Protein promiscuity and its implications for biotechnology

Nature Biotechnology

Volumn 27, Issue 2, 2009, Pages 157-167

  Nobeli, Irene ^a   Favia, Angelo D ^b   Thornton, Janet M ^b  

^a UNIVERSITY OF LONDON   (United Kingdom)

^b EUROPEAN MOLECULAR BIOLOGY LABORATORY   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BIOCHEMICAL ENGINEERING; BIOCHEMISTRY; BIOTECHNOLOGY; FUNCTIONS; GENETIC ENGINEERING; MOLECULAR BIOLOGY; MOLECULAR RECOGNITION; PROBABILITY DENSITY FUNCTION; PROTEINS;

ATTRITION RATES; BIOLOGICAL FUNCTIONS; CATALYTIC PROPERTIES; DRUG DISCOVERIES; EXPERIMENTAL EVIDENCES; LIVING ORGANISMS; METAGENOMICS; PROTEIN ENGINEERINGS; PROTEIN FUNCTIONS; SIDE EFFECTS; SYNTHETIC BIOLOGIES;

DRUG INTERACTIONS;

LIGAND; POLYMER; PROTEIN;

BIOCHEMISTRY; BIOLOGY; BIOTECHNOLOGY; DRUG DESIGN; ENERGY TRANSFER; GENETIC TRANSCRIPTION; METAGENOMICS; MOLECULAR EVOLUTION; MOLECULAR RECOGNITION; MUTATION; NONHUMAN; POLYPHARMACY; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN ENGINEERING; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN PROCESSING; REVIEW;

EID: 59849106371     PISSN: 10870156     EISSN: 15461696     Source Type: Journal    
DOI: 10.1038/nbt1519     Document Type: Review

References (119)

1. O'Brien, P.J. & Herschlag, D. Catalytic promiscuity and the evolution of new enzymatic activities. Chem. Biol. 6, R91-R105 (1999).
2. Copley, S.D. Enzymes with extra talents: moonlighting functions and catalytic promiscuity. Curr. Opin. Chem. Biol. 7, 265-272 (2003).
3. Colman, P.M. & Smith, B.J. Specificity and promiscuity in protein-ligand and protein-protein interactions. Aust. J. Chem. 56, 763-767 (2003).
4. Khersonsky, O., Roodveldt, C. & Tawfik, D.S. Enzyme promiscuity: evolutionary and mechanistic aspects. Curr. Opin. Chem. Biol. 10, 498-508 (2006).
5. Hult, K. & Berglund, P. Enzyme promiscuity: mechanism and applications. Trends Biotechnol. 25, 231-238 (2007).
6. Bornscheuer, U.T. & Kazlauskas, R.J. Catalytic promiscuity in biocatalysis: Using old enzymes to form new bonds and follow new pathways. Angew. Chem. Int. Edn Engl. 43, 6032-6040 (2004).
7. Jeffery, C.J. Moonlighting proteins. Trends Biochem. Sci. 24, 8-11 (1999).
8. D'Ari, R. & Casadesus, J. Underground metabolism. Bioessays 20, 181-186 (1998).
9. Sriram, G., Martinez, J.A., McCabe, E.R., Liao, J.C. & Dipple, K.M. Single-gene disorders: what role could moonlighting enzymes play? Am. J. Hum. Genet. 76, 911-924 (2005).
10. Kim, J. & Copley, S.D. Why metabolic enzymes are essential or nonessential for growth of Escherichia coli K12 on glucose. Biochemistry 46, 12501-12511 (2007).
11. Miller, B.G. & Raines, R.T. Identifying latent enzyme activities: substrate ambiguity within modern bacterial sugar kinases. Biochemistry 43, 6387-6392 (2004).
12. James, L.C. & Tawfik, D.S. Conformational diversity and protein evolution - a 60-year-old hypothesis revisited. Trends Biochem. Sci. 28, 361-368 (2003).
13. Farinas, E.T., Bulter, T. & Arnold, F.H. Directed enzyme evolution. Curr. Opin. Biotechnol. 12, 545-551 (2001).
14. Andrianantoandro, E., Basu, S., Karig, D.K. & Weiss, R. Synthetic biology: new engineering rules for an emerging discipline. Mol. Syst. Biol. 2, 2006 0028 (2006).
15. Watanabe, H., Takehana, K., Date, M., Shinozaki, T. & Raz, A. Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. Cancer Res. 56, 2960-2963 (1996).
16. Birney, E. et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799-816 (2007).
17. Jensen, R.A. Enzyme recruitment in evolution of new function. Annu. Rev. Microbiol. 30, 409-425 (1976).
18. Todd, A.E., Orengo, C.A. & Thornton, J.M. Evolution of function in protein superfamilies, from a structural perspective. J. Mol. Biol. 307, 1113-1143 (2001).
19. Nobeli, I., Spriggs, R.V., George, R.A. & Thornton, J.M. A ligand-centric analysis of the diversity and evolution of protein-ligand relationships in E.coli. J. Mol. Biol. 347, 415-436 (2005).
20. Devos, D. & Valencia, A. Practical limits of function prediction. Proteins 41, 98-107 (2000).
21. Gerlt, J.A. & Babbitt, P.C. Divergent evolution of enzymatic function: mechanistically diverse superfamilies and functionally distinct suprafamilies. Annu. Rev. Biochem. 70, 209-246 (2001).
22. Gerlt, J.A., Babbitt, P.C. & Rayment, I. Divergent evolution in the enolase superfamily: the interplay of mechanism and specificity. Arch. Biochem. Biophys. 433, 59-70 (2005).
23. Glasner, M.E., Gerlt, J.A. & Babbitt, P.C. Evolution of enzyme superfamilies. Curr. Opin. Chem. Biol. 10, 492-497 (2006).
24. Chiang, R.A., Sali, A. & Babbitt, P.C. Evolutionarily conserved substrate substructures for automated annotation of enzyme superfamilies. PLOS Comput. Biol. 4, e1000142 (2008).
25. Arevalo, J.H., Taussig, M.J. & Wilson, I.A. Molecular basis of crossreactivity and the limits of antibody-antigen complementarity. Nature 365, 859-863 (1993).
26. Kliewer, S.A., Goodwin, B. & Willson, T.M. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr. Rev. 23, 687-702 (2002).
27. Paulsen, I.T. Multidrug efflux pumps and resistance: regulation and evolution. Curr. Opin. Microbiol. 6, 446-451 (2003).
28. Wong, S.K. G protein selectivity is regulated by multiple intracellular regions of GPCRs. Neurosignals 12, 1-12 (2003).
29. Kallberg, Y., Oppermann, U., Jornvall, H. & Persson, B. Short-chain dehydrogenase/reductase (SDR) relationships: a large family with eight clusters common to human, animal, and plant genomes. Protein Sci. 11, 636-641 (2002).
30. Han, Q., Fang, J. & Li, J. Kynurenine aminotransferase and glutamine transaminase K of Escherichia coli: identity with aspartate aminotransferase. Biochem. J. 360, 617-623 (2001).
31. Allende, C.C. & Allende, J.E. Promiscuous subunit interactions: a possible mechanism for the regulation of protein kinase CK2. J. Cell. Biochem. Suppl. 30-31, 129-136 (1998).
32. Wietek, C. & O'Neill, L.A. Diversity and regulation in the NF-kappaB system. Trends Biochem. Sci. 32, 311-319 (2007).
33. Lazcano, A., Diaz-Villagomez, E., Mills, T. & Oro, J. On the levels of enzymatic substrate specificity: implications for the early evolution of metabolic pathways. Adv. Space Res. 15, 345-356 (1995).
34. Valeyev, N.V., Bates, D.G., Heslop-Harrison, P., Postlethwaite, I. & Kotov, N.V. Elucidating the mechanisms of cooperative calcium-calmodulin interactions: a structural systems biology approach. BMC Syst. Biol. 2, 48 (2008).
35. Kirschner, K. & Bisswanger, H. Multifunctional proteins. Annu. Rev. Biochem. 45, 143-166 (1976).
36. Pocker, Y. & Stone, J.T. The catalytic versatility of erythrocyte carbonic anhydrase. VII. Kinetic studies of esterase activity and competitive inhibition by substrate analogs. Biochemistry 7, 3021-3031 (1968).
37. Head, M.W. & Goldman, J.E. Small heat shock proteins, the cytoskeleton, and inclusion body formation. Neuropathol. Appl. Neurobiol. 26, 304-312 (2000).
38. van Noort, J.M. et al. The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis. Nature 375, 798-801 (1995).
39. Wang, J.T. et al. Detection of Epstein-Barr virus BGLF4 protein kinase in virus replication compartments and virus particles. J. Gen. Virol. 86, 3215-3225 (2005).
40. Lutz, S., Lichter, J. & Liu, L. Exploiting temperature-dependent substrate promiscuity for nucleoside analogue activation by thymidine kinase from Thermotoga maritima. J. Am. Chem. Soc. 129, 8714-8715 (2007).
41. Kennedy, M.C., Mende-Mueller, L., Blondin, G.A. & Beinert, H. Purification and characterization of cytosolic aconitase from beef liver and its relationship to the iron-responsive element binding protein. Proc. Natl. Acad. Sci. USA 89, 11730-11734 (1992).
42. Noy, N. Ligand specificity of nuclear hormone receptors: sifting through promiscuity. Biochemistry 46, 13461-13467 (2007).
43. Pal-Bhowmick, I., Vora, H.K. & Jarori, G.K. Sub-cellular localization and post-translational modifications of the Plasmodium yoelii enolase suggest moonlighting functions. Malar. J. 6, 45 (2007).
44. Matarasso, N., Schuster, S. & Avni, A. A novel plant cysteine protease has a dual function as a regulator of 1-aminocyclopropane-1-carboxylic Acid synthase gene expression. Plant Cell 17, 1205-1216 (2005).
45. Duncan, K., Edwards, R.M. & Coggins, J.R. The pentafunctional arom enzyme of Saccharomyces cerevisiae is a mosaic of monofunctional domains. Biochem. J. 246, 375-386 (1987).
46. Vogel, C., Bashton, M., Kerrison, N.D., Chothia, C. & Teichmann, S.A. Structure, function and evolution of multidomain proteins. Curr. Opin. Struct. Biol. 14, 208-216 (2004).
47. Bashton, M. & Chothia, C. The generation of new protein functions by the combination of domains. Structure 15, 85-99 (2007).
48. Parkison, C., Ashizawa, K., McPhie, P., Lin, K.H. & Cheng, S.Y. The monomer of pyruvate kinase, subtype M1, is both a kinase and a cytosolic thyroid hormone binding protein. Biochem. Biophys. Res. Commun. 179, 668-674 (1991).
49. Mazurek, S., Boschek, C.B., Hugo, F. & Eigenbrodt, E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol. 15, 300-308 (2005).
50. Koshland, D.E., Jr. Correlation of Structure and Function in Enzyme Action. Science 142, 1533-1541 (1963).
51. Ma, B., Shatsky, M., Wolfson, H.J. & Nussinov, R. Multiple diverse ligands binding at a single protein site: a matter of pre-existing populations. Protein Sci. 11, 184-197 (2002).
52. James, L.C., Roversi, P. & Tawfik, D.S. Antibody multispecificity mediated by conformational diversity. Science 299, 1362-1367 (2003).
53. Lange, O.F. et al. Recognition dynamics up to microseconds revealed from an RDC-derived ubiquitin ensemble in solution. Science 320, 1471-1475 (2008).
54. Grunberg, R., Leckner, J. & Nilges, M. Complementarity of structure ensembles in protein-protein binding. Structure 12, 2125-2136 (2004).
55. Ekroos, M. & Sjogren, T. Structural basis for ligand promiscuity in cytochrome P450 3A4. Proc. Natl. Acad. Sci. USA 103, 13682-13687 (2006).
56. Teague, S.J. Implications of protein flexibility for drug discovery. Nat. Rev. Drug Discov. 2, 527-541 (2003).
57. Celikel, R. et al. Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ibalpha. Science 301, 218-221 (2003).
58. Dumas, J.J., Kumar, R., Seehra, J., Somers, W.S. & Mosyak, L. Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation. Science 301, 222-226 (2003).
59. Zimmermann, J. et al. Antibody evolution constrains conformational heterogeneity by tailoring protein dynamics. Proc. Natl. Acad. Sci. USA 103, 13722-13727 (2006).
60. Oppermann, U. et al. Short-chain dehydrogenases/reductases (SDR): the 2002 update. Chem. Biol. Interact. 143-144, 247-253 (2003).
61. Seibert, C.M. & Raushel, F.M. Structural and catalytic diversity within the amidohydrolase superfamily. Biochemistry 44, 6383-6391 (2005).
62. Yamniuk, A.P. & Vogel, H.J. Calmodulin's flexibility allows for promiscuity in its interactions with target proteins and peptides. Mol. Biotechnol. 27, 33-58 (2004).
63. Hou, L. et al. Functional promiscuity correlates with conformational heterogeneity in A-class glutathione S-transferases. J. Biol. Chem. 282, 23264-23274 (2007).
64. Savir, Y. & Tlusty, T. Conformational proofreading: the impact of conformational changes on the specificity of molecular recognition. PLoS ONE 2, e468 (2007).
65. Guillet, V., Lapthorn, A., Hartley, R.W. & Mauguen, Y. Recognition between a bacterial ribonuclease, barnase, and its natural inhibitor, barstar. Structure 1, 165-176 (1993).
66. Mariuzza, R.A. Multiple paths to multispecificity. Immunity 24, 359-361 (2006).
67. Sethi, D.K., Agarwal, A., Manivel, V., Rao, K.V. & Salunke, D.M. Differential epitope positioning within the germline antibody paratope enhances promiscuity in the primary immune response. Immunity 24, 429-438 (2006).
68. Spiller, B., Gershenson, A., Arnold, F.H. & Stevens, R.C. A structural view of evolutionary divergence. Proc. Natl. Acad. Sci. USA 96, 12305-12310 (1999).
69. Orencia, M.C., Hanson, M.A. & Stevens, R.C. Structural analysis of affinity matured antibodies and laboratory-evolved enzymes. Adv. Protein Chem. 55, 227-259 (2000).
70. Schmidt, D.M. et al. Evolutionary potential of (beta/alpha)8-barrels: functional promiscuity produced by single substitutions in the enolase superfamily. Biochemistry 42, 8387-8393 (2003).
71. Woodhall, T., Williams, G., Berry, A. & Nelson, A. Creation of a tailored aldolase for the parallel synthesis of sialic acid mimetics. Angew. Chem. Int. Edn. Engl. 44, 2109-2112 (2005).
72. Babbitt, P.C. & Gerlt, J.A. Understanding enzyme superfamilies. Chemistry As the fundamental determinant in the evolution of new catalytic activities. J. Biol. Chem. 272, 30591-30594 (1997).
73. Raillard, S. et al. Novel enzyme activities and functional plasticity revealed by recombining highly homologous enzymes. Chem. Biol. 8, 891-898 (2001).
74. Taylor Ringia, E.A. et al. Evolution of enzymatic activity in the enolase superfamily: functional studies of the promiscuous o-succinylbenzoate synthase from Amycolatopsis. Biochemistry 43, 224-229 (2004).
75. Panchenko, A.R., Wolf, Y.I., Panchenko, L.A. & Madej, T. Evolutionary plasticity of protein families: coupling between sequence and structure variation. Proteins 61, 535-544 (2005).
76. Bloom, J.D., Labthavikul, S.T., Otey, C.R. & Arnold, F.H. Protein stability promotes evolvability. Proc. Natl. Acad. Sci. USA 103, 5869-5874 (2006).
77. Wagner, A. Robustness, evolvability, and neutrality. FEBS Lett. 579, 1772-1778 (2005).
78. Stockwell, G.R. & Thornton, J.M. Conformational diversity of ligands bound to proteins. J. Mol. Biol. 356, 928-944 (2006).
79. Perola, E. & Charifson, P.S. Conformational analysis of drug-like molecules bound to proteins: an extensive study of ligand reorganization upon binding. J. Med. Chem. 47, 2499-2510 (2004).
80. Denessiouk, K.A. & Johnson, M.S. When fold is not important: a common structural framework for adenine and AMP binding in 12 unrelated protein families. Proteins 38, 310-326 (2000).
81. Azzaoui, K. et al. Modeling promiscuity based on in vitro safety pharmacology profiling data. ChemMedChem 2, 874-880 (2007).
82. Allu, T.K. & Oprea, T.I. Rapid evaluation of synthetic and molecular complexity for in silico chemistry. J. Chem. Inf. Model. 45, 1237-1243 (2005).
83. Hopkins, A.L., Mason, J.S. & Overington, J.P. Can we rationally design promiscuous drugs? Curr. Opin. Struct. Biol. 16, 127-136 (2006).
84. Radhakrishnan, M.L. & Tidor, B. Specificity in molecular design: a physical framework for probing the determinants of binding specificity and promiscuity in a biological environment. J. Phys. Chem. B 111, 13419-13435 (2007).
85. Hann, M.M., Leach, A.R. & Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci. 41, 856-864 (2001).
86. Andreini, C., Banci, L., Bertini, I. & Rosato, A. Counting the zinc-proteins encoded in the human genome. J. Proteome Res. 5, 196-201 (2006).
87. Redinbo, M.R. Promiscuity: what protects us, perplexes us. Drug Discov. Today 9, 431-432 (2004).
88. Dimitrov, J.D., Lacroix-Desmazes, S., Kaveri, S.V. & Vassilev, T.L. Transition towards antigen-binding promiscuity of a monospecific antibody. Mol. Immunol. 44, 1854-1863 (2007).
89. Kang, J. & Warren, A.S. Enthalpy-entropy compensation in the transition of a monospecific antibody towards antigen-binding promiscuity. Mol. Immunol. 44, 3623-3624 (2007).
90. Aharoni, A. et al. The 'evolvability' of promiscuous protein functions. Nat. Genet. 37, 73-76 (2005).
91. Padlan, E.A. Anatomy of the antibody molecule. Mol. Immunol. 31, 169-217 (1994).
92. James, L.C. & Tawfik, D.S. The specificity of cross-reactivity: promiscuous antibody binding involves specific hydrogen bonds rather than nonspecific hydrophobic stickiness. Protein Sci. 12, 2183-2193 (2003).
93. Basdevant, N., Weinstein, H. & Ceruso, M. Thermodynamic basis for promiscuity and selectivity in protein-protein interactions: PDZ domains, a case study. J. Am. Chem. Soc. 128, 12766-12777 (2006).
94. Ohtaka, H. et al. Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors with adaptability to mutations and high selectivity towards unwanted targets. Int. J. Biochem. Cell Biol. 36, 1787-1799 (2004).
95. Weber, P.C., Pantoliano, M.W. & Salemme, F.R. Crystallographic and thermodynamic comparison of structurally diverse molecules binding to streptavidin. Acta Crystallogr. D Biol. Crystallogr. 51, 590-596 (1995).
96. Brannigan, J.A. & Wilkinson, A.J. Protein engineering 20 years on. Nat. Rev. Mol. Cell Biol. 3, 964-970 (2002).
97. Leisola, M. & Turunen, O. Protein engineering: opportunities and challenges. Appl. Microbiol. Biotechnol. 75, 1225-1232 (2007).
98. Bornscheuer, U.T. & Pohl, M. Improved biocatalysts by directed evolution and rational protein design. Curr. Opin. Chem. Biol. 5, 137-143 (2001).
99. Arnold, F.H. Combinatorial and computational challenges for biocatalyst design. Nature 409, 253-257 (2001).
100. Matsumura, I. & Ellington, A.D. In vitro evolution of beta-glucuronidase into a beta-galactosidase proceeds through non-specific intermediates. J. Mol. Biol. 305, 331-339 (2001).
101. Jurgens, C. et al. Directed evolution of a (beta alpha)8-barrel enzyme to catalyze related reactions in two different metabolic pathways. Proc. Natl. Acad. Sci. USA 97, 9925-9930 (2000).
102. Fischbach, M.A. & Clardy, J. One pathway, many products. Nat. Chem. Biol. 3, 353-355 (2007).
103. Gancedo, C. & Flores, C.L. Moonlighting proteins in yeasts. Microbiol. Mol. Biol. Rev. 72, 197-210 (2008).
104. Pleiss, J. The promise of synthetic biology. Appl. Microbiol. Biotechnol. 73, 735-739 (2006).
105. Merlot, C. In silico methods for early toxicity assessment. Curr. Opin. Drug Discov. Devel. 11, 80-85 (2008).
106. Campillos, M., Kuhn, M., Gavin, A.C., Jensen, L.J. & Bork, P. Drug target identification using side-effect similarity. Science 321, 263-266 (2008).
107. Fedorov, O. et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl. Acad. Sci. USA 104, 20523-20528 (2007).
108. Trubetskoy, O.V. et al. High throughput screening assay for UDP-glucuronosyltransferase 1A1 glucuronidation profiling. Assay Drug Dev. Technol. 5, 343-354 (2007).
109. Hopkins, A.L. & Groom, C.R. The druggable genome. Nat. Rev. Drug Discov. 1, 727-730 (2002).
110. Ohren, J.F. et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol. 11, 1192-1197 (2004).
111. Ekins, S. Predicting undesirable drug interactions with promiscuous proteins in silico. Drug Discov. Today 9, 276-285 (2004).
112. Chong, C.R. & Sullivan, D.J., Jr. New uses for old drugs. Nature 448, 645-646 (2007).
113. Weber, A. et al. Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition. J. Med. Chem. 47, 550-557 (2004).
114. Mencher, S.K. & Wang, L.G. Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC Clin. Pharmacol. 5, 3 (2005).
115. Roth, B.L., Sheffler, D.J. & Kroeze, W.K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov. 3, 353-359 (2004).
116. Morphy, R., Kay, C. & Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today 9, 641-651 (2004).
117. Gómez, A., Domedel; N., Cedaño' J., Pinol, J. & Querol, E. Do current sequence analysis algorithms disclose multifunctional (moonlighting) proteins? Bioinformatics 19, 895-896 (2003).
118. Macchiarulo, A., Nobeli; I. & Thornton, J.M. Ligand selectivity and competition between enzymes in silico. Nat. Biotechnol. 22, 1039-1045 (2004).
119. Favia, A.D., Nobeli, I., Glaser, F. & Thornton, J.M. Molecular docking for substrate identification: the short-chain dehydrogenases/reductases. J. Mol. Biol. 375, 855-874 (2008).