Professor of Chemistry
Professor of Molecular and Cell Biology
CH and Annie Li Chair in the Molecular Biology of Diseases
Questions under investigation in our laboratory lie at the interface of chemistry and biology with a particular emphasis on the study of protein function and enzyme reaction mechanisms and a focus on molecular answers to complex function in biology.
NO Signaling and gas sensing
The lab has had a long-standing interest in nitric oxide (NO) function in biology. We have brought chemical thinking to bear on how a reactive and toxic molecule like NO functions selectively in biological responses such as blood vessel dilation, central nervous system signaling and signaling in prokaryotes. We have uncovered many aspects of NO function including key elements of the enzyme nitric oxide synthase and the receptor for NO, the soluble isoform of guanylate cyclase (sGC). Our continued studies on NO signaling have led to a more general molecular understanding of gas sensing mechanisms in biology.
Molecular questions on how the heme in sGC is able to capture NO in competition with the much more abundant oxygen led to the discovery of a novel family of prokaryotic and eukaryotic hemoprotein sensor proteins that have been termed H-NOX proteins (Heme-Nitric oxide OXygen). Some bacterial H-NOXs have ligand properties identical to sGC and some form stable complexes with oxygen, CO and NO. With John Kuriyan, H-NOX structures were solved that led to the key molecular determinants for ligand discrimination against oxygen. Since then we have solved many more structures, including recent electron microscopy views of nitric oxide synthase and sGC. The ability to link structure to ligand specificity has allowed us to discover novel sGCs regulated by oxygen, oxygen sensing in C. elegans, decipher an NO-dependent two-component signaling pathway in prokaryotes involved in biofilm formation, and other aspects of H-NOX function in biology. H-NOX signaling in pathogens such as Vibrio cholerae is a current focus of study.
The lab has recently investigated cellulose degradation with the hope of getting past a long-standing bottleneck in producing biofuels from feedstock. We assumed organisms that efficiently degrade cellulose such as the fungus Neurospora, must have an enzyme repertoire beyond those that utilize hydrolytic general acid and base catalysis. Using transcriptomics, knockouts, and quantitative proteomics, we discovered a new class of copper-dependent hydroxylases, termed polysaccharide monooxygenases (PMOs), which play a significant role in cellulose degradation. Structure and function relationships are currently under study. In addition, PMOs have been found in fungal and bacterial pathogens as well as some thought to be involved in development. Study of these novel PMOs is underway.
Born 1951.A.B., S.U.N.Y. College at Fredonia (1973); Ph.D., University of California, San Francisco (1978); NIH Postdoctoral Fellow, Department of Chemistry, M.I.T. (1978-80); Assistant/Associate Professor, M.I.T. (1980-87); Associate Professor, Univ. of Michigan (1987-91); John G. Searle Professor of Medicinal Chemistry, Univ. of Michigan (1991-01); Professor, Univ. of Michigan (1991-01); Investigator, Howard Hughes Medical Institute (1997-01); Professor of Chemistry and Biochemistry and Molecular Biology, U.C. Berkeley (2001-11); President Elect, The Scripps Research Institute, La Jolla, CA (2011-12); President and CEO, The Scripps Research Institute (2012-14); Cecil H. and Ida M. Green Chair in Chemistry, The Scripps Research Institute (2011-15); Professor of Chemistry and Molecular and Cell Biology, U.C. Berkeley (2015-present); George H. Hitchings Award for Innovative Methods in Drug Discovery and Design (1991); Faculty recognition Award, The University of Michigan (1992); Outstanding Alumni Achievement Award, S.U.N.Y. College at Fredonia (1992); MacArthur Foundation Fellowship (1995); S.U.N.Y. Alumni Honor Roll (1996); Distinguished Faculty Lectureship Award in Biomedical Research (2000); State of Michigan Scientist of the Year (2000); Distinguished Faculty Achievement Award, University of Michigan (2000); Member, Institute of Medicine; Fellow, American Academy of Arts and Sciences; Member, National Academy of Sciences; Repligen Award, Division of Biological Chemistry of the American Chemical Society (2007); Gustavus John Esselen Award for Chemistry in the Public Interest (2007); Emil Thomas Kaiser Award of the Protein Society (2007); Murray Goodman Memorial Prize (2008); Fellow, Royal Society of Chemistry (2009); Fellow, National Academy of Inventors (2013); American Association of State Colleges and Universities AASCU Distinguished Alumnus (2014); Alfred Bader Award in Bioinorganic or Bioorganic Chemistry (2015); UCSF 150th Anniversary Alumni Excellence Award (2015).