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Chapter 36 : Enzyme Promiscuity and Evolution of New Protein Functions

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Abstract:

This chapter introduces the various categories of promiscuity and their possible role in enzyme evolution. It also reviews some of the well-known examples of enzymes for which the promiscuous function is industrially relevant, leading to conversions of nonnatural compounds. Enzyme promiscuity is becoming an increasingly important phenomenon in the field of biocatalysis, both directly and indirectly: directly, because many desirable conversions are “unnatural,” so expansion of the existing functions of protein catalysts is necessary to convert these “promiscuous” substrates; indirectly, through the observation that promiscuous enzymes may be particularly evolvable, opening a wide range of possibilities for engineering these potentially valuable side activities. lipase B (CALB) is a typical representative of the α/β-hydrolase fold family of enzymes comprising not only a number of other esterases, but also haloalkane dehalogenases and epoxide hydrolases. Many of these natural products have unique bioactivity and are thus of great interest to the pharmaceutical industry. Halohydrin lyases or haloalcohol dehalogenases are found in various bacteria that are able to use halogenated hydrocarbons as a sole source of carbon and energy. The improvement of several of the promiscuous reactions of CALB was obtained by removing the catalytic nucleophile, naturally resulting in decreased performance for the native activity.

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36

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Multienzyme Complex
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Isobutyryl-Coenzyme A
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Pseudomonas aeruginosa
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Image of FIGURE 1
FIGURE 1

Different types of enzyme promiscuity. Promiscuous molecular recognition can take place at different stages of a reaction cycle. (A) In substrate promiscuity, the enzyme is able to recognize substrates with different structural features, but the chemical transformation performed is identical despite different substituents. (B) In product promiscuity, one substrate can be converted to many alternative products. The molecular recognition of the intermediate is conserved, but the folding of the intermediate or rearrangements of the reactive centers on the intermediate, e.g., by steric complementarity of the active-site template, lead to a variety of products onward from this reactive intermediate. (C) To achieve catalytic promiscuity, the tightest interactions—those in the transition state—have to be tolerant enough to recognize different reaction centers and bond-making and -breaking processes around them.

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 2
FIGURE 2

Mechanism of the native esterolytic activity of CALB. Upon substrate binding, the carbonyl functionality becomes positioned and polarized by the oxyanion hole (step a). The activated Asp-His pair activates the serine nucleophile, which performs a nucleophilic attack on the carbonyl carbon (b), ultimately resulting in the release of an alcohol and binding of a water molecule (c). The Asp-His pair now activates a water molecule for nucleophilic attack on the carbonyl carbon by general base catalysis, and the oxyanion hole performs the same role as it did for the first step, resulting in hydrolysis of the acyl-enzyme complex and release of the carboxylic acid (d).

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 3
FIGURE 3

Catalytic promiscuity of CALB. The oxyanion hole is a key catalytic feature, polarizing the carbonyl bond of the electrophile in each reaction and offsetting the development of negative charge at oxygen. The reactions catalyzed by CALB are: (A) native carboxylic ester hydrolysis ( ); (B) aldol condensation ( ); (C) Michael-type addition ( ); (D) epoxidation ( ); and (E) the predicted Baeyer-Villiger reaction ( ). For the promiscuous functions, the catalytic nucleophile does not take part in catalysis. The other parts of the active-site residues play a similar role, and the serine has been replaced by an external nucleophile that is activated by the Asp-His pair, which acts as a general base.

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 4
FIGURE 4

Substrate promiscuity allows the combinatorial biosynthesis of avermectin analogs. The R group in the avermectin structure originates from either 2-methylbutyryl-coenzyme A or isobutyryl-coenzyme A, which are generated from -leucine and -valine, respectively. In ATCC 53569, a branched-chain α-keto acid dehydrogenase that is essential for the in vivo production of the branched-chain fatty acids is absent ( ), rendering this strain unable to produce avermectins. Feeding up 40 different fatty acid compounds (with a variety of substitutions in R) to this mutant strain restores the biosynthetic machinery, resulting, in each case, in a different avermectin analog ( ). For instance, in doramectin biosynthesis, cyclohexane carboxylic acid is incorporated ( ), replacing either methyl-butyric acid or isobutyric acid in the wild-type strain ( ).

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 5
FIGURE 5

Biodegradation routes for halogenated hydrocarbons involving haloalcohol dehaloge-nases. (A) Degradation of 1,3-dichloro-2-propanol to glycerol in AD1, catalyzed by a haloalcohol dehalogenase (HheC) and an epoxide hydrolase (EchA) ( ). (B) Degradation of 1,2-dibromoethane to ethylene oxide in sp. GP1, catalyzed by a haloalkane deha-logenase (DhaAf) and a haloalcohol dehalogenase (HheB) ( ).

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 6
FIGURE 6

Mechanism of haloalcohol dehalogenases and their likely precursors, the short-chain dehydrogenases/reductases (SDRs). (A) Proposed mechanism of AD1 haloalcohol dehalogenase (HheC)-catalyzed ring closure of a vicinal haloalcohol. The Tyr145/Arg149 pair acts as a general base to abstract a proton from the hydroxyl group, resulting in an intramolecular nucleo-philic displacement of the halide, aided by leaving group stabilization by the halide binding site ( ). (B) Proposed mechanism of SDR enzymes, in which the proton abstraction from the hydroxyl group is followed by hydrogen abstraction by the NAD, resulting in the corresponding ketone.

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 7
FIGURE 7

Nucleophile promiscuity for the halohydrin dehalogenase-catalyzed epoxide ring opening. The position of the equilibrium is dependent on the nucleophile.

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 8
FIGURE 8

Schematic representation of (A) ()- and (B) ()-pNSO in the active site of haloalcohol dehalogenase from AD1 (HheC) ( ). The proposed difference in binding modes is based on X-ray structures of HheC in complex with ()- and ()-pNSO, respectively. Both structures were refined with -nitrophenylcyclopropane as the substrate to obtain an unbiased view of the interactions of the Ser132/Tyr145 pair with the epoxide ring. These data show that the refinement data for both structures can be completely superimposed, apart from the epoxide ring, in which the ()-enantiomer comes close enough to the Ser/Tyr pair to form a productive hydrogen bond. The calculated difference in Gibbs binding energy for both structures is also in agreement with the loss of one hydrogen bond.

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 9
FIGURE 9

One-pot synthesis of ()-4-cyano-3-hydroxybutanoate methyl ester from racemic 4-chloro-3-hydroxybutanoate methylester using a mutant haloalcohol dehalogenase (HheC W249F [ ]). This method makes use of both the native activity (step a) and one of the promiscuous activities (step b) of HheC ( ).

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 10
FIGURE 10

Catalytic promiscuity of BVMOs. (A) Proposed reaction cycle for each of the different conversions ( ). The reaction cycle starts with reduction of the oxidized flavin (I) by NADPH, resulting in reduced flavin (II) and NADP, which is released from the enzyme only at the end of the catalytic cycle. The reduced flavin subsequently reacts with molecular oxygen to form the peroxyflavin intermediate (IIIa), which has been suggested to exist also in the protonated state (IIIb). This highly reactive intermediate is stabilized by various interactions with residues in the active site and can react with a variety of different substrates, both electron-rich and electron-deficient substrates (B) ( ). The resulting hydroxyflavin (IV) subsequently decomposes into oxidized flavin (I) by eliminating water. Finally, NADP is released from the enzyme, allowing the enzyme to start another catalytic cycle.

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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Image of FIGURE 11
FIGURE 11

Mechanisms of the various hydrolases that belong to the alkaline phosphatase su-perfamily. (A) AP ( ). (B) NPP ( ). (C) arylsulfatase ( ). (D) Mechanism proposed for the PMH from (PMH), based on X-ray structural data and the kinetic data of various active-site mutants ( ). The active-site residues of PMH from (PMH) superimpose ideally on PMH (86% amino acid identity), suggesting that PMH uses the same mechanism ( ).

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36
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References

/content/book/10.1128/9781555816827.ch36
1. Aharoni, A.,, A. D. Griffiths, and, D. S. Tawfik. 2005. High-throughput screens and selections of enzyme-encoding genes. Curr. Opin. Chem. Biol. 9:210216.
2. Aharoni, A.,, L. Gaidukov,, O. Khersonsky,, S. McQ Gould,, C. Roodveldt, and, D. S. Tawfik. 2005. The “evolvability” of promiscuous protein functions. Nat. Genet. 37:7376.
3. Archelas, A., and, R. Furstoss. 2001. Synthetic applications of epoxide hydrolases. Curr. Opin. Chem. Biol. 5:112119.
4. Babtie, A. C.,, S. Bandyopadhyay,, L. F. Olguin, and, F. Hollfelder. 2009. Efficient catalytic promiscuity for chemically distinct reactions. Angew. Chem. Int. Ed. 48:36923694.
5. Belshaw, P. J.,, C. T. Walsh, and, T. Stachelhaus. 1999. Aminoacyl-CoAs as probes of condensation domain selectivity in nonribosomal peptide synthesis. Science 284:486489.
6. Berezina, N.,, V. Alphand, and, R. Furstoss. 2002. Microbiological transformations. Part 51. The first example of a dynamic kinetic resolution process applied to a microbiological Baeyer-Villiger oxidation. Tetrahedron Asymmetry 13:19531955.
7. Boltes, I.,, H. Czapinska,, A. Kahnert,, R. von Bulow,, T. Dierks,, B. Schmidt,, K. von Figura,, M. A. Kertesz, and, I. Uson. 2001. 1.3 Å structure of arylsulfatase from Pseudomonas aeruginosa establishes the catalytic mechanism of sulfate ester cleavage in the sulfatase family. Structure 9:483491.
8. Bornscheuer, U. T., and, R. J. Kazlauskas. 2004. Catalytic promiscuity in biocatalysis: using old enzymes to form new bonds and follow new pathways. Angew. Chem. Int. Ed. 43:60326040.
9. Branchaud, B. P., and, C. T. Walsh. 1985. Functional group diversity in enzymatic oxygenation reactions catalyzed by bacterial flavin-containing cyclohexanone oxygenase. J. Am. Chem. Soc. 107:21532161.
10. Branneby, C.,, P. Carlqvist,, A. Magnusson,, K. Hult,, T. Brinck, and, P. Berglund. 2003. Carbon-carbon bonds by hydrolytic enzymes. J. Am. Chem. Soc. 125:874875.
11. Cane, D. E., and, C. T. Walsh. 1999. The parallel and convergent universes of polyketide synthases and nonribo-somal peptide synthetases. Chem. Biol. 6:R319R325.
12. Carlqvist, P.,, R. Eklund,, K. Hult, and, T. Brinck. 2003. Rational design of a lipase to accommodate catalysis of Baeyer-Villiger oxidation with hydrogen peroxide. J. Mol. Model. 9:164171.
13. Carlqvist, P.,, M. Svedendahl,, C. Branneby,, K. Hult,, T. Brinck, and, P. Berglund. 2005. Exploring the active-site of a rationally redesigned lipase for catalysis of Michael-type additions. Chembiochem 6:331336.
14. Castro, C. E., and, E. W. Bartnicki. 1968. Biodehaloge-nation. Epoxidation of halohydrins, epoxide opening and transhalogenation by Flavobacterium sp. Biochemistry 7:32133218.
15. Chen, G.,, M. M. Kayser,, M. D. Mihovilovic,, M. E. Mrstik,, C. A. Martinez, and, J. D. Stewart. 1999. Asymmetric oxidation at sulfur catalyzed by engineered strains that overexpress cyclohexanone monooxygenase. New J. Chem. 23:827832.
16. Chen, Y. C.,, O. P. Peoples, and, C. T. Walsh. 1988. Aci-netobacter cyclohexanone monooxygenase: gene cloning and sequence determination. J. Bacteriol. 170:781789.
17. Colonna, S.,, N. Gaggero,, G. Carrea,, G. Ottolina,, P. Pasta, and, F. Zambianchi. 2002. First asymmetric ep-oxidation catalysed by cyclohexanone monooxygenase. Tetrahedron Lett. 43:17971799.
18. Colonna, S.,, N. Gaggero,, G. Carrea, and, P. Pasta. 1998. Oxidation of organic cyclic sulfites to sulfates: a new reaction catalyzed by cyclohexanone monooxygenase. Chem. Commun. 415416.
19. Colonna, S.,, N. Gaggero,, G. Carrea,, P. Pasta,, V. Alphand, and, R. Furstoss. 2001. Enantioselective synthesis of tert-butyl tert-butanethiosulfinate catalyzed by cyclohexanone monooxygenase. Chirality 13:4042.
20. Colonna, S.,, V. Pironti,, P. Pasta, and, F. Zambianchi. 2003. Oxidation of amines catalyzed by cyclohexanone monooxygenase. Tetrahedron Lett. 44:869871.
21. Copley, S. D. 2003. Enzymes with extra talents: moonlighting functions and catalytic promiscuity. Curr. Opin. Chem. Biol. 7:265272.
22. de Gonzalo, G.,, D. E. Torres Pazmino,, G. Ottolina,, M. W. Fraaije, and, G. Carrea. 2006. 4-Hydroxyacetophenone monooxygenase from Pseudomonas fluorescens ACB as an oxidative biocatalyst in the synthesis of optically active sulfoxides. Tetrahedron Asymmetry 17:130135.
23. de Gonzalo, G.,, D. E. Torres Pazmino,, G. Ottolina,, M. W. Fraaije, and, G. Carrea. 2005. Oxidations catalyzed by phenylacetone monooxygenase from Thermobifida fusca. Tetrahedron Asymmetry 16:30773083.
24. de Jong, R. M.,, K. H. Kalk,, L. Tang,, D. B. Janssen, and, B. W. Dijkstra. 2006. The X-ray structure of the haloalcohol dehalogenase HheA from Arthrobacter sp. strain AD2: insight into enantioselectivity and halide binding in the halo-alcohol dehalogenase family. J. Bacteriol. 188:40514056.
25. de Jong, R. M.,, J. J. Tiesinga,, H. J. Rozeboom,, K. H. Kalk,, L. Tang,, D. B. Janssen, and, B. W. Dijkstra. 2003. Structure and mechanism of a bacterial haloalcohol de-halogenase: a new variation of the short-chain dehydro-genase/reductase fold without an NAD(P)H binding site. EMBO J. 22:49334944.
26. de Jong, R. M.,, J. J. Tiesinga,, A. Villa,, L. Tang,, D. B. Janssen, and, B. W. Dijkstra. 2005. Structural basis for the enantioselectivity of an epoxide ring opening reaction catalyzed by halo alcohol dehalogenase HheC. J. Am. Chem. Soc. 127:1333813343.
27. Denoya, C. D.,, R. W. Fedechko,, E. W. Hafner,, H. A. McArthur,, M. R. Morgenstern,, D. D. Skinner,, K. Stutzman-Engwall,, R. G. Wax, and, W. C. Wernau. 1995. A second branched-chain alpha-keto acid de-hydrogenase gene cluster (bkdFGH) from Streptomyces avermitilis: its relationship to avermectin biosynthesis and the construction of a bkdF mutant suitable for the production of novel antiparasitic avermectins. J. Bacteriol. 177:35043411.
28. Dutton, C. J.,, S. P. Gibson,, A. C. Goudie,, K. S. Holdom,, M. S. Pacey,, J. C. Ruddock,, J. D. Bu’Lock, and, M. K. Richards. 1991. Novel avermectins produced by mutational biosynthesis. J. Antibiot. (Tokyo) 44:357365.
29. Ehmann, D. E.,, J. W. Trauger,, T. Stachelhaus, and, C. T. Walsh. 2000. Aminoacyl-SNACs as small-molecule substrates for the condensation domains of nonribosomal peptide synthetases. Chem. Biol. 7:765772.
30. Firn, R. D., and, C. G. Jones. 2000. The evolution of secondary metabolism—a unifying model. Mol. Microbiol. 37:989994.
31. Fischbach, M. A., and, J. Clardy. 2007. One pathway, many products. Nat. Chem. Biol. 3:353355.
32. Fox, R. J.,, S. C. Davis,, E. C. Mundorff,, L. M. Newman,, V. Gavrilovic,, S. K. Ma,, L. M. Chung,, C. Ching,, S. Tam,, S. Muley,, J. Grate,, J. Gruber,, J. C. Whitman,, R. A. Sheldon, and, G. W. Huisman. 2007. Improving catalytic function by ProSAR-driven enzyme evolution. Nat. Biotechnol. 25:338344.
33. Fraaije, M. W.,, N. M. Kamerbeek,, A. J. Heidekamp,, R. Fortin, and, D. B. Janssen. 2004. The prodrug activator EtaA from Mycobacterium tuberculosis is a Baeyer-Villiger monooxygenase. J. Biol. Chem. 279:33543360.
34. Fraaije, M. W.,, J. Wu,, D. P. Heuts,, E. W. van Hellemond,, J. H. Spelberg, and, D. B. Janssen. 2005. Discovery of a thermostable Baeyer-Villiger monooxygenase by genome mining. Appl. Microbiol. Biotechnol. 66:393400.
35. Frueh, D. P.,, H. Arthanari,, A. Koglin,, D. A. Vosburg,, A. E. Bennett,, C. T. Walsh, and, G. Wagner. 2008. Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase. Nature 454:903906.
36. Frykman, H.,, N. Ohrner,, T. Norin, and, K. Hult. 1993. S-Ethyl thiooctanoate as acyl donor in lipase catalysed resolution of secondary alcohols. Tetrahedron Lett. 34:13671370.
37. Galli, G.,, F. Rodriguez,, P. Cosmina,, C. Pratesi,, R. Nogarotto,, F. de Ferra, and, G. Grandi. 1994. Characterization of the surfactin synthetase multi-enzyme complex. Biochim. Biophys. Acta 1205:1928.
38. Glasner, M. E.,, J. A. Gerlt, and, P. C. Babbitt. 2006. Evolution of enzyme superfamilies. Curr. Opin. Chem. Biol. 10:492497.
39. Hafner, E. W.,, B. W. Holley,, K. S. Holdom,, S. E. Lee,, R. G. Wax,, D. Beck,, H. A. McArthur, and, W. C. Wernau. 1991. Branched-chain fatty acid requirement for avermec-tin production by a mutant of Streptomyces avermitilis lacking branched-chain 2-oxo acid dehydrogenase activity. J. Antibiot. (Tokyo) 44:349356.
40. Hans, M.,, A. Hornung,, A. Dziarnowski,, D. E. Cane, and, C. Khosla. 2003. Mechanistic analysis of acyl trans-ferase domain exchange in polyketide synthase modules. J. Am. Chem. Soc. 125:53665374.
41. Hasnaoui, G.,, J. H. Lutje Spelberg,, E. J. de Vries,, L. Tang,, B. Hauer, and, D. B. Janssen. 2005. Nitrite-mediated hydrolysis of epoxides catalyzed by halohydrin dehalogenase from Agrobacterium radiobacter AD1: a new tool for the kinetic resolution of epoxides. Tetrahedron Asymmetry 16:16851692.
42. Hasnaoui-Dijoux, G.,, M. Majeric Elenkov,, J. H. Lutje Spelberg,, B. Hauer, and, D. B. Janssen. 2008. Catalytic promiscuity of halohydrin dehalogenase and its application in enantioselective epoxide ring opening. Chembiochem 9:10481051.
43. Hecht, M. H.,, A. Das,, A. Go,, L. H. Bradley, and, Y. Wei. 2004. De novo proteins from designed combinatorial libraries. Protein Sci. 13:17111723.
44. Hengge, A. C., and, I. Onyido. 2005. Physical organic perspectives on phospho group transfer from phosphates and phosphonates. Curr. Org. Chem. 9:6174.
45. Hollfelder, F., and, D. Herschlag. 1995. The nature of the transition state for enzyme-catalyzed phosphoryl transfer. Hydrolysis of O-aryl phosphorothioates by alkaline phosphatase. Biochemistry 34:1225512264.
46. Holmquist, M. 2000. Alpha/beta-hydrolase fold enzymes: structures, functions and mechanisms. Curr. Protein Pept. Sci. 1:209235.
47. Huebner, A.,, S. Sharma,, M. Srisa-Art,, F. Hollfelder,, J. B. Edel, and, A. J. Demello. 2008. Microdroplets: a sea of applications? Lab. Chip 8:12441254.
48. Hughes, A. L. 1994. The evolution of functionally novel proteins after gene duplication. Proc. Biol. Sci. 256:119124.
49. Hult, K., and, P. Berglund. 2007. Enzyme promiscuity: mechanism and applications. Trends Biotechnol. 25:231238.
50. Iwaki, H.,, Y. Hasegawa,, S. Wang,, M. M. Kayser, and, P. C. Lau. 2002. Cloning and characterization of a gene cluster involved in cyclopentanol metabolism in Comamonas sp. strain NCIMB 9872 and biotransformations effected by Escherichia coli-expressed cyclopen-tanone 1,2-monooxygenase. Appl. Environ. Microbiol. 68:56715684.
51. Jensen, R. A. 1976. Enzyme recruitment in evolution of new function. Annu. Rev. Microbiol. 30:409425.
52. Jiang, L.,, E. A. Althoff,, F. R. Clemente,, L. Doyle,, D. Rothlisberger,, A. Zanghellini,, J. L. Gallaher,, J. L. Betker,, F. Tanaka,, C. F. Barbas III,, D. Hilvert,, K. N. Houk,, B. L. Stoddard, and, D. Baker. 2008. De novo computational design of retro-aldol enzymes. Science 319:13871391.
53. Jing, Q., and, R. J. Kazlauskas. 2008. Determination of absolute configuration of secondary alcohols using lipase-catalyzed kinetic resolutions. Chirality 20:724735.
54. Jonas, S., and, F. Hollfelder. 2009. Mechanism and catalytic promiscuity: emerging mechanistic principles for identification and manipulation of catalytically promiscuous enzymes, p. 4779. In S. Lutz and, U. T. Bornscheuer (ed.), Protein Engineering Handbook, vol. 1. Wiley VCH, Weinheim, Germany.
55. Jonas, S., and, F. Hollfelder. 2009. Mapping catalytic promiscuity in the alkaline phosphatase superfamily. Pure Appl. Chem. 81:733744.
56. Jonas, S.,, B. van Loo,, M. Hyvonen, and, F. Hollfelder. 2008. A new member of the alkaline phosphatase superfam-ily with a formylglycine nucleophile: structural and kinetic characterisation of a phosphonate monoester hydrolase/phosphodiesterase from Rhizobium leguminosarum. J. Mol. Biol. 384:120136.
57. Kamerbeek, N. M.,, D. B. Janssen,, W. J. H. van Berkel, and, M. W. Fraaije. 2003. Baeyer-Villiger monooxygen-ases, an emerging family of flavin-dependent biocatalysts. Adv. Synth. Catal. 345:667678.
58. Kamerbeek, N. M.,, M. J. Moonen,, J. G. Van Der Ven,, W. J. Van Berkel,, M. W. Fraaije, and, D. B. Janssen. 2001. 4-Hydroxyacetophenone monooxygenase from Pseudomonas fluorescens ACB. A novel flavoprotein catalyzing Baeyer-Villiger oxidation of aromatic compounds. Eur. J. Biochem. 268:25472557.
59. Kapur, S., and, C. Khosla. 2008. Biochemistry: fit for an enzyme. Nature 454:832833.
60. Kelly, B. T.,, J. C. Baret,, V. Taly, and, A. D. Griffiths. 2007. Miniaturizing chemistry and biology in microdroplets. Chem. Commun. 17731788.
61. Khersonsky, O.,, C. Roodveldt, and, D. S. Tawfik. 2006. Enzyme promiscuity: evolutionary and mechanistic aspects. Curr. Opin. Chem. Biol. 10:498508.
62. Khosla, C.,, S. Kapur, and, D. E. Cane. 2009. Revisiting the modularity of modular polyketide synthases. Curr. Opin. Chem. Biol. 13:135143.
63. Kirby, A. J., and, W. P. Jencks. 1965. The reactivity of nucleophilic reagents toward the p-nitrophenyl phosphate dianion. J. Am. Chem. Soc. 87:32093216.
64. Kohli, R. M.,, C. T. Walsh, and, M. D. Burkart. 2002. Biomimetic synthesis and optimization of cyclic peptide antibiotics. Nature 418:658661.
65. Kostichka, K.,, S. M. Thomas,, K. J. Gibson,, V. Nagarajan, and, Q. Cheng. 2001. Cloning and characterization of a gene cluster for cyclododecanone oxidation in Rhodococcus ruber SC1. J. Bacteriol. 183:64786486.
66. Lassila, J. K., and, D. Herschlag. 2008. Promiscuous sulfatase activity and thio-effects in a phosphodiester-ase of the alkaline phosphatase superfamily. Biochemistry 47:1285312859.
67. Lawen, A., and, R. Traber. 1993. Substrate specificities of cyclosporin synthetase and peptolide SDZ 214–103 synthetase. Comparison of the substrate specificities of the related multifunctional polypeptides. J. Biol. Chem. 268:2045220465.
68. Lutje Spelberg, J. H.,, L. Tang,, M. van Gelder,, R. M. Kellogg, and, D. B. Janssen. 2002. Exploration of the bio-catalytic potential of a halohydrin dehalogenase using chro-mogenic substrates. Tetrahedron Asymmetry 13:10831089.
69. Lutje Spelberg, J. H.,, J. E. van Hylckama Vlieg,, T. Bosma,, R. M. Kellogg, and, D. B. Janssen. 1999. A tandem enzyme reaction to produce optically active halohydrins, epoxides and diols. Tetrahedron Asymmetry 10:29632870.
70. Lutje Spelberg, J. H.,, J. E. van Hylckama Vlieg,, L. Tang,, D. B. Janssen, and, R. M. Kellogg. 2001. Highly enantioselective and regioselective biocatalytic azidolysis of aromatic epoxides. Org. Lett. 3:4143.
71. Majeric Elenkov, M.,, B. Hauer, and, D. B. Janssen. 2006. Enantioselective ring opening of epoxides with cyanide catalysed by halohydrin dehalogenase: a new approach to non-racemic β-hydroxy nitriles. Adv. Synth. Catal. 348:579585.
72. Majeric Elenkov, M.,, L. Tang,, B. Hauer, and, D. B. Janssen. 2006. Sequential kinetic resolution catalyzed by halohydrin dehalogenase. Org. Lett. 8:42274229.
73. Majeric Elenkov, M.,, L. Tang,, A. Meetsma,, B. Hauer, and, D. B. Janssen. 2008. Formation of enantiopure 5-substituted oxazolidinones through enzyme-catalysed kinetic resolution of epoxides. Org. Lett. 10:24172420.
74. Majerić Elenkov, M.,, H. W. Hoeffken,, L. Tang,, B. Hauer, and, D. B. Janssen. 2007. Enzyme-catalyzed nucleophilic ring opening of epoxides for the preparation of enantiopure tertiary alcohols. Adv. Synth. Catal. 349:22792285.
75. Malito, E.,, A. Alfieri,, M. W. Fraaije, and, A. Mattevi. 2004. Crystal structure of a Baeyer-Villiger monooxygen-ase. Proc. Natl. Acad. Sci. USA 101:1315713162.
76. Marsden, A. F.,, B. Wilkinson,, J. Cortes,, N. J. Dunster,, J. Staunton, and, P. F. Leadlay. 1998. Engineering broader specificity into an antibiotic-producing polyketide synthase. Science 279:199202.
77. Mihovilovic, M. D.,, B. Müller, and, P. Stanetty. 2002. Monooxygenase-mediated Baeyer-Villiger oxidations. Eur. J. Org. Chem. 37113730.
78. Mootz, H. D., and, M. A. Marahiel. 1997. The tyro-cidine biosynthesis operon of Bacillus brevis: complete nucleotide sequence and biochemical characterization of functional internal adenylation domains. J. Bacteriol. 179:68436850.
79. Morii, S.,, S. Sawamoto,, Y. Yamauchi,, M. Miyamoto,, M. Iwami, and, E. Itagaki. 1999. Steroid monooxygenase of Rhodococcus rhodochrous: sequencing of the genomic DNA, and hyperexpression, purification, and characterization of the recombinant enzyme. J. Biochem. 126:624631.
80. Nakamura, T.,, T. Nagasawa,, F. Yu,, I. Watanabe, and, H. Yamada. 1991. A new catalytic function of halohydrin hydrogen-halide-lyase, synthesis of β-hydroxynitriles from epoxides and cyanide. Biochem. Biophys. Res. Commun. 180:124130.
81. Nakamura, T.,, T. Nagasawa,, F. Yu,, I. Watanabe, and, H. Yamada. 1994. A new enzymatic synthesis of (R)-g-chloro-β-hydroxybutyronitrile. Tetrahedron 50:1182111826.
82. Nguyen, K. T.,, D. Ritz,, J. Q. Gu,, D. Alexander,, M. Chu,, V. Miao,, P. Brian, and, R. H. Baltz. 2006. Combinatorial biosynthesis of novel antibiotics related to daptomycin. Proc. Natl. Acad. Sci. USA 103:1746217467.
83. Nobeli, I.,, A. D. Favia, and, J. M. Thornton. 2009. Protein promiscuity and its implications for biotechnology. Nat. Biotechnol. 27:157167.
84. O’Brien, P. J., and, D. Herschlag. 1998. Sulfatase activity of E. coli alkaline phosphatase demonstrates a functional link to arylsulfatases, an evolutionary related enzyme family. J. Am. Chem. Soc. 120:1236912370.
85. O’Brien, P. J., and, D. Herschlag. 1999. Catalytic promiscuity and the evolution of new enzymatic activities. Chem. Biol. 6:R91R105.
86. O’Brien, P. J., and, D. Herschlag. 2001. Functional interrelationships in the alkaline phosphatase superfamily: phosphodiesterase activity of Escherichia coli alkaline phosphatase. Biochemistry 40:56915699.
87. Olguin, L. F.,, S. E. Askew,, A. C. O’Donoghue, and, F. Hollfelder. 2008. Efficient catalytic promiscuity in an enzyme superfamily: an arylsulfatase shows a rate acceleration of 1013 for phosphate monoester hydrolysis. J. Am. Chem. Soc. 130:1654716555.
88. Ollis, D. L.,, E. Cheah,, M. Cygler,, B. Dijkstra,, F. Frolow,, S. M. Franken,, M. Harel,, S. J. Remington,, I. Silman,, J. Schrag,, J. L. Sussman,, K. H. G. Verschueren, and, A. Goldman. 1992. The α/β hydrolase fold. Protein Eng. 5:197211.
89. Ottolina, G.,, S. Bianchi,, B. Belloni,, G. Carrea, and, B. Danieli. 1999. First asymmetric oxidation of tertiary amines by cyclohexanone monooxygenase. Tetrahedron Lett. 40:84838486.
90. Patrick, W. M., and, I. Matsumura. 2008. A study in molecular contingency: glutamine phosphoribosylpyrophosphate amidotransferase is a promiscuous and evolvable phosphori-bosylanthranilate isomerase. J. Mol. Biol. 377:323336.
91. Poelarends, G. J.,, W. H. Johnson, Jr.,, H. Serrano, and, C. P. Whitman. 2007. Phenylpyruvate tautomerase activity of trans-3-chloroacrylic acid dehalogenase: evidence for an enol intermediate in the dehalogenase reaction? Biochemistry 46:95969604.
92. Poelarends, G. J.,, H. Serrano,, W. H. Johnson, Jr.,, D. W. Hoffman, and, C. P. Whitman. 2004. The hydratase activity of malonate semialdehyde decarboxylase: mechanistic and evolutionary implications. J. Am. Chem. Soc. 126:1565815659.
93. Poelarends, G. J.,, H. Serrano,, M. D. Person,, W. H. Johnson, Jr.,, A. G. Murzin, and, C. P. Whitman. 2004. Cloning, expression, and characterization of a cis-3-chloroacrylic acid dehalogenase: insights into the mechanistic, structural, and evolutionary relationship between isomer-specific 3-chloroacrylic acid dehalogenases. Biochemistry 43:759772.
94. Poelarends, G. J.,, J. E. van Hylckama Vlieg,, J. R. Marchesi,, L. M. Freitas Dos Santos, and, D. B. Janssen. 1999. Degradation of 1,2-dibromoethane by Mycobacterium sp. strain GP1. J. Bacteriol. 181:20502058.
95. Poelarends, G. J.,, V. P. Veetil, and, C. P. Whitman. 2008. The chemical versatility of the β-α-β fold: catalytic promiscuity and divergent evolution in the tautomerase superfamily. Cell. Mol. Life Sci. 65:36063618.
96. Rothlisberger, D.,, O. Khersonsky,, A. M. Wollacott,, L. Jiang,, J. DeChancie,, J. Betker,, J. L. Gallaher,, E. A. Althoff,, A. Zanghellini,, O. Dym,, S. Albeck,, K. N. Houk,, D. S. Tawfik, and, D. Baker. 2008. Kemp elimination catalysts by computational enzyme design. Nature 453:190195.
97. Schneider, A.,, T. Stachelhaus, and, M. A. Marahiel. 1998. Targeted alteration of the substrate specificity of peptide synthetases by rational module swapping. Mol. Gen. Genet. 257:308318.
98. Stachelhaus, T.,, A. Schneider, and, M. A. Marahiel. 1995. Rational design of peptide antibiotics by targeted replacement of bacterial and fungal domains. Science 269:6972.
99. Stec, B.,, K. M. Holtz, and, E. R. Kantrowitz. 2000. A revised mechanism for the alkaline phosphatase reaction involving three metal ions. J. Mol. Biol. 299:13031311.
100. Steele, C. L.,, J. Crock,, J. Bohlmann, and, R. Croteau. 1998. Sesquiterpene synthases from grand fir (Abies grandis). Comparison of constitutive and wound-induced activities, and cDNA isolation, characterization, and bacterial expression of delta-selinene synthase and g-humulene synthase. J. Biol. Chem. 273:20782089.
101. Steinreiber, A., and, K. Faber. 2001. Microbial epox-ide hydrolases for preparative biotransformations. Curr. Opin. Biotechnol. 12:552558.
102. Stutzman-Engwall, K.,, S. Conlon,, R. Fedechko,, F. Kaczmarek,, H. McArthur,, A. Krebber,, Y. Chen,, J. Minshull,, S. A. Raillard, and, C. Gustafsson. 2003. Engineering the aveC gene to enhance the ratio of dora-mectin to its CHC-B2 analogue produced in Streptomyces avermitilis. Biotechnol. Bioeng. 82:359369.
103. Stutzman-Engwall, K.,, S. Conlon,, R. Fedechko,, H. McArthur,, K. Pekrun,, Y. Chen,, S. Jenne,, C. La,, N. Trinh,, S. Kim,, Y. X. Zhang,, R. Fox,, C. Gustafsson, and, A. Krebber. 2005. Semi-synthetic DNA shuffling of aveC leads to improved industrial scale production of doramec-tin by Streptomyces avermitilis. Metab. Eng. 7:2737.
104. Svedendahl, M.,, P. Carlqvist,, C. Branneby,, O. Allner,, A. Frise,, K. Hult,, P. Berglund, and, T. Brinck. 2008. Direct epoxidation in Candida antarctica lipase B studied by experiment and theory. Chembiochem 9:24432451.
105. Svedendahl, M.,, K. Hult, and, P. Berglund. 2005. Fast carbon-carbon bond formation by a promiscuous lipase. J. Am. Chem. Soc. 127:1798817989.
106. Taly, V.,, B. T. Kelly, and, A. D. Griffiths. 2007. Droplets as microreactors for high-throughput biology. Chembiochem 8:263272.
107. Tang, L.,, A. E. van Merode,, J. H. Lutje Spelberg,, M. W. Fraaije, and, D. B. Janssen. 2003. Steady-state kinetics and tryptophan fluorescence properties of halohy-drin dehalogenase from Agrobacterium radiobacter. Roles of W139 and W249 in the active site and halide-induced conformational change. Biochemistry 42:1405714065.
108. Tanovic, A.,, S. A. Samel,, L. O. Essen, and, M. A. Marahiel. 2008. Crystal structure of the termination module of a nonribosomal peptide synthetase. Science 321:659663.
109. Torres Pazmino, D. E.,, B. J. Baas,, D. B. Janssen, and, M. W. Fraaije. 2008. Kinetic mechanism of phenylacetone monooxygenase from Thermobifida fusca. Biochemistry 47:40824093.
110. Torres Pazmino, D. E.,, R. Snajdrova,, D. V. Rial,, M. D. Mihovilovic, and, M. W. Fraaije. 2007. Altering the substrate specificity and enantioselectivity of phenylacetone monooxygenase by structure-inspired redesign. Adv. Synth. Catal. 349:13611368.
111. Trauger, J. W.,, R. M. Kohli,, H. D. Mootz,, M. A. Marahiel, and, C. T. Walsh. 2000. Peptide cyclization catalysed by the thioesterase domain of tyrocidine syn-thetase. Nature 407:215218.
112. Uppenberg, J.,, N. Ohrner,, M. Norin,, K. Hult,, G. J. Kleywegt,, S. Patkar,, V. Waagen,, T. Anthonsen, and, T. A. Jones. 1995. Crystallographic and molecular-modeling studies of lipase B from Candida antarctica reveal a stereospecificity pocket for secondary alcohols. Biochemistry 34:1683816851.
113. van den Wijngaard, A. J.,, D. B. Janssen, and, B. Witholt. 1989. Degradation of epichlorohydrin and halohydrins by bacterial cultures isolated from freshwater sediment. J. Gen. Microbiol. 135:21992208.
114. van den Wijngaard, A. J.,, P. T. Reuvekamp, and, D. B. Janssen. 1991. Purification and characterization of halo-alcohol dehalogenase from Arthrobacter sp. strain AD2. J. Bacteriol. 173:124129.
115. van Hylckama Vlieg, J. E.,, L. Tang,, J. H. Lutje Spelberg,, T. Smilda,, G. J. Poelarends,, T. Bosma,, A. E. van Merode,, M. W. Fraaije, and, D. B. Janssen. 2001. Halohydrin dehalogenases are structurally and mechanistically related to short-chain dehydrogenases/reductases. J. Bacteriol. 183:50585066.
116. van Loo, B.,, S. Jonas,, A. C. Babtie,, A. Benjdia,, O. Berteau,, M. Hyvonen, and, F. Hollfelder. 2010. An efficient multiply promiscuous hydrolase in the alkaline phosphatase superfamily. Proc. Natl. Acad. Sci. USA doi/10.1073/pnas.0903951107.
117. van Loo, B.,, J. Kingma,, M. Arand,, M. G. Wubbolts, and, D. B. Janssen. 2006. Diversity and biocatalytic potential of epoxide hydrolases identified by genome analysis. Appl. Environ. Microbiol. 72:29052917.
118. Villiers, B., and, F. Hollfelder. 2009. Mapping the limits of substrate specificity of the adenylation domain of TycA. Chembiochem 10:671682.
119. Waagen, V.,, I. Hollingsaeter,, V. Partali,, O. Thorstad, and, T. Anthonsen. 1993. Enzymatic resolution of butanoic esters of 1-phenyl, 1-phenylmethyl, 1-[2-phenylethyl] and 1-[2-phenoxyethyl] ethers of 3-methoxy-1,2-propanediol. Tetrahedron Asymmetry 4:22652274.
120. Walsh, C. T., and, Y. C. J. Chen. 1988. Enzymic Baeyer-Villiger oxidations by flavin-dependent monooxygenases. Angew. Chem. Int. Ed. 27:333343.
121. Wang, S. C.,, W. H. Johnson, Jr., and, C. P. Whitman. 2003. The 4-oxalocrotonate tautomerase- and YwhB-catalyzed hydration of 3E-haloacrylates: implications for the evolution of new enzymatic activities. J. Am. Chem. Soc. 125:1428214283.
122. Wang, S. C.,, M. D. Person,, W. H. Johnson, Jr., and, C. P. Whitman. 2003. Reactions of trans-3-chloroacrylic acid dehalogenase with acetylene substrates: consequences of and evidence for a hydration reaction. Biochemistry 42:87628773.
123. Weissman, K. J. 2009. Introduction to polyketide biosynthesis. Methods Enzymol. 459:316.
124. Wolfenden, R. 2006. Degrees of difficulty of water-consuming reactions in the absence of enzymes. Chem. Rev. 106:33793396.
125. Zalatan, J. G.,, T. D. Fenn,, A. T. Brunger, and, D. Herschlag. 2006. Structural and functional comparisons of nucleotide pyrophosphatase/phosphodiesterase and alkaline phosphatase: implications for mechanism and evolution. Biochemistry 45:97889803.

Tables

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TABLE 1

Catalytic promiscuity in the alkaline phosphatase superfamily

Citation: Van Loo B, Hollfelder F. 2010. Enzyme Promiscuity and Evolution of New Protein Functions, p 524-538. In Baltz R, Demain A, Davies J, Bull A, Junker B, Katz L, Lynd L, Masurekar P, Reeves C, Zhao H (ed), Manual of Industrial Microbiology and Biotechnology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816827.ch36

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