September 2017 Meeting Announcement, Delaware Valley Mass Spectrometry Discussion Group
- Topic: "Progress in top-down analysis of branched proteins: conjugated ubiquitin and polyubiquitins
- Speaker:Catherine Fenselau,University of Maryland
- Date: Monday, Sepbember 11, 2017. 6:00 PM
- Please RSVP to XQiu2@ITS.JNJ.com by Thursday September 7.
- Time: Social Hour: 6:00 PM.
Talk: 7:00 PM.
- Place: Department of Chemistry, Villanova University (Mendel Hall 154)
Conjugated ubiquitin and polyubiquitins play critical but incompletely understood roles in cell signaling and cell biology. For the mass spectrometrist these conjugates offer the challenge/opportunity to extend top-down proteomic strategies to the analysis of branched proteins. We have succeeded in trapping sufficient numbers of ubiquitin trimer ions (25.5 kDa), tetramer ions (34 kDa) and pentamer ions (42.5 kDa) using a tribrid mass spectrometer, and obtained sufficiently dense fragmentation using combinations of ETD and CID (EThcD) to provide MS/MS spectra that contain the required structural information, including sites of conjugation and topology. We have facilitated interpretation of these spectra with a novel use of existing software. Our standards have been custom-synthesized to provide an assortment of topologies. HPLC is carried out on a monolith column that provides moderate separation. Currently, the strategy is being extended to characterize ubiquitin chains conjugated to target proteins and synthetic peptides.
Catherine Fenselau was the first woman to be promoted to full professor (1982) in a pre-clinical department at the Johns Hopkins Medical School. Her job description there was to exploit mass spectrometry in support of biomedical research. Among many firsts, her team elucidated the structure of the active metabolite of the widely used anticancer agent cyclophosphamide (Cancer Research 1973) and discovered that the controversial antitumor compound being sold as Laetrile was a glycoside, not the patented glucuronide (Science 1977). Her laboratory demonstrated that acyl-linked glucuronides can alkylate proteins to provide toxic side effects in drug metabolism (Drug Metab. Disp. 1985). As mass spectrometry evolved for peptide analysis, her laboratory provided the critical value of the proton affinity of arginine (Rapid Commun. Mass Spectrom. 1992). She first reported that bacteria could be distinguished at the species level by direct desorption of intact chemical biomarkers into the mass spectrometer (Anal. Chem. 1975) and through several decades of subsequent research her team helped lay the groundwork for recent approval by the FDA of MALDI-TOF for rapid clinical diagnosis of microorganisms. She is currently Professor of Chemistry and Biochemistry at the University of Maryland, where she is funded to characterize the protein and small RNA cargo of extracellular vesicles shed by myeloid-derived suppressor cells, and to extend top-down MS strategies to elucidate polyubiquitin and other branched protein structures. Her contributions to mass spectrometry and its biomedical applications have been recognized by awards from the American Chemical Society, the International Mass Spectrometry Foundation, American Society for Mass Spectrometry, Eastern Analytical Symposium, Pittsburg Conference, American Society for Pharmacology and Experimental Therapeutics, Human Proteome Organization and others. She was recently designated Distinguished University Professor at the University of Maryland.
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