1932

Abstract

After an undergraduate degree in biology at Harvard, I started graduate school at The Rockefeller Institute for Medical Research in New York City in July 1965. I was attracted to the chemical side of biochemistry and joined Fritz Lipmann's large, hierarchical laboratory to study enzyme mechanisms. That work led to postdoctoral research with Robert Abeles at Brandeis, then a center of what, 30 years later, would be called chemical biology. I spent 15 years on the Massachusetts Institute of Technology faculty, in both the Chemistry and Biology Departments, and then 26 years on the Harvard Medical School Faculty. My research interests have been at the intersection of chemistry, biology, and medicine. One unanticipated major focus has been investigating the chemical logic and enzymatic machinery of natural product biosynthesis, including antibiotics and antitumor agents. In this postgenomic era it is now recognized that there may be from 105 to 106 biosynthetic gene clusters as yet uncharacterized for potential new therapeutic agents.

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2017-06-20
2024-03-29
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Literature Cited

  1. Walsh C, Law JH, Wislon EO. 1.  1965. Purification of the fire ant trail substance. Nature 207:320–21 [Google Scholar]
  2. Gevers W, Kleinkauf H, Lipmann F. 2.  1968. The activation of amino acids for biosynthesis of gramicidin S. PNAS 60:1269–76 [Google Scholar]
  3. Gevers W, Kleinkauf H, Lipmann F. 3.  1969. Peptidyl transfers in gramicidin S bisoynthesis from enzyme-bound thioester intermediates. PNAS 63:41335–42 [Google Scholar]
  4. Lipmann F, Roskoski R Jr., Kleinhauf H, Gevers W. 4.  1970. Isolation of enzyme-bound peptide intermediates in tyrocidine biosynthesis. Biochemistry 9:254846–51 [Google Scholar]
  5. Kleinkauf H, Gevers W, Roskoski R Jr, Lipmann F. 5.  1970. Enzyme-bound phosphopantetheine in tyrocidine biosynthesis. Biochem. Biophys. Res. Commun. 41:51218–22 [Google Scholar]
  6. Westheimer F. 6.  1987. Why nature chose phosphates. Science 235:1173–78 [Google Scholar]
  7. Frey PA, Abeles RH. 7.  1966. The role of the B12 coenzyme in the conversion of 1,2-propanediol to propionaldehdye. J. Biol. Chem. 241:2732–33 [Google Scholar]
  8. Walsh C. 8.  1982. Suicide substrates: mechanism-based enzyme inactivators. Tetrahedron 38:871–909 [Google Scholar]
  9. Walsh CT, Schonbrunn A, Abeles RH. 9.  1971. Studies on the mechanism of action of D-amino acid oxidase. Evidence for removal of substrate α-hydrogen as a proton. J. Biol. Chem. 246:226855–66 [Google Scholar]
  10. Walsh CT, Krodel E, Massey V, Abeles RH. 10.  1973. Studies on the elimination reaction of D-amino acid oxidase with α-amino-β-chlorobutyrate. Further evidence for abstraction of substrate α-hydrogen as a proton. J. Biol. Chem. 248:61946–55 [Google Scholar]
  11. Walsh C. 11.  1979. Enzymatic Reaction Mechanisms San Francisco: W.H. Freeman
  12. Wang E, Walsh C. 12.  1978. Suicide substrates for the alanine racemase of Escherichia coli B. Biochemistry 17:71313–21 [Google Scholar]
  13. Walsh C. 13.  2000. Molecular mechanisms that confer antibacterial drug resistance. Nature 406:6797775–81 [Google Scholar]
  14. Walsh C. 14.  2003. Antibiotics: Actions, Origins, Resistance Washington, DC: Am. Soc. Microbiol. Press [Google Scholar]
  15. Walsh C, Wencewicz T. 15.  2016. Antibiotics: Challenges, Mechanisms, Opportunities Washington, DC: Am. Soc. Microbiol. Press
  16. Spencer R, Fisher J, Walsh C. 16.  1976. Preparation, characterization, and chemical properties of the flavin coenzyme analogues 5-deazariboflavin, 5-deazariboflavin 5′-phosphate, and 5-deazariboflavin 5′-diphosphate, 5′ → 5′-adenosine ester. Biochemistry 15:51043–53 [Google Scholar]
  17. Fisher J, Spencer R, Walsh C. 17.  1976. Enzyme-catalyzed redox reactions with the flavin analogues 5-deazariboflavin, 5-deazariboflavin 5′-phosphate, and 5-deazariboflavin 5′-diphosphate, 5′ → 5′-adenosine ester. Biochemistry 15:51054–64 [Google Scholar]
  18. Walsh C. 18.  1985. Naturally occurring 5-deazaflavin coenzymes: biological redox rules. Acc. Chem. Res. 19:216–21 [Google Scholar]
  19. DiMarco AA, Bobik TA, Wolfe RS. 19.  1990. Unusual coenzymes of methanogenesis. Annu. Rev. Biochem. 59:355–94 [Google Scholar]
  20. Fox JA, Livingston DJ, Orme-Johnson WH, Walsh CT. 20.  1987. 8-Hydroxy-5-deazaflavin-reducing hydrogenase from Methanobacterium thermoautotrophicum: 1. Purification and characterization. Biochemistry 26:144219–27 [Google Scholar]
  21. Livingston DJ, Fox JA, Orme-Johnson WH, Walsh CT. 21.  1987. 8-Hydroxy-5-deazaflavin-reducing hydrogenase from Methanobacterium thermoautotrophicum: 2. Kinetic and hydrogen-transfer studies. Biochemistry 26:144228–37 [Google Scholar]
  22. Walsh CT, Orme-Johnson WH. 22.  1987. Nickel enzymes. Biochemistry 26:164901–6 [Google Scholar]
  23. Fox B, Walsh CT. 23.  1982. Mercuric reductase. Purification and characterization of a transposon-encoded flavoprotein containing an oxidation-reduction-active disulfide. J. Biol. Chem. 257:52498–503 [Google Scholar]
  24. Begley TP, Walts AE, Walsh CT. 24.  1986. Mechanistic studies of a protonolytic organomercurial cleaving enzyme: bacterial organomercurial lyase. Biochemistry 25:227192–200 [Google Scholar]
  25. Begley TP, Walts AE, Walsh CT. 25.  1986. Bacterial organomercurial lyase: overproduction, isolation, and characterization. Biochemistry 25:227186–92 [Google Scholar]
  26. O'Halloran T, Walsh C. 26.  1987. Metalloregulatory DNA-binding protein encoded by the merR gene: isolation and characterization. Science 235:211–14 [Google Scholar]
  27. Peiser GD, Wang TT, Hoffman NE, Yang SF, Liu HW, Walsh CT. 27.  1984. Formation of cyanide from carbon 1 of 1-aminocyclopropane-1-carboxylic acid during its conversion to ethylene. PNAS 81:103059–63 [Google Scholar]
  28. Wackett LP, Shames SL, Venditti CP, Walsh CT. 28.  1987. Bacterial carbon-phosphorus lyase: products, rates, and regulation of phosphonic and phosphinic acid metabolism. J. Bacteriol. 169:2710–17 [Google Scholar]
  29. Wackett LP, Wanner BL, Venditti CP, Walsh CT. 29.  1987. Involvement of the phosphate regulon and the psiD locus in carbon-phosphorus lyase activity of Escherichia coli K-12. J. Bacteriol 169:41753–56 [Google Scholar]
  30. Chen CM, Ye QZ, Zhu Z, Wanner BL, Walsh CT. 30.  1990. Molecular biology of carbon–phosphorus bond cleavage. Cloning and sequencing of the phn (psiD) genes involved in alkylphosphonate uptake and C–P lyase activity in Escherichia coli B. J. Biol. Chem 265:84461–71 [Google Scholar]
  31. Kamat SS, Williams HJ, Dangott LJ, Chakrabarti M, Raushel FM. 31.  2013. The catalytic mechanism for aerobic formation of methane by bacteria. Nature 497:7447132–36 [Google Scholar]
  32. Hubbard BK, Walsh CT. 32.  2003. Vancomycin assembly: nature's way. Angew. Chem. Int. Ed. Engl. 42:7730–65 [Google Scholar]
  33. Rusnak F, Sakaitani M, Drueckhammer D, Reichert J, Walsh CT. 33.  1991. Biosynthesis of the Escherichia coli siderophore enterobactin: sequence of the entF gene, expression and purification of EntF, and analysis of covalent phosphopantetheine. Biochemistry 30:112916–27 [Google Scholar]
  34. Lambalot RH, Walsh CT. 34.  1995. Cloning, overproduction, and characterization of the Escherichia coli holo-acyl carrier protein synthase. J. Biol. Chem. 270:4224658–61 [Google Scholar]
  35. Gehring AM, Mori I, Walsh CT. 35.  1998. Reconstitution and characterization of the Escherichia coli enterobactin synthetase from EntB, EntE, and EntF. Biochemistry 37:82648–59 [Google Scholar]
  36. Lambalot RH, Gehring AM, Flugel RS, Zuber P, LaCelle M. 36.  et al. 1996. A new enzyme superfamily—the phosphopantetheinyl transferases. Chem. Biol. 3:11923–36 [Google Scholar]
  37. Walsh CT, Fischbach MA. 37.  2010. Natural products version 2.0: connecting genes to molecules. J. Am. Chem. Soc. 132:82469–93 [Google Scholar]
  38. Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT. 38.  2006. Nature's inventory of halogenation catalysts: oxidative strategies predominate. Chem. Rev. 106:83364–78 [Google Scholar]
  39. Vaillancourt FH, Yeh E, Vosburg DA, O'Connor SE, Walsh CT. 39.  2005. Cryptic chlorination by a non-haem iron enzyme during cyclopropyl amino acid biosynthesis. Nature 436:70541191–94 [Google Scholar]
  40. Vaillancourt FH, Yin J, Walsh CT. 40.  2005. SyrB2 in syringomycin E biosynthesis is a nonheme FeII α-ketoglutarate- and O2-dependent halogenase. PNAS 102:2910111–16 [Google Scholar]
  41. Bugg TDH, Wright GD, Dutka-Malen S, Arthur M, Courvalin P, Walsh CT. 41.  1991. Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. Biochemistry 30:4310408–15 [Google Scholar]
  42. Walsh CT, Fisher SL, Park IS, Prahalad M, Wu Z. 42.  1996. Bacterial resistance to vancomycin: Five genes and one missing hydrogen bond tell the story. Chem. Biol. 3:121–28 [Google Scholar]
  43. Chen H, Thomas MG, Hubbard BK, Losey HC, Walsh CT, Burkart MD. 43.  2000. Deoxysugars in glycopeptide antibiotics: enzymatic synthesis of TDP-L-epivancosamine in chloroeremomycin biosynthesis. PNAS 97:2211942–47 [Google Scholar]
  44. Crosa JH, Walsh CT. 44.  2002. Genetics and assembly line enzymology of siderophore biosynthesis in bacteria. Microbiol. Mol. Biol. Rev. 66:2223–49 [Google Scholar]
  45. Freel Myers CL, Oberthür M, Heide L, Kahne D, Walsh CT. 45.  2004. Assembly of dimeric variants of coumermycins by tandem actions of the four biosynthetic enzymes CouL, CouM, CouP, and NovN. Biochemistry 43:15022–36 [Google Scholar]
  46. Walsh CT, Zhang W. 46.  2011. Chemical logic and enzymatic machinery for biological assembly of peptidyl nucleoside antibiotics. ACS Chem. Biol. 6:101000–7 [Google Scholar]
  47. Fujimori DG, Hrvatin S, Neumann CS, Strieker M, Marahiel MA, Walsh CT. 47.  2007. Cloning and characterization of the biosynthetic gene cluster for Kutznerides. PNAS 104:16498–504 [Google Scholar]
  48. Sinha Roy R, Belshaw PMJ, Gehring A, Walsh C. 48.  1999. Thiazole and oxazole peptides: biosynthesis and molecular machinery. Nat. Prod. Rep. 16:249–63 [Google Scholar]
  49. Li Y-M, Madison LLMJ, Kolyter R, Walsh C. 49.  1996. From peptide precursors to oxazole and thiazole peptide antibiotics. Science 274:1188–93 [Google Scholar]
  50. Walsh CT, Acker MG, Bowers AA. 50.  2010. Thiazolyl peptide antibiotic biosynthesis: a cascade of post-translational modifications on ribosomal nascent proteins. J. Biol. Chem. 285:3627525–31 [Google Scholar]
  51. Cacho RA, Jiang W, Chooi YH, Walsh CT, Tang Y. 51.  2012. Identification and characterization of the echinocandin B biosynthetic gene cluster from Emericella rugulosa NRRL 11440. J. Am. Chem. Soc. 134:4016781–90 [Google Scholar]
  52. Walsh CT, Haynes SW, Ames BD, Gao X, Tang Y. 52.  2013. Short pathways to complexity generation: fungal peptidyl alkaloid multicyclic scaffolds from anthranilate building blocks. ACS Chem. Biol. 8:71366–82 [Google Scholar]
  53. Stephen L. 53.  1921. Dictionary of National Biography 21 London: Smith, Elder, and Co.
  54. Walsh C. 54.  2005. Posttranslational Modifications of Proteins: Expanding Nature's Inventory Englewood, CO: W.H. Freeman
  55. Wilczek F. 55.  2015. A Beautiful Question: Finding Nature's Deep Design New York: Penguin Books
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