Frustration can Limit the Adaptation of Promiscuous Enzymes Through Gene Duplication and Specialisation.
Enzyme kinetics
Enzyme promiscuity
Evolution
Evolutionary biophysics
Gene duplication
Journal
Journal of molecular evolution
ISSN: 1432-1432
Titre abrégé: J Mol Evol
Pays: Germany
ID NLM: 0360051
Informations de publication
Date de publication:
12 Mar 2024
12 Mar 2024
Historique:
received:
07
10
2023
accepted:
16
02
2024
medline:
12
3
2024
pubmed:
12
3
2024
entrez:
12
3
2024
Statut:
aheadofprint
Résumé
Virtually all enzymes catalyse more than one reaction, a phenomenon known as enzyme promiscuity. It is unclear whether promiscuous enzymes are more often generalists that catalyse multiple reactions at similar rates or specialists that catalyse one reaction much more efficiently than other reactions. In addition, the factors that shape whether an enzyme evolves to be a generalist or a specialist are poorly understood. To address these questions, we follow a three-pronged approach. First, we examine the distribution of promiscuity in empirical enzymes reported in the BRENDA database. We find that the promiscuity distribution of empirical enzymes is bimodal. In other words, a large fraction of promiscuous enzymes are either generalists or specialists, with few intermediates. Second, we demonstrate that enzyme biophysics is not sufficient to explain this bimodal distribution. Third, we devise a constraint-based model of promiscuous enzymes undergoing duplication and facing selection pressures favouring subfunctionalization. The model posits the existence of constraints between the catalytic efficiencies of an enzyme for different reactions and is inspired by empirical case studies. The promiscuity distribution predicted by our constraint-based model is consistent with the empirical bimodal distribution. Our results suggest that subfunctionalization is possible and beneficial only in certain enzymes. Furthermore, the model predicts that conflicting constraints and selection pressures can cause promiscuous enzymes to enter a 'frustrated' state, in which competing interactions limit the specialisation of enzymes. We find that frustration can be both a driver and an inhibitor of enzyme evolution by duplication and subfunctionalization. In addition, our model predicts that frustration becomes more likely as enzymes catalyse more reactions, implying that natural selection may prefer catalytically simple enzymes. In sum, our results suggest that frustration may play an important role in enzyme evolution.
Identifiants
pubmed: 38470504
doi: 10.1007/s00239-024-10161-4
pii: 10.1007/s00239-024-10161-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : H2020 European Research Council
ID : 739874
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 31003A_172887
Informations de copyright
© 2024. The Author(s).
Références
Aharoni A, Gaidukov L, Khersonsky O et al (2005) The ‘evolvability’ of promiscuous protein functions. Nat Genet 37(1):73–76. https://doi.org/10.1038/ng1482
doi: 10.1038/ng1482
pubmed: 15568024
Araya CL, Fowler DM (2011) Deep mutational scanning: assessing protein function on a massive scale. Trends Biotechnol 29(9):435–442. https://doi.org/10.1016/j.tibtech.2011.04.003
doi: 10.1016/j.tibtech.2011.04.003
pubmed: 21561674
Babtie A, Tokuriki N, Hollfelder F (2010) What makes an enzyme promiscuous? Curr Opin Chem Biol 14(2):200–207. https://doi.org/10.1016/j.cbpa.2009.11.028
doi: 10.1016/j.cbpa.2009.11.028
pubmed: 20080434
Bar-Even A, Noor E, Savir Y et al (2011) The moderately efficient enzyme: evolutionary and physicochemical trends shaping enzyme parameters. Biochemistry 50(21):4402–4410. https://doi.org/10.1021/bi2002289
doi: 10.1021/bi2002289
pubmed: 21506553
Bayer CD, van Loo B, Hollfelder F (2017) Specificity effects of amino acid substitutions in promiscuous hydrolases: context-dependence of catalytic residue contributions to local fitness landscapes in nearby sequence space. ChemBioChem 18(11):1001–1015. https://doi.org/10.1002/cbic.201600657
doi: 10.1002/cbic.201600657
pubmed: 28464395
Ben-David M, Elias M, Filippi JJ et al (2012) Catalytic versatility and backups in enzyme active sites: the case of serum paraoxonase 1. J Mol Biol 418(3):181–196. https://doi.org/10.1016/j.jmb.2012.02.042
doi: 10.1016/j.jmb.2012.02.042
pubmed: 22387469
Bendixsen DP, Collet J, Østman B et al (2019) Genotype network intersections promote evolutionary innovation. PLOS Biol 17(5):e3000300. https://doi.org/10.1371/journal.pbio.3000300
doi: 10.1371/journal.pbio.3000300
pubmed: 31136568
Benson DA, Cavanaugh M, Clark K et al (2013) GenBank. Nucleic Acids Res 41:D36-42. https://doi.org/10.1093/nar/gks1195
doi: 10.1093/nar/gks1195
pubmed: 23193287
Bergthorsson U, Andersson DI, Roth JR (2007) Ohno’s dilemma: evolution of new genes under continuous selection. PNAS 104(43):17004–17009. https://doi.org/10.1073/pnas.0707158104
doi: 10.1073/pnas.0707158104
pubmed: 17942681
Bommer GT, van Schaftingen E, Veiga-da Cunha M (2020) Metabolite repair enzymes control metabolic damage in glycolysis. Trends Biochem Sci 45(3):228–243. https://doi.org/10.1016/j.tibs.2019.07.004
doi: 10.1016/j.tibs.2019.07.004
pubmed: 31473074
Boxshall GA (2004) The evolution of arthropod limbs. Biol Rev 79(2):253–300. https://doi.org/10.1017/S1464793103006274
doi: 10.1017/S1464793103006274
pubmed: 15191225
Camacho C, Coulouris G, Avagyan V et al (2009) BLAST+: architecture and applications. BMC Bioinform 10(1):421. https://doi.org/10.1186/1471-2105-10-421
doi: 10.1186/1471-2105-10-421
Campbell E, Kaltenbach M, Correy GJ et al (2016) The role of protein dynamics in the evolution of new enzyme function. Nat Chem Biol 12(11):944–950. https://doi.org/10.1038/nchembio.2175
doi: 10.1038/nchembio.2175
pubmed: 27618189
Chou HH, Delaney NF, Draghi JA et al (2014) Mapping the fitness landscape of gene expression uncovers the cause of antagonism and sign epistasis between adaptive mutations. PLOS Genet 10(2):e1004149. https://doi.org/10.1371/journal.pgen.1004149
doi: 10.1371/journal.pgen.1004149
pubmed: 24586190
Conant GC, Wolfe KH (2008) Turning a hobby into a job: how duplicated genes find new functions. Nat Rev Genet 9(12):938–950. https://doi.org/10.1038/nrg2482
doi: 10.1038/nrg2482
pubmed: 19015656
Copley SD (2017) Shining a light on enzyme promiscuity. Curr Opin Struct Biol 47:167–175. https://doi.org/10.1016/j.sbi.2017.11.001
doi: 10.1016/j.sbi.2017.11.001
pubmed: 29169066
Copley SD (2020) Evolution of new enzymes by gene duplication and divergence. FEBS J 287(7):1262–1283. https://doi.org/10.1111/febs.15299
doi: 10.1111/febs.15299
pubmed: 32250558
Copley SD (2021) Setting the stage for evolution of a new enzyme. Curr Opin Struct Biol 69:41–49. https://doi.org/10.1016/j.sbi.2021.03.001
doi: 10.1016/j.sbi.2021.03.001
pubmed: 33865035
D’Ari R, Casadesús J (1998) Underground metabolism. BioEssays 20(2):181–186. https://doi.org/10.1002/(SICI)1521-1878(199802)20:2<181::AID-BIES10>3.0.CO;2-0
doi: 10.1002/(SICI)1521-1878(199802)20:2<181::AID-BIES10>3.0.CO;2-0
pubmed: 9631663
Davidi D, Longo LM, Jabłońska J et al (2018) A bird’s-eye view of enzyme evolution: chemical, physicochemical, and physiological considerations. Chem Rev 118(18):8786–8797. https://doi.org/10.1021/acs.chemrev.8b00039
doi: 10.1021/acs.chemrev.8b00039
pubmed: 30133258
DeLuna A, Vetsigian K, Shoresh N et al (2008) Exposing the fitness contribution of duplicated genes. Nat Genet 40(5):676–681. https://doi.org/10.1038/ng.123
doi: 10.1038/ng.123
pubmed: 18408719
Des Marais DL, Rausher MD (2008) Escape from adaptive conflict after duplication in an anthocyanin pathway gene. Nature 454(7205):762–765. https://doi.org/10.1038/nature07092
doi: 10.1038/nature07092
pubmed: 18594508
Drost HG, Gabel A, Grosse I et al (2015) Evidence for active maintenance of phylotranscriptomic hourglass patterns in animal and plant embryogenesis. Mol Biol Evol 32(5):1221–1231. https://doi.org/10.1093/molbev/msv012
doi: 10.1093/molbev/msv012
pubmed: 25631928
Eisenthal R, Danson MJ, Hough DW (2007) Catalytic efficiency and kcat/KM: a useful comparator? Trends Biotechnol 25(6):247–249. https://doi.org/10.1016/j.tibtech.2007.03.010
doi: 10.1016/j.tibtech.2007.03.010
pubmed: 17433847
Espinosa-Cantú A, Ascencio D, Barona-Gómez F et al (2015) Gene duplication and the evolution of moonlighting proteins. Front Genet 6:227. https://doi.org/10.3389/fgene.2015.00227
doi: 10.3389/fgene.2015.00227
pubmed: 26217376
Ferreiro DU, Komives EA, Wolynes PG (2014) Frustration in biomolecules. Q Rev Biophys 47(4):285–363. https://doi.org/10.1017/S0033583514000092
doi: 10.1017/S0033583514000092
pubmed: 25225856
Force A, Lynch M, Pickett FB et al (1999) Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151(4):1531–1545. https://doi.org/10.1093/genetics/151.4.1531
doi: 10.1093/genetics/151.4.1531
pubmed: 10101175
Glasner ME, Truong DP, Morse BC (2020) How enzyme promiscuity and horizontal gene transfer contribute to metabolic innovation. FEBS J 287(7):1323–1342. https://doi.org/10.1111/febs.15185
doi: 10.1111/febs.15185
pubmed: 31858709
Gould SM, Tawfik DS (2005) Directed evolution of the promiscuous esterase activity of carbonic anhydrase II. Biochemistry 44(14):5444–5452. https://doi.org/10.1021/bi0475471
doi: 10.1021/bi0475471
pubmed: 15807537
Huang H, Pandya C, Liu C et al (2015) Panoramic view of a superfamily of phosphatases through substrate profiling. PNAS 112(16):E1974–E1983. https://doi.org/10.1073/pnas.1423570112
doi: 10.1073/pnas.1423570112
pubmed: 25848029
James LC, Tawfik DS (2003) Conformational diversity and protein evolution—a 60-year-old hypothesis revisited. Trends Biochem Sci 28(7):361–368. https://doi.org/10.1016/S0968-0004(03)00135-X
doi: 10.1016/S0968-0004(03)00135-X
pubmed: 12878003
Janzen E, Blanco C, Peng H et al (2020) Promiscuous ribozymes and their proposed role in prebiotic evolution. Chem Rev 120(11):4879–4897. https://doi.org/10.1021/acs.chemrev.9b00620
doi: 10.1021/acs.chemrev.9b00620
pubmed: 32011135
Jeske L, Placzek S, Schomburg I et al (2019) BRENDA in 2019: a European ELIXIR core data resource. Nucleic Acids Res 47(D1):D542–D549. https://doi.org/10.1093/nar/gky1048
doi: 10.1093/nar/gky1048
pubmed: 30395242
Kacser H, Burns JA (1981) The molecular basis of dominance. Genetics 97(3–4):639–666. https://doi.org/10.1093/genetics/97.3-4.639
doi: 10.1093/genetics/97.3-4.639
pubmed: 7297851
Kaltenbach M, Tokuriki N (2014) Dynamics and constraints of enzyme evolution. J Exp Zool B Mol Dev Evo 322(7):468–487. https://doi.org/10.1002/jez.b.22562
doi: 10.1002/jez.b.22562
Kaltenbach M, Emond S, Hollfelder F et al (2016) Functional trade-offs in promiscuous enzymes cannot be explained by intrinsic mutational robustness of the native activity. PLOS Genet 12(10):e1006305. https://doi.org/10.1371/journal.pgen.1006305
doi: 10.1371/journal.pgen.1006305
pubmed: 27716796
Kanehisa M, Goto S (2000) Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28(1):27–30. https://doi.org/10.1093/nar/28.1.27
doi: 10.1093/nar/28.1.27
pubmed: 10592173
Keeling DM, Garza P, Nartey CM et al (2019) The meanings of ‘function’ in biology and the problematic case of de novo gene emergence. eLife 8:e47014. https://doi.org/10.7554/eLife.47014
doi: 10.7554/eLife.47014
pubmed: 31674305
Khersonsky O, Tawfik DS (2010) Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biochem 79(1):471–505. https://doi.org/10.1146/annurev-biochem-030409-143718
doi: 10.1146/annurev-biochem-030409-143718
pubmed: 20235827
Kim J, Flood JJ, Kristofich MR et al (2019) Hidden resources in the Escherichia coli genome restore PLP synthesis and robust growth after deletion of the essential gene pdxB. PNAS 116(48):24164–24173. https://doi.org/10.1073/pnas.1915569116
doi: 10.1073/pnas.1915569116
pubmed: 31712440
Kondrashov FA, Kondrashov AS (2006) Role of selection in fixation of gene duplications. J Theor Biol 239(2):141–151. https://doi.org/10.1016/j.jtbi.2005.08.033
doi: 10.1016/j.jtbi.2005.08.033
pubmed: 16242725
Labourel F, Rajon E (2021) Resource uptake and the evolution of moderately efficient enzymes. Mol Biol Evol 38(9):3938–3952. https://doi.org/10.1093/molbev/msab132
doi: 10.1093/molbev/msab132
pubmed: 33964160
Lite TLV, Grant RA, Nocedal I et al (2020) Uncovering the basis of protein-protein interaction specificity with a combinatorially complete library. eLife 9:e60924. https://doi.org/10.7554/eLife.60924
doi: 10.7554/eLife.60924
pubmed: 33107822
van Loo B, Bayer CD, Fischer G et al (2019) Balancing specificity and promiscuity in enzyme evolution: multidimensional activity transitions in the alkaline phosphatase superfamily. J Am Chem Soc 141(1):370–387. https://doi.org/10.1021/jacs.8b10290
doi: 10.1021/jacs.8b10290
pubmed: 30497259
Lynch M, Conery JS (2000) The evolutionary fate and consequences of duplicate genes. Science 290(5494):1151–1155. https://doi.org/10.1126/science.290.5494.1151
doi: 10.1126/science.290.5494.1151
pubmed: 11073452
Lynch M, Force A (2000) The probability of duplicate gene preservation by subfunctionalization. Genetics 154(1):459–473. https://doi.org/10.1093/genetics/154.1.459
doi: 10.1093/genetics/154.1.459
pubmed: 10629003
Markin CJ, Mokhtari DA, Sunden F et al (2021) Revealing enzyme functional architecture via high-throughput microfluidic enzyme kinetics. Science 373(6553):eabf8761. https://doi.org/10.1126/science.abf8761
doi: 10.1126/science.abf8761
pubmed: 34437092
Martínez-Núñez MA, Pérez-Rueda E (2016) Do lifestyles influence the presence of promiscuous enzymes in bacteria and archaea metabolism? Sustain Chem Process 4(1):3. https://doi.org/10.1186/s40508-016-0047-8
doi: 10.1186/s40508-016-0047-8
McLoughlin SY, Copley SD (2008) A compromise required by gene sharing enables survival: implications for evolution of new enzyme activities. PNAS 105(36):13497–13502. https://doi.org/10.1073/pnas.0804804105
doi: 10.1073/pnas.0804804105
pubmed: 18757760
Morgenthaler AB, Kinney WR, Ebmeier CC et al (2019) Mutations that improve efficiency of a weak-link enzyme are rare compared to adaptive mutations elsewhere in the genome. eLife 8:e53535. https://doi.org/10.7554/eLife.53535
doi: 10.7554/eLife.53535
pubmed: 31815667
Nath A, Atkins WM (2008) A quantitative index of substrate promiscuity. Biochemistry 47(1):157–166. https://doi.org/10.1021/bi701448p
doi: 10.1021/bi701448p
pubmed: 18081310
Newton MS, Arcus VL, Patrick WM (2015) Rapid bursts and slow declines: on the possible evolutionary trajectories of enzymes. J R Soc Interface 12(107):20150036. https://doi.org/10.1098/rsif.2015.0036
doi: 10.1098/rsif.2015.0036
pubmed: 25926697
Newton MS, Arcus VL, Gerth ML et al (2018) Enzyme evolution: innovation is easy, optimization is complicated. Curr Opin Struct Biol 48:110–116. https://doi.org/10.1016/j.sbi.2017.11.007
doi: 10.1016/j.sbi.2017.11.007
pubmed: 29207314
Nobeli I, Favia AD, Thornton JM (2009) Protein promiscuity and its implications for biotechnology. Nat Biotechnol 27(2):157–167. https://doi.org/10.1038/nbt1519
doi: 10.1038/nbt1519
pubmed: 19204698
Noda-Garcia L, Tawfik DS (2020) Enzyme evolution in natural products biosynthesis: target- or diversity-oriented? Curr Opin Chem Biol 59:147–154. https://doi.org/10.1016/j.cbpa.2020.05.011
doi: 10.1016/j.cbpa.2020.05.011
pubmed: 32771972
Payne JL, Wagner A (2013) Constraint and contingency in multifunctional gene regulatory circuits. PLOS Comput Biol 9(6):e1003071. https://doi.org/10.1371/journal.pcbi.1003071
doi: 10.1371/journal.pcbi.1003071
pubmed: 23762020
Peracchi A (2018) The limits of enzyme specificity and the evolution of metabolism. Trends Biochem Sci 43(12):984–996. https://doi.org/10.1016/j.tibs.2018.09.015
doi: 10.1016/j.tibs.2018.09.015
pubmed: 30472990
Rueffler C, Hermisson J, Wagner GP (2012) Evolution of functional specialization and division of labor. PNAS 109(6):E326–E335. https://doi.org/10.1073/pnas.1110521109
doi: 10.1073/pnas.1110521109
pubmed: 22308336
Savir Y, Noor E, Milo R et al (2010) Cross-species analysis traces adaptation of Rubisco toward optimality in a low-dimensional landscape. PNAS 107(8):3475–3480. https://doi.org/10.1073/pnas.0911663107
doi: 10.1073/pnas.0911663107
pubmed: 20142476
Scannell DR, Wolfe KH (2008) A burst of protein sequence evolution and a prolonged period of asymmetric evolution follow gene duplication in yeast. Genome Res 18(1):137–147. https://doi.org/10.1101/gr.6341207
doi: 10.1101/gr.6341207
pubmed: 18025270
Sikosek T, Chan HS, Bornberg-Bauer E (2012) Escape from adaptive conflict follows from weak functional trade-offs and mutational robustness. PNAS 109(37):14888–14893. https://doi.org/10.1073/pnas.1115620109
doi: 10.1073/pnas.1115620109
pubmed: 22927372
Sousa SF, Calixto AR, Ferreira P et al (2020) Activation free energy, substrate binding free energy, and enzyme efficiency fall in a very narrow range of values for most enzymes. ACS Catal 10(15):8444–8453. https://doi.org/10.1021/acscatal.0c01947
doi: 10.1021/acscatal.0c01947
Tawfik DS, Gruic-Sovulj I (2020) How evolution shapes enzyme selectivity- lessons from aminoacyl-tRNA synthetases and other amino acid utilizing enzymes. FEBS J 287(7):1284–1305. https://doi.org/10.1111/febs.15199
doi: 10.1111/febs.15199
pubmed: 31891445
The UniProt Consortium (2023) UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res 51(D1):D523–D531. https://doi.org/10.1093/nar/gkac1052
doi: 10.1093/nar/gkac1052
Tokuriki N, Jackson CJ, Afriat-Jurnou L et al (2012) Diminishing returns and tradeoffs constrain the laboratory optimization of an enzyme. Nat Commun 3(1):1257. https://doi.org/10.1038/ncomms2246
doi: 10.1038/ncomms2246
pubmed: 23212386
Tomatis PE, Fabiane SM, Simona F et al (2008) Adaptive protein evolution grants organismal fitness by improving catalysis and flexibility. PNAS 105(52):20605–20610. https://doi.org/10.1073/pnas.0807989106
doi: 10.1073/pnas.0807989106
pubmed: 19098096
Weiss KM (1990) Duplication with variation: metameric logic in evolution from genes to morphology. Am J Phys Anthropol 33(S11):1–23. https://doi.org/10.1002/ajpa.1330330503
doi: 10.1002/ajpa.1330330503
Wolf YI, Katsnelson MI, Koonin EV (2018) Physical foundations of biological complexity. PNAS 115(37):E8678–E8687. https://doi.org/10.1073/pnas.1807890115
doi: 10.1073/pnas.1807890115
pubmed: 30150417
Wrenbeck EE, Azouz LR, Whitehead TA (2017) Single-mutation fitness landscapes for an enzyme on multiple substrates reveal specificity is globally encoded. Nat Commun 8(1):15695. https://doi.org/10.1038/ncomms15695
doi: 10.1038/ncomms15695
pubmed: 28585537
Yi X, Dean AM (2019) Adaptive landscapes in the age of synthetic biology. Mol Biol Evol 36(5):890–907. https://doi.org/10.1093/molbev/msz004
doi: 10.1093/molbev/msz004
pubmed: 30657938
Zhang W, Dourado DFAR, Fernandes PA et al (2012) Multidimensional epistasis and fitness landscapes in enzyme evolution. Biochem J 445(1):39–46. https://doi.org/10.1042/BJ20120136
doi: 10.1042/BJ20120136
pubmed: 22533640
Zou T, Risso VA, Gavira JA et al (2015) Evolution of conformational dynamics determines the conversion of a promiscuous generalist into a specialist enzyme. Mol Biol Evol 32(1):132–143. https://doi.org/10.1093/molbev/msu281
doi: 10.1093/molbev/msu281
pubmed: 25312912