Smell is one of five senses through which we perceive the world. By one estimate, humans can sense more than one trillion olfactory stimuli (1). My talk will focus on strong-smelling sulfur-containing odorants, whose chemistry I have been studying for more than 50 years (2, 3), with a major focus being on sulfur compounds from garlic, onions and related species ("Allium chemistry") (4). Humans and animals have an exquisitely sensitive sense of smell toward low-valent, volatile sulfur compounds. In 1887, Emil Fischer wrote that concentrations of ethanethiol as low as 0.05 ppb are “clearly perceptible to the sense of smell” (5). Chiral 3-methyl-3-sulfanylhexan-1-ol, in onions and in armpit odor (6), can be perceived at levels as low as 0.000001 ppb (7). In 2005 we identified (methylthio)methanethiol (MeSCH2SH; MTMT) as a garlic-smelling social-signaling compound found in mouse urine (8). We subsequently identified the mouse odorant receptor (OR), MOR244-3, responding robustly to MTMT, finding that it employs Cu as a cofactor (9, 10). Extending this research, I will describe the identification of a Cu-requiring human OR, responding robustly to 2-methyl-2-propanethiol, the odorant in natural gas, and related thiols. Taking a broader look at the sense of smell, I will discuss the vibrational theory of olfaction, focusing on musk odorants and their human ORs (11). Our collaborative OR studies use QM/MM modeling and site-directed mutagenesis to understand the molecular basis for olfactory detection of strong-smelling compounds (12). (1) Bushdid, C. et al. Science 2014, 343, 1370–2. (2) Corey, E.J.; Block, E. J. Org. Chem. 1966, 31, 1663–68. (3) Block, E. Reactions of Organosulfur Compounds, Academic Press, New York, 1978, 317 p. (4) Block, E. Garlic and Other Alliums: The Lore and the Science, RSC, Cambridge, 454 pp., 2010. (5) Fischer, E.; Penzoldt, F. Liebigs Ann. Chem. 1887, 239, 131–5. (6) Natsch, A.; Schmid, J.; Flachsmann, F. Chem. Biodiversity 2004, 1,1058–72. (7) Kraft, P.; Mannschreck, A. J. Chem. Educ. 2010, 87, 598–603. (8) Lin, D.Y.; Zhang, S.-Z.; Block, E.; Katz, L.C. Nature, 2005, 434, 470–7. (9) Duan, X. et al., PNAS, 2012, 109, 3492–7. (10) Block, E., Zhuang, H. In Biochalcogen Chemistry: The Biological Chemistry of Sulfur, Selenium, and Tellurium, ACS Symposium Series 1152, C.A. Bayse, J. Brumaghim Ed., ACS: Washington DC, 2013, Ch. 1. (11) Block, E. et al. PNAS, 2015, 112, E2766–74, and E3155. (12) Sekharan, S. et al. Biophysical Journal, 2014, 107, L05-8.

Award Address (Ernest Guenther Award in the Chemistry of Natural Products sponsored by Givaudan). Fifty years of smelling sulfur: From the chemistry of garlic and onion to the molecular basis for olfaction

251st National Meeting (2016)

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