个人简介
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).
研究领域
Chemical Biology
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.
Polysaccharide Monooxygenases
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.
近期论文
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Rao M, Herzik MA, Iavarone AT, Marletta MA. Nitric oxide-induced conformational changes govern H-NOX and histidine kinase interaction and regulation in Shewanella oneidensis. Biochemistry 2017, 56 (9), 1274–1284
Span E, Suess DLM, Deller MC, Britt RD, Marletta MA. The role of the secondary coordination sphere in a fungal polysaccharide monooxygenase. ACS Chem Biol. 2017
Hespen CW, Bruegger JJ, Phillips-Piro CM, Marletta MA. Structural and Functional Evidence Indicates Selective Oxygen Signaling in Caldanaerobacter subterraneus H-NOX. ACS Chem Biol. 2016 Jun 21.
Vu VV and Marletta MA. Starch-degrading polysaccharide monooxygenases. Cell Mol Life Sci. 2016; 73, 2809-19. doi: 10.1007/s00018-016-2251-9.
Span EA and Marletta MA. The framework of polysaccharide monooxygenase structure and chemistry. Curr Opin Struct Biol. 2015; 35, 93-99. doi: 10.1016/j.sbi.2015.10.002.
Sürmeli NB, Müskens FM, Marletta MA. The Influence of Nitric Oxide on Soluble Guanylate Cyclase Regulation by Nucleotides: Role of the Pseudosymmetric Site. J Biol Chem. 2015; 290, 15570-15580. doi: 10.1074/jbc.M115.641431.
Beeson WT, Vu VV, Span EA, Phillips CM, Marletta MA. Cellulose degradation by polysaccharide monooxygenases. Annu Rev Biochem. 2015; 84, 923-946. doi: 10.1146/annurev-biochem-060614-034439.
Rao M, Smith BC, Marletta MA. Nitric Oxide Mediates Biofilm Formation and Symbiosis in Silicibacter sp. Strain TrichCH4B. MBio. 2015; 6, e00206-00215. doi: 10.1128/mBio.00206-15.
Wilkins MR, Aldashev AA, Wharton J, Rhodes CJ, Vandrovcova J, Kasperaviciute D, Bhosle SG, Mueller M, Geschka S, Rison S, Kojonazarov B, Morrell NW, Neidhardt I, Surmeli NB, Aitman TJ, Stasch JP, Behrends S, Marletta MA. α1-A680T variant in GUCY1A3 as a candidate conferring protection from pulmonary hypertension among Kyrgyz highlanders. Circ Cardiovasc Genet. 2014; 7, 920-929. doi: 10.1161/CIRCGENETICS.114.000763.
Herzik MA Jr, Jonnalagadda R, Kuriyan J, Marletta MA. Structural insights into the role of iron-histidine bond cleavage in nitric oxide-induced activation of H-NOX gas sensor proteins. Proc Natl Acad Sci USA. 2014; 111, E4156-4164. doi: 10.1073/pnas.1416936111.
Vu VV, Beeson WT, Span EA, Farquhar ER, Marletta MA. A family of starch-active polysaccharide monooxygenases. Proc Natl Acad Sci USA. 2014; 111, 13822-13827. doi: 10.1073/pnas.1408090111.
Campbell MG, Smith BC, Potter CS, Carragher B, Marletta MA. Molecular architecture of mammalian nitric oxide synthases. Proc Natl Acad Sci USA. 2014; 111, E3614-3623. doi: 10.1073/pnas.1413763111.
Underbakke ES, Iavarone AT, Chalmers MJ, Pascal BD, Novick S, Griffin PR, Marletta MA. Nitric oxide-induced conformational changes in soluble guanylate cyclase. Structure. 2014; 22, 602-611. doi: 10.1016/j.str.2014.01.008.
Nierth A, Marletta MA. Direct meso-alkynylation of metalloporphyrins through gold catalysis for hemoprotein engineering. Angew Chem Int Ed Engl. 2014; 53, 2611-2614. doi: 10.1002/anie.201310145.
Campbell MG, Underbakke ES, Potter CS, Carragher B, Marletta MA. Single-particle EM reveals the higher-order domain architecture of soluble guanylate cyclase. Proc Natl Acad Sci USA. 2014; 111, 2960-2965. doi: 10.1073/pnas.1400711111.
Vu VV, Beeson WT, Phillips CM, Cate JH, Marletta MA. Determinants of regioselective hydroxylation in the fungal polysaccharide monooxygenases. J Am Chem Soc. 2014; 136, 562-565. doi: 10.1021/ja409384b.
Plate L, Marletta MA. Phosphorylation-dependent derepression by the response regulator HnoC in the Shewanella oneidensis nitric oxide signaling network. Proc Natl Acad Sci USA. 2013, 110, E4648-4657. doi: 10.1073/pnas.1318128110.
Plate L, Marletta MA. Nitric oxide-sensing H-NOX proteins govern bacterial communal behavior. Trends Biochem Sci. 2013, 38, 566-575. doi: 10.1016/j.tibs.2013.08.008.
Weinert EE, Phillips-Piro CM, Marletta MA. Porphyrin π-stacking in a heme protein scaffold tunes gas ligand affinity. J Inorg Biochem. 2013, 127, 7-12. doi: 10.1016/j.jinorgbio.2013.06.004.
Smith BC, Underbakke ES, Kulp DW, Schief WR, Marletta MA. Nitric oxide synthase domain interfaces regulate electron transfer and calmodulin activation. Proc Natl Acad Sci USA. 2013, 110, E3577-3586. doi: 10.1073/pnas.1313331110.
Ivanisevic J, Zhu ZJ, Plate L, Tautenhahn R, Chen S, O'Brien PJ, Johnson CH, Marletta MA, Patti GJ, Siuzdak G. Toward 'omic scale metabolite profiling: a dual separation-mass spectrometry approach for coverage of lipid and central carbon metabolism. Anal Chem. 2013, 85, 6876-6884. doi: 10.1021/ac401140h.
Underbakke ES, Iavarone AT, Marletta MA. Higher-order interactions bridge the nitric oxide receptor and catalytic domains of soluble guanylate cyclase. Proc Natl Acad Sci USA. 2013, 110, 6777-6782.
Winter MB, Klemm PJ, Phillips-Piro CM, Raymond KN, Marletta MA. Porphyrin-substituted H-NOX proteins as high-relaxivity MRI contrast agents. Inorg Chem. 2013, 52, 2277-2279. doi: 10.1021/ic302685h.
Winter MB, Woodward JJ, Marletta MA. An Escherichia coli expression-based approach for porphyrin substitution in heme proteins. Methods Mol Biol. 2013, 987, 95-106. doi: 10.1007/978-1-62703-321-3_8.
Fernhoff NB, Derbyshire ER, Underbakke ES, Marletta MA. Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide. J Biol Chem. 2012, 287, 43053-43062.
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