK, Shi Y, Levasseur IN, Maldonato BJ, Totah RA. Drug Metab Dispos. 2023 Aug;51(8):1024-1034.

Plasma hydrogen sulfide, nitric oxide, and thiocyanate levels are lower during pregnancy compared to postpartum in a cohort of women from the Pacific northwest of the United States. Zeigler MB, Fay EE, Moreni SL, Mao J, Totah RA, Hebert MF. Life Sci. 2023 Jun 1;322:121625.

The Effects of Pregnancy on Amino Acid Levels and Nitrogen Disposition. Enthoven LF, Shi Y, Fay EE, Moreni S, Mao J, Honeyman EM, Smith CK, Whittington D, Brockerhoff SE, Isoherranen N, Totah RA, Hebert MF. Metabolites. 2023 Feb 7;13(2):242.

Cardiac Disease Alters Myocardial Tissue Levels of Epoxyeicosatrienoic Acids and Key Proteins Involved in Their Biosynthesis and Degradation. Aliwarga T, Dinh JC, Heyward S, Prasad B, Gharib SA, Lemaitre RN, Sotoodehnia N, Totah RA. Int J Mol Sci. 2022 Oct 17;23(20):12433.

Selective deuteration of bupropion slows epimerization and reduces metabolism. Shi Y, Dinh J, Pelletier R, Raccor B, Yusuff N, Morgan AJ, Harbeson S, Uttamsingh V, Totah RA. Bioorg Med Chem Lett. 2022 Nov 15;76:129009.

Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study. Lemaitre RN, Jensen PN, Zeigler M, Fretts AM, Umans JG, Howard BV, Sitlani CM, McKnight B, Gharib SA, King IB, Siscovick DS, Psaty BM, Sotoodehnia N, Totah RA. EBioMedicine. 2022 Sep;83:104189.

Reductions in Hydrogen Sulfide and Changes in Mitochondrial Quality Control Proteins Are Evident in the Early Phases of the Corneally Kindled Mouse Model of Epilepsy. Cho C, Zeigler M, Mizuno S, Morrison RS, Totah RA, Barker-Haliski M. Int J Mol Sci. 2022 Jan 27;23(3):1434.

Future of Biotransformation Science in the Pharmaceutical Industry. Kramlinger VM, Dalvie D, Heck CJS, Kalgutkar AS, O’Neill J, Su D, Teitelbaum AM, Totah RA. Drug Metab Dispos. 2022 Mar;50(3):258-267.

Full PubMed Listing

Dave Porubek

Education

  • PhD, Medicinal Chemistry, 1984, University of Washington
  • BA, Chemistry, 1979, Eastern Washington University

Research Interests

  • Analytical methods for studying drug metabolism and drug targets in drug development for industry. Major focus on anti-cancer drugs.

Taking Students: No

Biography

In 1984, after completing his PhD in the Department of Medicinal Chemistry under the guidance of his adviser, the late Sidney Nelson, Dr. Porubek received a postdoctoral fellowship at the Karolinska Institute in Sweden. After that fellowship, he returned to the UW School of Pharmacy to serve as a postdoctoral fellow in the lab of then-Professor of Medicinal Chemistry (and now School of Pharmacy Dean) Thomas Baillie.

Throughout his career, Porubek has worked for several Seattle area research companies – many of which focused on cancer drug development. He has worked in roles from research scientist to project manager at places including Cell Therapeutics, Pathogenesis Corp. and OncoGenex. He joined the Department of Medicinal Chemistry faculty in 2012, and he is currently a research consultant.

Selected Publications

Wendel Nelson

Education

  • B.S., 1962, Idaho State University
  • Ph.D., 1965, University of Kansas

Research Interests

  • Chemical aspects of drug metabolism and drug action.
  • Stereochemical aspects of drug disposition.
  • Putative metabolic intermediates and chemical mechanisms for their formation.

Taking Students: No

Biography

Dr. Nelson holds degrees in Pharmacy and Medicinal Chemistry. He teaches both PharmD program courses and Medicinal Chemistry graduate courses. He has served as Chair of Medicinal Chemistry, Senior Editor for the Journal of Medicinal Chemistry, and Chairman of the Division of Medicinal Chemistry, American Chemical Society.

Selected Publications

  • Teitelbaum AM, Scian M, Nelson WL, Rettie AE. “Efficient Syntheses of Vitamin K Chain-Shortened Acid Metabolites.” Synthesis (Stuttg), 2015 Apr;47(7):944-948. PubMed link.
  • Topletz AR, Tripathy S, Foti RS, Shimshoni JA, Nelson WL, Isoherranen N. “Induction of CYP26A1 by metabolites of retinoic acid: evidence that CYP26A1 is an important enzyme in the elimination of active retinoids.” Mol Pharmacol. 2015; 87(3):430-41. PubMed link.
  • Lutz JD, VandenBrink BM, Babu KN, Nelson WL, Kunze KL, Isoherranen N. “Stereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite: implications for risk assessment of multiple time-dependent inhibitor systems.” Drug Metab Dispos. 2013 Dec; 41(12):2056-65. PubMed link.
  • Shimshoni JA, Roberts AG, Scian M, Topletz AR, Blankert SA, Halpert JR, Nelson WL, Isoherranen N. “Stereoselective formation and metabolism of 4-hydroxy-retinoic Acid enantiomers by cytochrome P450 enzymes.” J Biol Chem. 2012 Dec 7;287(50):42223-32. PubMed link.
  • Peng CC, Shi W, Lutz JD, Kunze KL, Liu JO, Nelson WL, Isoherranen N. “Stereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungals.” Drug Metab Dispos. 2012 Mar; 40(3):426-35. PubMed link.
  • Topletz AR, Thatcher JE, Zelter A, Lutz JD, Tay S, Nelson WL, Isoherranen N. “Comparison of the Function and Expression of CYP26A1 and CYP26B1, the Two Retinoic Acid Hydroxylases.” Biochem Pharmacol. 2012 Jan 1; 83:149-163. PubMed link.
  • Peng CC, Shi W, Lutz JD, Kunze KL, Liu JO, Nelson WL, Isoherranen N. “Stereospecific Metabolism of Itraconazole by CYP3A4: Dioxolane Ring Scission of Azole Antifungals.” Drug Metab Dispos. 2012 Mar; 40:426-435. PubMed link.
  • Nelson WL. “Chapter 32. Antihistamines and Related Antiallergic and Antiulcer Agents.” Foye’s Principles of Medicinal Chemistry, 7th Edition. Williams DA and Lemke TL, Eds; pp 1045-1072 (2012).
  • Babu KN, Kunze KL, and Nelson WL. “Metabolism of Diltiazem. A Short Efficient Synthesis of N,N-Didesmethyldiltiazem – An Important Product of N-Demethylation.” Synthesis 553-554 (2011).

Kelly Lee

Education

  • AB (Honors), Harvard University
  • PhD, Johns Hopkins University

Research Interests

  • HIV, Influenza A virus
  • Biophysical, structural, and biochemical techniques including X-ray scattering, cryo-electron microscopy, hydrogen/deuterium-exchange mass spectrometry, and fluorescence microscopy to understand the function of viral machinery

Taking Students: Yes

Biography

Our lab uses complementary structural and biophysical methods to characterize the conformational changes viruses carry out in order to invade host cells. We focus on the transitions and the critical functional states that often are too transient or dynamic to characterize by classical structural methods. Understanding these events is essential to understanding mechanisms of cell entry, for understanding the activity of neutralizing antibodies, and also for developing novel antivirals that can target the virus prior to infection. Our core expertise is in using Hydrogen/Deuterium-Exchange Mass Spectrometry (HDX-MS), cryo-electron microscopy (cryo-EM) and small-angle X-ray scattering (SAXS) to monitor conformational change of protein complexes and viruses. An NIH K99/R00 Career Award supported my transition to studying influenza virus with techniques such as cryo-electron tomography and SAXS. Current projects apply cryo-ET, SAXS, and HDX-MS to dissect the spring-loaded membrane fusion mechanism of influenza virus hemagglutinin (HA) and HIV Env.

For example, in recent studies using cryo-ET and HDX-MS, for the first time we have been able to visualize the nature of fusion protein-mediated membrane remodeling and to determine the sequence of events in whole viruses and isolated fusion proteins that are needed to produce efficient fusion.

With the support of a Center for AIDS Research Creative and Novel Ideas in HIV Research (CNIHR) award for new investigators and with Gates Foundation support, my lab is working with Shiu-Lok Hu’s group (Pharmaceutics) to investigate the structural basis for antigenicity and immunogenicity of HIV Env glycoproteins. In addition, we have been able to characterize isolate-specific structural differences and their impact on antigenicity of Env; these effects are difficult to study by conventional approaches. Our biophysical approaches have also enabled us to analyze CD4 receptor, entry inhibitors, and neutralizing Abs in complex with the native-like HIV Env trimers. In collaboration with Julie Overbaugh’s group at the Fred Hutchinson Cancer Research Center, we are gaining insight into the nature of Env-dependent HIV transmission and the development of neutralizing antibodies in response to infection.

Dr. Lee also holds an adjunct appointment in the UW Microbiology Department and is a member of a number of cross-departmental graduate programs including the Biological Physics Structure and Design Program, the Pathobiology Graduate Program and the Molecular and Cellular Biology Program.

Recent Publications

Visualizing intermediate stages of viral membrane fusion by cryo-electron tomography. Kephart SM, Hom N, Lee KK.Trends Biochem Sci. 2024 Oct;49(10):916-931. doi: 10.1016/j.tibs.2024.06.012. Epub 2024 Jul 24.

Potent neutralization of SARS-CoV-2 variants by RBD nanoparticle and prefusion-stabilized spike immunogens. Miranda MC, Kepl E, Navarro MJ, Chen C, Johnson M, Sprouse KR, Stewart C, Palser A, Valdez A, Pettie D, Sydeman C, Ogohara C, Kraft JC, Pham M, Murphy M, Wrenn S, Fiala B, Ravichandran R, Ellis D, Carter L, Corti D, Kellam P, Lee K, Walls AC, Veesler D, King NP. NPJ Vaccines. 2024 Oct 8;9(1):184.

mRNA-based VP8* nanoparticle vaccines against rotavirus are highly immunogenic in rodents. Roier S, Mangala Prasad V, McNeal MM, Lee KK, Petsch B, Rauch S. NPJ Vaccines. 2023 Dec 22;8(1):190.

Combinatorial immune refocusing within the influenza hemagglutinin RBD improves cross-neutralizing antibody responses Dosey A, Ellis D, Boyoglu-Barnum S, Syeda H, Saunders M, Watson MJ, Kraft JC, Pham MN, Guttman M, Lee KK, Kanekiyo M, King NP. Cell Rep. 2023 Dec 26;42(12):113553.

De novo design of monomeric helical bundles for pH-controlled membrane lysis. Goldbach N, Benna I, Wicky BIM, Croft JT, Carter L, Bera AK, Nguyen H, Kang A, Sankaran B, Yang EC, Lee KK, Baker D. Protein Sci. 2023 Nov;32(11):e4769.

An HIV-1 broadly neutralizing antibody overcomes structural and dynamic variation through highly focused epitope targeting. Hodge EA, Chatterjee A, Chen C, Naika GJ, Laohajaratsang M, Mangala Prasad V, Lee KK. NPJ Viruses 1, 2 (2023). https://doi.org/10.1038/s44298-023-00002-4

Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection. Guenthoer J, Lilly M, Starr TN, Dadonaite B, Lovendahl KN, Croft JT, Stoddard CI, Chohan V, Ding S, Ruiz F, Kopp MS, Finzi A, Bloom JD, Chu HY, Lee KK, Overbaugh J. Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2220948120.

hACE2-Induced Allosteric Activation in SARS-CoV versus SARS-CoV-2 Spike Assemblies Revealed by Structural Dynamics. Chen C, Zhu R, Hodge EA, Díaz-Salinas MA, Nguyen A, Munro JB, Lee KK. ACS Infect Dis. 2023 Jun 9;9(6):1180-1189.

Structural dynamics reveal subtype-specific activation and inhibition of influenza virus hemagglutinin. Garcia NK, Kephart SM, Benhaim MA, Matsui T, Mileant A, Guttman M, Lee KK. J Biol Chem. 2023 Jun;299(6):104765.

Cytoplasmic Tail Truncation Stabilizes S1-S2 Association and Enhances S Protein Incorporation into SARS-CoV-2 Pseudovirions. Zhang L, Hom N, Ojha A, Lovendahl KN, Mou H, Lee KK, Choe H. J Virol. 2023 Mar 30;97(3):e0165022.

Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses. McLeod B, Mabrouk MT, Miura K, Ravichandran R, Kephart S, Hailemariam S, Pham TP, Semesi A, Kucharska I, Kundu P, Huang WC, Johnson M, Blackstone A, Pettie D, Murphy M, Kraft JC, Leaf EM, Jiao Y, van de Vegte-Bolmer M, van Gemert GJ, Ramjith J, King CR, MacGill RS, Wu Y, Lee KK, Jore MM, King NP, Lovell JF, Julien JP. Immunity. 2022 Sep 13;55(9):1680-1692.e8.

Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery. Mangala Prasad V, Blijleven JS, Smit JM, Lee KK. Nat Commun. 2022 Aug 15;13(1):4772.

Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env.  Hodge EA, Naika GS, Kephart SM, Nguyen A, Zhu R, Benhaim MA, Guo W, Moore JP, Hu SL, Sanders RW, Lee KK. iScience. 2022 May 23;25(6):104449.

Structure-based design of stabilized recombinant influenza neuraminidase tetramers. Ellis D, Lederhofer J, Acton OJ, Tsybovsky Y, Kephart S, Yap C, Gillespie RA, Creanga A, Olshefsky A, Stephens T, Pettie D, Murphy M, Sydeman C, Ahlrichs M, Chan S, Borst AJ, Park YJ, Lee KK, Graham BS, Veesler D, King NP, Kanekiyo M. Nat Commun. 2022 Apr 5;13(1):1825.

Structure-guided changes at the V2 apex of HIV-1 clade C trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies. Sahoo A, Hodge EA, LaBranche CC, Styles TM, Shen X, Cheedarla N, Shiferaw A, Ozorowski G, Lee WH, Ward AB, Tomaras GD, Montefiori DC, Irvine DJ, Lee KK, Amara RR. Cell Rep. 2022 Mar 1;38(9):110436.

Cryo-ET of Env on intact HIV virions reveals structural variation and positioning on the Gag lattice. Mangala Prasad V, Leaman DP, Lovendahl KN, Croft JT, Benhaim MA, Hodge EA, Zwick MB, Lee KK. Cell. 2022 Feb 17;185(4):641-653.e17.

Mannose-binding lectin and complement mediate follicular localization and enhanced immunogenicity of diverse protein nanoparticle immunogens. Read BJ, Won L, Kraft JC, Sappington I, Aung A, Wu S, Bals J, Chen C, Lee KK, Lingwood D, King NP, Irvine DJ. Cell Rep. 2022 Jan 11;38(2):110217.

Miklos Guttman

Education

  • BS in Chemistry, 2003, University of California, Irvine
  • PhD in Chemistry/Biochemistry, 2009, University of California, San Diego
  • Postdoctoral Studies in viral surface glycoproteins and immune complexes, University of Washington

Research Interests

  • Understanding the structural and biophysical aspects of antigen recognition by the humoral immune system.
  • Development of structural mass spectrometry techniques for structural glycobiology.

Taking Students: Yes

Biography

Miklos “Mike” Guttman received his B.S. in Chemistry from the University of California, Irvine with a focus in organic chemistry. He transitioned into biochemistry and earned his Ph.D. from the University of California, San Diego with Elizabeth Komives examining the interactions that regulate cholesterol uptake. He received a NIH Ruth L. Krischstein F32 award to work with Kelly Lee’s group as a postdoc to apply structural mass spectrometry to understand how antibodies recognize the viral surface glycoprotein of HIV. More recently Mike has worked with the Global Health Vaccine Accelerator Platform (GH-VAP) through the Bill and Melinda Gates Foundation to characterize emerging biotherapeutics.

Research Overview

Antibody-antigen recognition is a critically important biological process, underlying the immune response and the mechanism of action of biotherapeutics and vaccines. Due to the size and complexity of intact antibody-antigen complexes, our understanding of what constitutes an effective antibody interaction is often limited to static structures of isolated subunits. Using emerging biophysical and structural tools such as structural mass spectrometry, our lab seeks to characterize the interactions of intact antibody-antigen complexes in their native solution state and use this information to advance the development of biotherapeutic approaches against infectious diseases and cancer. We are currently investigating such interactions for understanding antibody-mediated neutralization of staphylococcal enterotoxins and cancer recognition by immunoglobulin μ (IgM).

Glycosylation plays a role in nearly all aspects of biology, it is estimated that over 50% of the human proteome is decorated with glycosylation. Yet despite its importance, our knowledge of glycobiology has been hindered by the analytical challenges posed by the structural complexity of carbohydrates. Mass spectrometry provides a sensitive and rapid tool for analyzing protein glycosylation, but it provides little regarding stereochemistry or linkage information. Another focus of our lab is developing and implementing novel mass spectrometry-based methods for obtaining a higher level of structural information for biologically relevant glycans and oligosaccharides.

Recent Publications

A type-specific B-cell epitope at the apex of outer surface protein C (OspC) of the Lyme disease spirochete, Borreliella burgdorferi. Vance DJ, Freeman-Gallant G, McCarthy K, Piazza CL, Chen Y, Vorauer C, Muriuki B, Rudolph MJ, Cavacini L, Guttman M, Mantis NJ.Microbiol Spectr. 2025 Apr;13(4):e0288324. doi: 10.1128/spectrum.02883-24. Epub 2025 Feb 14.

Large-scale discovery, analysis, and design of protein energy landscapes. Ferrari ÁJR, Dixit SM, Thibeault J, Garcia M, Houliston S, Ludwig RW, Notin P, Phoumyvong CM, Martell CM, Jung MD, Tsuboyama K, Carter L, Arrowsmith CH, Guttman M, Rocklin GJ.bioRxiv [Preprint]. 2025 Mar 25:2025.03.20.644235. doi: 10.1101/2025.03.20.644235.

Defining the Features of Complement-Active IgM. Watson MJ, Mundorff CC, Lynch EM, Kollman JM, Kearney JF, Guttman M.J Mol Biol. 2025 Mar 26:169104. doi: 10.1016/j.jmb.2025.169104. Online ahead of print.

Rigorous Analysis of Multimodal HDX-MS Spectra. Tuttle LM, James EI, Georgescauld F, Wales TE, Weis DD, Engen JR, Nath A, Klevit RE, Guttman M. J Am Soc Mass Spectrom. 2025 Feb 5;36(2):416-423. doi: 10.1021/jasms.4c00471. Epub 2025 Jan 21.

High-Throughput Determination of Exchange Rates of Unmodified and PTM-Containing Peptides Using HX-MS. Moroco JA, Jacome ASV, Beltran PMJ, Reiter A, Mundorff C, Guttman M, Morrow J, Coales S, Mayne L, Hamuro Y, Carr SA, Papanastasiou M. Mol Cell Proteomics. 2025 Feb;24(2):100904. doi: 10.1016/j.mcpro.2025.100904. Epub 2025 Jan 7.

Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress. Cao S, Garcia SF, Shi H, James EI, Kito Y, Shi H, Mao H, Kaisari S, Rona G, Deng S, Goldberg HV, Ponce J, Ueberheide B, Lignitto L, Guttman M, Pagano M, Zheng N. Cell. 2024 Dec 26;187(26):7568-7584.e22.

Direct Mapping of Polyclonal Epitopes in Serum by HDX-MS. Vorauer C, Boniche-Alfaro C, Murphree T, Matsui T, Weiss T, Fries BC, Guttman M. Anal Chem. 2024 Oct 22;96(42):16758-16767.

Structure of a Human Monoclonal Antibody in Complex with Outer Surface Protein C of the Lyme Disease Spirochete, Borreliella burgdorferi. Rudolph MJ, Chen Y, Vorauer C, Vance DJ, Piazza CL, Willsey GG, McCarthy K, Muriuki B, Cavacini LA, Guttman M, Mantis NJ. J Immunol. 2024 Oct 15;213(8):1234-1243.

HDXBoxeR: an R package for statistical analysis and visualization of multiple Hydrogen-Deuterium Exchange Mass-Spectrometry datasets of different protein states. Janowska MK, Reiter K, Magala P, Guttman M, Klevit RE. Bioinformatics. 2024 Aug 2;40(8):btae479.

Characterizing the human intestinal chondroitin sulfate glycosaminoglycan sulfation signature in inflammatory bowel disease. Francis KL, Zheng HB, Suskind DL, Murphree TA, Phan BA, Quah E, Hendrickson AS, Zhou X, Nuding M, Hudson AS, Guttman M, Morton GJ, Schwartz MW, Alonge KM, Scarlett JM. Sci Rep. 2024 May 23;14(1):11839.

Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation. James EI, Baggett DW, Chang E, Schachter J, Nixey T, Choi K, Guttman M, Nath A. bioRxiv [Preprint]. 2024 Feb 3:2024.02.02.578649.

Combinatorial immune refocusing within the influenza hemagglutinin RBD improves cross-neutralizing antibody responses. Dosey A, Ellis D, Boyoglu-Barnum S, Syeda H, Saunders M, Watson MJ, Kraft JC, Pham MN, Guttman M, Lee KK, Kanekiyo M, King NP. Cell Rep. 2023 Dec 26;42(12):113553.

Profiling of drug resistance in Src kinase at scale uncovers a regulatory network coupling autoinhibition and catalytic domain dynamics. Chakraborty S, Ahler E, Simon JJ, Fang L, Potter ZE, Sitko KA, Stephany JJ, Guttman M, Fowler DM, Maly DJ.Cell Chem Biol. 2023 Aug 30:S2451-9456(23)00277-5.

Structural dynamics reveal subtype-specific activation and inhibition of influenza virus hemagglutinin. Garcia NK, Kephart SM, Benhaim MA, Matsui T, Mileant A, Guttman M, Lee KK. J Biol Chem. 2023 Jun;299(6):104765. doi: 10.1016/j.jbc.2023.104765. Epub 2023 Apr 28.

Disordered region encodes α-crystallin chaperone activity toward lens client γD-crystallin. Woods CN, Ulmer LD, Guttman M, Bush MF, Klevit RE. Proc Natl Acad Sci U S A. 2023 Feb 7;120(6):e2213765120. doi: 10.1073/pnas.2213765120. Epub 2023 Jan 31. PMID: 36719917

IgM antibodies derived from memory B cells are potent cross-variant neutralizers of SARS-CoV-2. Hale M, Netland J, Chen Y, Thouvenel CD, Smith KN, Rich LM, Vanderwall ER, Miranda MC, Eggenberger J, Hao L, Watson MJ, Mundorff CC, Rodda LB, King NP, Guttman M, Gale M, Abraham J, Debley JS, Pepper M, Rawlings DJ. J Exp Med. 2022 Sep 5;219(9):e20220849. doi: 10.1084/jem.20220849. Epub 2022 Aug 8.

Cullin-independent recognition of HHARI substrates by a dynamic RBR catalytic domain. Reiter KH, Zelter A, Janowska MK, Riffle M, Shulman N, MacLean BX, Tamura K, Chambers MC, MacCoss MJ, Davis TN, Guttman M, Brzovic PS, Klevit RE. Structure. 2022 Sep 1;30(9):1269-1284.e6. doi: 10.1016/j.str.2022.05.017. Epub 2022 Jun 17.

Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems. James EI, Murphree TA, Vorauer C, Engen JR, Guttman M. Chem Rev. 2022 Apr 27;122(8):7562-7623. doi: 10.1021/acs.chemrev.1c00279. Epub 2021 Sep 7.

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Rapid Assessment of Pepsin Column Activity for Reliable HDX-MS Studies. Vorauer C, Wrigley MS, Rincon Pabon JP, Watson MJ, Mundorff CC, Weis DD, Guttman M. J Am Soc Mass Spectrom. 2021 May 13. doi: 10.1021/jasms.1c00080. Online ahead of print.

Quadrivalent influenza nanoparticle vaccines induce broad protection. Boyoglu-Barnum S, Ellis D, Gillespie RA, Hutchinson GB, Park YJ, Moin SM, Acton OJ, Ravichandran R, Murphy M, Pettie D, Matheson N, Carter L, Creanga A, Watson MJ, Kephart S, Ataca S, Vaile JR, Ueda G, Crank MC, Stewart L, Lee KK, Guttman M, Baker D, Mascola JR, Veesler D, Graham BS, King NP, Kanekiyo M. Nature. 2021 Apr;592(7855):623-628. doi: 10.1038/s41586-021-03365-x. Epub 2021 Mar 24.

Linkage Memory in Underivatized Protonated Carbohydrates. Mookherjee A, Uppal SS, Murphree TA, Guttman M. J Am Soc Mass Spectrom. 2021 Feb 3;32(2):581-589. doi: 10.1021/jasms.0c00440. Epub 2020 Dec 22.

Simple Platform for Automating Decoupled LC-MS Analysis of Hydrogen/Deuterium Exchange Samples. Watson MJ, Harkewicz R, Hodge EA, Vorauer C, Palmer J, Lee KK, Guttman M. J Am Soc Mass Spectrom. 2021 Feb 3;32(2):597-600. doi: 10.1021/jasms.0c00341. Epub 2020 Dec 7.

Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2. Walls AC, Fiala B, Schäfer A, Wrenn S, Pham MN, Murphy M, Tse LV, Shehata L, O’Connor MA, Chen C, Navarro MJ, Miranda MC, Pettie D, Ravichandran R, Kraft JC, Ogohara C, Palser A, Chalk S, Lee EC, Guerriero K, Kepl E, Chow CM, Sydeman C, Hodge EA, Brown B, Fuller JT, Dinnon KH 3rd, Gralinski LE, Leist SR, Gully KL, Lewis TB, Guttman M, Chu HY, Lee KK, Fuller DH, Baric RS, Kellam P, Carter L, Pepper M, Sheahan TP, Veesler D, King NP. Cell. 2020 Nov 25;183(5):1367-1382.e17. doi: 10.1016/j.cell.2020.10.043. Epub 2020 Oct 31.

Rapid Differentiation of Chondroitin Sulfate Isomers by Gas-phase Hydrogen-deuterium Exchange. Alonge KM, Harkewicz R, Guttman M. Curr Mol Med. 2020;20(10):821-827. doi: 10.2174/1566524020666200915110707.

Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats. Alonge KM, Mirzadeh Z, Scarlett JM, Logsdon AF, Brown JM, Cabrales E, Chan CK, Kaiyala KJ, Bentsen MA, Banks WA, Guttman M, Wight TN, Morton GJ, Schwartz MW. Nat Metab. 2020 Oct;2(10):1025-1033. doi: 10.1038/s42255-020-00275-6. Epub 2020 Sep 7.

The influence of proline isomerization on potency and stability of anti-HIV antibody 10E8. Guttman M, Padte NN, Huang Y, Yu J, Rocklin GJ, Weitzner BD, Scian M, Ho DD, Lee KK. Sci Rep. 2020 Aug 31;10(1):14313. doi: 10.1038/s41598-020-71184-7.

Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. Walls AC, Fiala B, Schäfer A, Wrenn S, Pham MN, Murphy M, Tse LV, Shehata L, O’Connor MA, Chen C, Navarro MJ, Miranda MC, Pettie D, Ravichandran R, Kraft JC, Ogohara C, Palser A, Chalk S, Lee EC, Kepl E, Chow CM, Sydeman C, Hodge EA, Brown B, Fuller JT, Dinnon KH 3rd, Gralinski LE, Leist SR, Gully KL, Lewis TB, Guttman M, Chu HY, Lee KK, Fuller DH, Baric RS, Kellam P, Carter L, Pepper M, Sheahan TP, Veesler D, King NP. bioRxiv. 2020 Aug 12:2020.08.11.247395. doi: 10.1101/2020.08.11.247395. Preprint.

Probing the Stability of Proline Cis/Trans Isomers in the Gas Phase with Ultraviolet Photodissociation. Silzel JW, Murphree TA, Paranji RK, Guttman MM, Julian RR. J Am Soc Mass Spectrom. 2020 Sep 2;31(9):1974-1980. doi: 10.1021/jasms.0c00242. Epub 2020 Aug 18.

Parallel Chemoselective Profiling for Mapping Protein Structure. Potter ZE, Lau HT, Chakraborty S, Fang L, Guttman M, Ong SE, Fowler DM, Maly DJ. Cell Chem Biol. 2020 Aug 20;27(8):1084-1096.e4. doi: 10.1016/j.chembiol.2020.06.014. Epub 2020 Jul 9.

Imidazolium Compounds as Internal Exchange Reporters for Hydrogen/Deuterium Exchange by Mass Spectrometry. Murphree TA, Vorauer C, Brzoska M, Guttman M. Anal Chem. 2020 Jul 21;92(14):9830-9837. doi: 10.1021/acs.analchem.0c01328. Epub 2020 Jul 7.

High-Precision, Gas-Phase Hydrogen/Deuterium-Exchange Kinetics by Mass Spectrometry Enabled by Exchange Standards. Uppal SS, Mookherjee A, Harkewicz R, Beasley SE, Bush MF, Guttman M. Anal Chem. 2020 Jun 2;92(11):7725-7732. doi: 10.1021/acs.analchem.0c00749. Epub 2020 May 18.

Structure-Activity Relationships for CYP4B1 Bioactivation of 4-Ipomeanol Congeners: Direct Correlation between Cytotoxicity and Trapped Reactive Intermediates. Kowalski JP, McDonald MG, Whittington D, Guttman M, Scian M, Girhard M, Hanenberg H, Wiek C, Rettie AE. Chem Res Toxicol. 2019 Dec 16;32(12):2488-2498. doi: 10.1021/acs.chemrestox.9b00330. Epub 2019 Dec 4.

Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of ‘quasi-ordered’ states. Clouser AF, Baughman HE, Basanta B, Guttman M, Nath A, Klevit RE. Elife. 2019 Oct 1;8:e50259. doi: 10.7554/eLife.50259.

Quantitative analysis of chondroitin sulfate disaccharides from human and rodent fixed brain tissue by electrospray ionization-tandem mass spectrometry. Alonge KM, Logsdon AF, Murphree TA, Banks WA, Keene CD, Edgar JS, Whittington D, Schwartz MW, Guttman M. Glycobiology. 2019 Nov 20;29(12):847-860. doi: 10.1093/glycob/cwz060.

Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments. Masson GR, Burke JE, Ahn NG, Anand GS, Borchers C, Brier S, Bou-Assaf GM, Engen JR, Englander SW, Faber J, Garlish R, Griffin PR, Gross ML, Guttman M, Hamuro Y, Heck AJR, Houde D, Iacob RE, Jørgensen TJD, Kaltashov IA, Klinman JP, Konermann L, Man P, Mayne L, Pascal BD, Reichmann D, Skehel M, Snijder J, Strutzenberg TS, Underbakke ES, Wagner C, Wales TE, Walters BT, Weis DD, Wilson DJ, Wintrode PL, Zhang Z, Zheng J, Schriemer DC, Rand KD. Nat Methods. 2019 Jul;16(7):595-602. doi: 10.1038/s41592-019-0459-y. Epub 2019 Jun 27.

Tracking Higher Order Protein Structure by Hydrogen-Deuterium Exchange Mass Spectrometry. Benhaim M, Lee KK, Guttman M. Protein Pept Lett. 2019;26(1):16-26. doi: 10.2174/0929866526666181212165037.

The ubiquitin ligase SspH1 from Salmonella uses a modular and dynamic E3 domain to catalyze substrate ubiquitylation. Cook M, Delbecq SP, Schweppe TP, Guttman M, Klevit RE, Brzovic PS. J Biol Chem. 2019 Jan 18;294(3):783-793. doi: 10.1074/jbc.RA118.004247. Epub 2018 Nov 20.
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William Atkins

Education

  • BS in Chemistry, The College of William and Mary
  • MA in Pharmacology, Harvard University
  • PhD in Biochemistry, The University of Illinois

Research Interests

  • Drug Metabolizing Enzymes
  • Therapeutic Antibodies
  • Protein structure and Function

Taking Students: No

Courses Taught

  • MEDCH 531
  • MEDCH 501
  • MEDCH 528
  • MEDCH 327
  • MEDCH 527
  • MEDCH 529

Biography

Dr. William M. Atkins earned a Masters Degree in Pharmacology from Harvard University in 1983 and a Ph.D. in Biochemistry from the University of Illinois at Urbana-Champaign in 1988. From 1988-1991 Dr. Atkins performed postdoctoral research in the Department of Chemistry at The Pennsylvania State University, as an NIH Kirschstein Postdoctoral Fellow.

Dr. Akins was the Sidney D. Nelson Professor and Chair of Medicinal Chemistry at The University of Washington from 2016-2025, having been on the faculty there since 1991. He was Graduate Program Director for the Department of Medicinal Chemistry and co-Director of the Analytical Biopharmacy Core. His research  focuses on the enzymology of detoxification enzymes and drug metabolism, with particular emphasis on biophysical mechanisms. Professor Atkins has been awarded NIH grants for research on several enzyme systems including Cytochrome P450s, Glutathione S-transferases, and the P-glycoprotein efflux transporter. Recent research efforts also include characterization of nanoparticles for drug delivery and therapeutic antibody drug conjugates.

Professor Atkins serves on the International Organizing Committee for The Biennial International Conferences on Cytochrome P450’s and the International Microsomes and Drug Oxidations Conference. Dr. Atkins has served on several NIH and NSF Review Panels. He is also a member of the Editorial Boards of Archives in Biochemistry and Biophysics and Environmental Toxicology.

 

Selected Publications

The origins of nonideality exhibited by monoclonal antibodies and Fab fragments in human serum. Larsen HA, Atkins WM, Nath A. Protein Sci. 2023 Dec;32(12):e4812. doi: 10.1002/pro.4812.

Nanodisc-embedded cytochrome P450 P3A4 binds diverse ligands by distributing conformational dynamics to its flexible elements. Paço L, Hackett JC, Atkins WM. J Inorg Biochem. 2023 Jul;244:112211. doi: 10.1016/j.jinorgbio.2023.112211. Epub 2023 Apr 5.

Low molecular weight ligands bind to CYP3A4 via a branched induced fit mechanism: Implications for O2 binding. Redhair M, Nath A, Hackett JC, Atkins WM. Arch Biochem Biophys. 2023 May 1;739:109582. doi: 10.1016/j.abb.2023.109582. Epub 2023 Mar 21.

Reversibility and Low Commitment to Forward Catalysis in the Conjugation of Lipid Alkenals by Glutathione Transferase A4-4. Scian M, Paço L, Murphree TA, Shireman LM, Atkins WM. Biomolecules. 2023 Feb 9;13(2):329. doi: 10.3390/biom13020329.

Long Range Communication between the Drug-Binding Sites and Nucleotide Binding Domains of the Efflux Transporter ABCB1. Clouser AF, Atkins WM. Biochemistry. 2022 Apr 19;61(8):730-740. doi: 10.1021/acs.biochem.2c00056. Epub 2022 Apr 6.

Allan Rettie

Education

  • PhD in Pharmaceutical Sciences, University of Newcastle-upon-Tyne, England
  • BSc, Heriot-Watt University, Scotland
  • Postdoctoral Fellow, UW

Research Areas

  • Biochemistry of the human CYP2 and CYP4 families of P450s
  • Pharmacogenomics of cardiovascular drugs
  • P450-dependent bioactivation and associated adverse reactions

Taking Students: No

Biography

Dr. Rettie obtained a PhD in Pharmaceutical Sciences in 1983 from the University of Newcastle-upon-Tyne, England, before moving to Seattle to post-doc with Drs. Mont Juchau and Dr. Bill Trager at the UW in the areas of extra-hepatic drug metabolism and mechanisms of drug-drug interactions. He joined the faculty of the UW School of Pharmacy in 1987 and was Department Chair from 2000-2014.

Dr. Rettie’s research interests have focused mainly on the human P450 enzymes and attempts to understand mechanisms of catalysis, substrate specificity, pharmacogenetic variability and adverse drug reactions related to these monooxygenases. He has published over 190 peer-reviewed papers and held research grants from the National Institutes of Health (NIH) in these topic areas for the last 25 years.

Dr. Rettie has served on the editorial boards of Drug Metabolism and Disposition, Drug Metabolism Reviews, Journal of Pharmacology and Therapeutics, Current Drug Metabolism, Chemico-Biological Interactions and Chemical Research in Toxicology, as well as numerous NIH grant review panels. He has chaired the Scientific Affairs Committee of the International Society for Study of Xenobiotics (ISSX) and is Past Chair of the International Union of Basic and Applied Pharmacology’s Section of Drug Metabolism and Transport. In 2005, Dr. Rettie received the North American Scientific Achievement Award from ISSX for his work on elucidating metabolic and pharmacogenetic mechanisms of adverse reactions to the anticoagulant drug, warfarin, and in 2016 was appointed a Fellow of the Japanese Society for the Study of Xenobiotics.

Research Overview

Metabolism by the cytochrome P450s is the principal means whereby lipid-soluble drugs and compounds foreign to the body are converted to water-soluble derivatives that can be readily excreted. This is a beneficial effect of the enzyme system. However, it is well recognized that P450-mediated bioactivation of drugs and other xenobiotics is an important mechanism of chemical toxicity (Baillie and Rettie, 2011). Moreover, unexpected interruptions in P450 activity, due to genetic variation (Danese et al., 2012) or administration of agents that inhibit P450 activity (McDonald et al., 2015), can cause serious adverse drug reactions and contribute to disease states.

Much of the research in the Rettie laboratory focuses on the biochemistry and pharmacogenetics of the vitamin K cycle with an emphasis on how P450 enzymes interact with components of the cycle to maintain homeostasis. Human CYP2C9, for example, is the primary catalyst of (S)-warfarin metabolism (Daly et al., 2018). This vitamin K antagonist is an anticoagulant drug that is very difficult to dose correctly, and there are many drug-drug and drug-gene interactions associated with its use (Rettie and Tai, 2006).

An important goal for the laboratory is to define sources of inter-individual variability in warfarin dosing that can span a 100-fold range (Cooper et al., 2008). We have shown that common genetic polymorphisms in CYP2C9 decrease warfarin dose requirements by reducing the metabolic clearance of (S)-warfarin, while common polymorphisms in the warfarin target enzyme, VKORC1, affect warfarin dose by changing hepatic concentrations of this critical recycling enzyme (Rieder et al., 2005). We found that CYP4F2 and CYP4F11 are key vitamin K catabolizing enzymes (Edson et al., 2013) and common variation in CYP4F2 at least, affects warfarin dose, likely by modulating hepatic vitamin K concentrations (McDonald et al., 2009). We are currently examining the role of novel genetic variation in determining warfarin response in underserved populations (Henderson et al., 2019).

Other research in the laboratory is concerned with CYP4 enzymes that are potential drug targets because of their critical roles in health and disease (Edson et al., 2013; Johnson et al., 2015). Efforts are ongoing to synthesize chemical inhibitors of specific CYP4-family members to better dissect their physiological roles. CYP4B1 metabolizes a host of pro-toxins, including furans, aromatic amines, and certain fatty acids to reactive intermediates that can damage the cell. In this regard, CYP4B1 is a curious member of the CYP4 family because these enzymes typically have
a restricted substrate specificity that does not extend much beyond endogenous fatty acids. To evaluate the role of CYP4B1 in chemical toxicity, we have also developed a knockout mouse model (Parkinson et al, 2013). Most recently, we identified structural determinants of human CYP4B1 that confer high activity towards 4-ipomeanol (Wiek et al., 2015), and evaluated the substrate specificity of the ‘optimized’ human enzyme (Roellecke et al., 2017).

Our CYP4 research extends to the study of ‘orphan P450s’, like CYP4V2 and CYP4Z1, whose substrate specificity is unknown. We have reported on the fatty acid substrate specificity of CYP4V2 (Nakano et al., 2009) and the enzyme’s distribution in the eye (Nakano et al., 2012). Intriguingly, polymorphisms in CYP4V2 are found in patients suffering from the eye disease Bietti’s Crystalline Dystrophy (BCD). A knockout mouse model for CYP4V2 that recapitulates BCD has been developed in collaboration with the Kelly laboratory that should be of help in ‘deorphanizing’ the enzyme (Lockhart et al., 2014). Finally, the newest project in the Rettie lab concerns CYP4Z1, an unusual CYP that is localized to mammary tissue in humans and is up-regulated in breast cancer. We have expressed the enzyme in yeast and HepG2 cells and reported on the fatty acid metabolite profile of the enzyme (McDonald et al., 2017) and the development of novel, selective chemical inhibitors of CYP4Z1 (Kowalski et al., 2020).

In general, we use genetic re-engineering coupled with conventional protein biochemistry methods for the expression and isolation of CYP2 and CYP4 proteins and mutants of interest from heterologous hosts such as E.coli, insect cells and yeast (Mosher et al., 2008; Roberts et al., 2010). We also make extensive use of mass spectrometry for analyte quantification, including evaluation of structural changes in mutant proteins and lipidomic analysis to probe changes in endogenous metabolism due to CYP4V and CYP2C enzyme polymorphisms. Gene sequencing to discover novel polymorphisms in important pharmacogenes and disease-associated P450s is a continuing focus of the laboratory. Synthetic chemistry comes into play in the preparation of new substrates, inhibitors and metabolites for P450s of interest. Our long-term goals are to understand how structure and function are related for these important P450 enzyme families, and how their dysregulation affects drug response and disease.

Recent Publications

Deep mutational scanning of CYP2C19 in human cells reveals a substrate specificity-abundance tradeoff. Boyle GE, Sitko KA, Galloway JG, Haddox HK, Bianchi AH, Dixon A, Wheelock MK, Vandi AJ, Wang ZR, Thomson RES, Garge RK, Rettie AE, Rubin AF, Geck RC, Gillam EMJ, DeWitt WS, Matsen FA 4th, Fowler DM. Genetics. 2024 Nov 6;228(3):iyae156.

Sodium Dehydroacetate and Dehydroacetic Acid. Cherian P, Bergfeld WF, Belsito DV, Cohen DE, Klaassen CD, Rettie AE, Ross D, Slaga TJ, Snyder PW, Tilton S, Fiume M, Heldreth B. Int J Toxicol. 2024 Oct;43(4_suppl):130-134.

Isobutane, Isopentane, Butane, and Propane. Tucker R, Bergfeld WF, Belsito DV, Cohen DE, Klaassen CD, Rettie AE, Ross D, Slaga TJ, Snyder PW, Tilton S, Fiume M, Heldreth B. Int J Toxicol. 2025 Feb;44(1_suppl):17S-21S.

There and Back Again: A Perspective on 20 Years of CYP4Z1. Kowalski JP, Rettie AE. Drug Metab Dispos. 2024 Apr 11:DMD-MR-2024-001670.

Cytochrome P450 Family 4F2 and 4F11 Haplotype Mapping and Association with Hepatic Gene Expression and Vitamin K Hydroxylation Activity. Alade AN, Claw KG, McDonald MG, Prasad B, Rettie AE, Thummel KE. ACS Pharmacol Transl Sci. 2024 Feb 3;7(3):716-732.

Characterization of Gla proteoforms and non-Gla peptides of gamma carboxylated proteins: Application to quantification of prothrombin proteoforms in human plasma. Singh DK, Basit A, Rettie AE, Alade N, Thummel K, Prasad B. Anal Chim Acta. 2023 Dec 15;1284:341972.

Improved methods for the detection of heme and protoporphyrin IX adducts and quantification of heme B from cytochrome P450 containing systems. Pelletier RD, Rettie AE, Kowalski JP. J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Dec 1;1231:123921.

Experimental pharmacology in precision medicine. Urbaniak A, Thummel KE, Alade AN, Rettie AE, Prasad B, De Nicolò A, Martin JH, Sheppard DN, Jarvis MF. Pharmacol Res Perspect. 2023 Dec;11(6):e01147.

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations. Nguyen JT, Tian DD, Tanna RS, Arian CM, Calamia JC, Rettie AE, Thummel KE, Paine MF. J Pharmacol Exp Ther. 2023 Dec;387(3):252-264.

Translating Kratom-Drug Interactions: From Bedside to Bench and Back.  Tanna RS, Cech NB, Oberlies NH, Rettie AE, Thummel KE, Paine MF. Drug Metab Dispos. 2023 Aug;51(8):923-935.

Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom. Tanna RS, Nguyen JT, Hadi DL, Layton ME, White JR, Cech NB, Oberlies NH, Rettie AE, Thummel KE, Paine MF. Clin Pharmacol Ther. 2023 Jun;113(6):1315-1325.

Spotlight on CYP4B1. Röder A, Hüsken S, Hutter MC, Rettie AE, Hanenberg H, Wiek C, Girhard M. Int J Mol Sci. 2023 Jan 20;24(3):2038.

A Physiological-Based Pharmacokinetic Model Embedded with a Target-Mediated Drug Disposition Mechanism Can Characterize Single-Dose Warfarin Pharmacokinetic Profiles in Subjects with Various CYP2C9 Genotypes under Different Cotreatments. Cheng S, Flora DR, Rettie AE, Brundage RC, Tracy TS. Drug Metab Dispos. 2023 Feb;51(2):257-267.

Pharmacokinetic Modeling of Warfarin І – Model-based Analysis of Warfarin Enantiomers with a Target Mediated Drug Disposition Model Reveals CYP2C9 Genotype-dependent Drug-drug Interactions of S-Warfarin. Cheng S, Flora DR, Rettie AE, Brundage RC, Tracy TS. Drug Metab Dispos. 2022 Jul 7;50(9):1287-301.

Pharmacokinetic Modeling of Warfarin ІI – Model-based Analysis of Warfarin Metabolites following Warfarin Administered either Alone or Together with Fluconazole or Rifampin. Cheng S, Flora DR, Rettie AE, Brundage RC, Tracy TS. Drug Metab Dispos. 2022 Jul 7;50(9):1302-11.

Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants. Tanna RS, Nguyen JT, Hadi DL, Manwill PK, Flores-Bocanegra L, Layton ME, White JR, Cech NB, Oberlies NH, Rettie AE, Thummel KE, Paine MF. Pharmaceutics. 2022 Mar 11;14(3):620.

Adapting regulatory drug-drug interaction guidance to design clinical pharmacokinetic natural product-drug interaction studies: A NaPDI Center recommended approach. Cox EJ, Rettie AE, Unadkat JD, Thummel KE, McCune JS, Paine MF. Clin Transl Sci. 2022 Feb;15(2):322-329.

Abhinav Nath

Education

  • B.A. (Chemistry and Biology), University of Virginia
  • Ph.D. (Medicinal Chemistry/Biomolecular Structure & Design), University of Washington
  • Postdoc (Molecular Biophysics & Biochemistry), Yale University

Research Interests

  • Protein aggregation in Alzheimer’s disease and related dementias
  • Protein self-assembly
  • Biologics and protein-based therapeutics

Taking Students: Yes

Biography

Abhinav “Abhi” Nath earned his BA (in Biology and Chemistry) from the University of Virginia in 2003, and his PhD (in Medicinal Chemistry and Biomolecular Structure & Design) from the University of Washington in 2008, where he worked with Bill Atkins on understanding the mechanisms of substrate binding by cytochrome P450s and other drug-metabolizing enzymes. He then moved to Yale University for postdoctoral training with professors Liz Rhoades and Andrew Miranker, where he was an American Heart Association Postdoctoral Fellow and studied intrinsically disordered and amyloid-forming proteins using single-molecule fluorescence and computational methods.

The Nath lab is interested in understanding the roles of protein dynamics in human health and disease. Proteins display a fascinating spectrum of dynamic behavior, ranging from some that are almost static to others that rapidly interconvert between a diverse ensemble of structures. The nature, amplitude and timescales of protein conformational fluctuations can be crucial to biological functions such as enzyme catalysis and intracellular signaling. Mutations, post-translational modifications and environmental factors can perturb protein dynamics – and hence normal function – in ways that are difficult to predict.

Abhi and his group are developing new and powerful methods to characterize and control protein dynamics, building on recent advances in biophysics, biochemistry and pharmacology from groups around the world. They focus on proteins involved in degenerative disorders (such as Alzheimer’s disease), the oxidative stress response, and drug metabolism.

Recent Publications

Rigorous Analysis of Multimodal HDX-MS Spectra. Tuttle LM, James EI, Georgescauld F, Wales TE, Weis DD, Engen JR, Nath A, Klevit RE, Guttman M. J Am Soc Mass Spectrom. 2025 Feb 5;36(2):416-423.

Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein (FABP1) and FABP1 Binding Alters Drug Metabolism. Yabut KCB, Martynova A, Nath A, Zercher BP, Bush MF, Isoherranen N. Mol Pharmacol. 2024 Apr 5:MOLPHARM-AR-2024-000878.

Investigating the association between CYP2J2 inhibitors and QT prolongation: a literature review. Wiley AM, Yang J, Madhani R, Nath A, Totah RA. Drug Metab Rev. 2024 Mar 20:1-19.

Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation. James EI, Baggett DW, Chang E, Schachter J, Nixey T, Choi K, Guttman M, Nath A. bioRxiv [Preprint]. 2024 Feb 3:2024.02.02.578649.

The origins of nonideality exhibited by monoclonal antibodies and Fab fragments in human serum. Larsen HA, Atkins WM, Nath A. Protein Sci. 2023 Dec;32(12):e4812.

The Utility of Mixed Effects Models in the Evaluation of Complex Genomic Traits In Vitro. Alade N, Nath A, Isoherranen N, Thummel KE. Drug Metab Dispos. 2023 Nov;51(11):1455-1462.

Low molecular weight ligands bind to CYP3A4 via a branched induced fit mechanism: Implications for O2 binding. Redhair M, Nath A, Hackett JC, Atkins WM. Arch Biochem Biophys. 2023 May 1;739:109582.

MitoNEET’s Reactivity of Lys55 toward Pyridoxal Phosphate Demonstrates its Activity as a Transaminase Enzyme. Kunk C, Kruger J, Mendoza G, Markitan J, Bias T, Mann A, Nath A, Geldenhuys WJ, Menze MA, Konkle ME. ACS Chem Biol. 2022 Oct 21;17(10):2716-2722.

Structure-Activity Relationships of Novel Tau Ligands: Passive Fibril Binders and Active Aggregation Inhibitors. Baggett DW, Nath A. ACS Chem Biol. 2022 Mar 18;17(3):701-708.