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Review Article

Hosts engineering and in vitro enzymatic synthesis for the discovery of novel natural products and their derivatives

, , ORCID Icon, , , , , , & show all
Received 03 Nov 2022, Accepted 17 Jun 2023, Published online: 13 Aug 2023

References

  • Stone S, Newman DJ, Colletti SL, et al. Cheminformatic analysis of natural product-based drugs and chemical probes. Nat Prod Rep. 2022;39:20–32. doi: 10.1039/d1np00039j.
  • Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79:629–661. doi: 10.1021/acs.jnatprod.5b01055.
  • Organization, W. H. The Ninth Edition of The International Pharmacopoeia. 2019.
  • Ignea C, Pontini M, Motawia MS, et al. Synthesis of 11-carbon terpenoids in yeast using protein and metabolic engineering. Nat Chem Biol. 2018;14:1090–1098. doi: 10.1038/s41589-018-0166-5.
  • Ignea C, Raadam MH, Koutsaviti A, et al. Expanding the terpene biosynthetic code with non-canonical 16 carbon atom building blocks. Nat Commun. 2022;13:5188. doi: 10.1038/s41467-022-32921-w.
  • Wang Y, Dansette PM, Pigeon P, et al. A new generation of ferrociphenols leads to a great diversity of reactive metabolites, and exhibits remarkable antiproliferative properties. Chem Sci. 2018;9:70–78. doi: 10.1039/c7sc04213b.
  • Luo Y, Cobb RE, Zhao H. Recent advances in natural product discovery. Curr Opin Biotechnol. 2014;30:230–237. doi: 10.1016/j.copbio.2014.09.002.
  • Sukmarini L. Recent advances in discovery of lead structures from microbial natural products: genomics- and metabolomics-guided acceleration. Molecules. 2021;26:2542. doi: 10.3390/molecules26092542.
  • Lu N, Niu K. Research on influencing factors of enzymatic preparation of cephalexin. Chinese Journal of Antibiotics. 2018;43:1469–1473.
  • Kenshole E, Herisse M, Michael M, et al. Natural product discovery through microbial genome mining. Curr Opin Chem Biol. 2021;60:47–54. doi: 10.1016/j.cbpa.2020.07.010.
  • Caesar LK, Montaser R, Keller NP, et al. Metabolomics and genomics in natural products research: complementary tools for targeting new chemical entities. Nat Prod Rep. 2021;38:2041–2065. doi: 10.1039/d1np00036e.
  • Liming O, Jianhe XU. Progress in biocatalysis and biotransformation. Chinese J Bioproc Engin. 2008;6:1–9.
  • Alcantara AR, Dominguez de Maria P, Littlechild JA, et al. Biocatalysis as key to sustainable industrial chemistry. ChemSusChem. 2022;15:e202200640. doi: 10.1002/cssc.202200640.
  • Yi D, Bayer T, Badenhorst CPS, et al. Recent trends in biocatalysis. Chem Soc Rev. 2021;50:8003–8049. doi: 10.1039/d0cs01575j.
  • Bornscheuer UT, Huisman GW, Kazlauskas RJ, et al. Engineering the third wave of biocatalysis. Nature. 2012;485:185–194. doi: 10.1038/nature11117.
  • Maithani D, Sharma A, Gangola S, et al. Insights into applications and strategies for discovery of microbial bioactive metabolites. Microbiol Res. 2022;261:127053. doi: 10.1016/j.micres.2022.127053.
  • Russell AH, Truman AW. Genome mining strategies for ribosomally synthesised and post-translationally modified peptides. Comput Struct Biotechnol J. 2020;18:1838–1851. doi: 10.1016/j.csbj.2020.06.032.
  • Alam K, Hao J, Zhang Y, et al. Synthetic biology-inspired strategies and tools for engineering of microbial natural product biosynthetic pathways. Biotechnol Adv. 2021;49:107759.
  • Albarano L, Esposito R, Ruocco N, et al. Genome mining as new challenge in natural products discovery. Mar Drugs. 2020;18:199. doi: 10.3390/md18040199.
  • Ren H, Wang B, Zhao H. Breaking the silence: new strategies for discovering novel natural products. Curr Opin Biotechnol. 2017;48:21–27. doi: 10.1016/j.copbio.2017.02.008.
  • Zhang MM, Wang Y, Ang EL, et al. Engineering microbial hosts for production of bacterial natural products. Nat Prod Rep. 2016;33:963–987. doi: 10.1039/c6np00017g.
  • Dai LP, Li W, Wang HX, et al. Three new polyketides from vasR2 gene over-expressed mutant strain of Verrucosispora sp. NS0172. Chin J Nat Med. 2021;19:536–539. doi: 10.1016/S1875-5364(21)60053-5.
  • Wu Q-B, Chen X-A, Lv Z-Y, et al. Activation and discovery of tsukubarubicin from Streptomyces tsukubaensis through overexpressing SARPs. Appl Microbiol Biotechnol. 2021;105:4731–4741. doi: 10.1007/s00253-021-11344-5.
  • Mukherji R, Zhang S, Chowdhury S, et al. Chimeric LuxR Transcription Factors Rewire Natural Product Regulation. Angew Chem Int Ed Engl. 2020;59:6192–6195. doi: 10.1002/anie.201914449.
  • Liu ZZ, Xiao F, Cai SQ, et al. Effective generation of glucosylpiericidins with selective cytotoxicities and insights into their biosynthesis. Appl Environ Microb. 2021;87:e00294-21.
  • Kwon MJ, Steiniger C, Cairns TC, et al. Beyond the biosynthetic gene cluster paradigm: genome-wide coexpression networks connect clustered and unclustered transcription factors to secondary metabolic pathways. Microbiol Spectr. 2021;9:e0089821. doi: 10.1128/Spectrum.00898-21.
  • Ding WJ, Tu JJ, Zhang HR, et al. Genome mining and metabolic profiling uncover polycyclic tetramate macrolactams from Streptomyces koyangensis SCSIO 5802. Mar Drugs. 2021;19:440.
  • Zhang MM, Wong FT, Wang Y, et al. CRISPR-Cas9 strategy for activation of silent Streptomyces biosynthetic gene clusters. Nat Chem Biol. 2017;13:607–U173. doi: 10.1038/nchembio.2341.
  • Zhu JW, Zhang SJ, Wang WG, et al. Strategies for discovering new antibiotics from bacteria in the post-genomic era. Curr Microbiol. 2020;77:3213–3223. doi: 10.1007/s00284-020-02197-8.
  • Cazier AP, Blazeck J. Advances in promoter engineering: novel applications and predefined transcriptional control. Biotechnol J. 2021;16:e2100239. doi: 10.1002/biot.202100239.
  • Rajkumar AS, Liu G, Bergenholm D, et al. Engineering of synthetic, stress-responsive yeast promoters. Nucleic Acids Res. 2016;44:e136. doi: 10.1093/nar/gkw553.
  • Myronovskyi M, Luzhetskyy A. Native and engineered promoters in natural product discovery. Nat Prod Rep. 2016;33:1006–1019. doi: 10.1039/c6np00002a.
  • Kang HS, Charlop-Powers Z, Brady SF. Multiplexed CRISPR/Cas9- and TAR-mediated promoter engineering of natural product biosynthetic gene clusters in yeast. ACS Synth Biol. 2016;5:1002–1010. doi: 10.1021/acssynbio.6b00080.
  • Yue XJ, Cui XW, Zhang Z, et al. Effects of transcriptional mode on promoter substitution and tandem engineering for the production of epothilones in Myxococcus xanthus. Appl Microbiol Biotechnol. 2018;102:5599–5610. doi: 10.1007/s00253-018-9023-4.
  • Kang H-S, Kim E-S. Recent advances in heterologous expression of natural product biosynthetic gene clusters in Streptomyces hosts. Curr Opin Biotechnol. 2021;69:118–127. doi: 10.1016/j.copbio.2020.12.016.
  • Eyles TH, Vior NM, Truman AW. Rapid and robust yeast-mediated pathway refactoring generates multiple new bottromycin-related metabolites. ACS Synth Biol. 2018;7:1211–1218. doi: 10.1021/acssynbio.8b00038.
  • Harvey CJB, Tang M, Schlecht U, et al. HEx: a heterologous expression platform for the discovery of fungal natural products. Sci Adv. 2018;4:eaar5459. doi: 10.1126/sciadv.aar5459.
  • Pedersen TB, Nielsen MR, Kristensen SB, et al. Heterologous expression of the core genes in the complex fusarubin gene cluster of Fusarium Solani. Int J Mol Sci. 2020;21:7601. doi: 10.3390/ijms21207601.
  • Li L, Jiang W, Lu Y. New strategies and approaches for engineering biosynthetic gene clusters of microbial natural products. Biotechnol Adv. 2017;35:936–949. doi: 10.1016/j.biotechadv.2017.03.007.
  • Tsukada K, Shinki S, Kaneko A, et al. Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones. Nat Commun. 2020;11:1830. doi: 10.1038/s41467-020-15664-4.
  • Song X, Lv J, Cao Z, et al. Extensive expansion of the chemical diversity of fusidane-type antibiotics using a stochastic combinational strategy. Acta Pharm Sin B. 2021;11:1676–1685. doi: 10.1016/j.apsb.2020.12.007.
  • Matsuda Y, Abe I. Biosynthesis of fungal meroterpenoids. Nat Prod Rep. 2016;33:26–53. doi: 10.1039/c5np00090d.
  • Yuan Y, Cheng S, Bian G, et al. Efficient exploration of terpenoid biosynthetic gene clusters in filamentous fungi. Nat Catal. 2022;5:277–287. doi: 10.1038/s41929-022-00762-x.
  • Jia H, Schwille P. Bottom-up synthetic biology: reconstitution in space and time. Curr Opin Biotechnol. 2019;60:179–187. doi: 10.1016/j.copbio.2019.05.008.
  • Rodríguez Estévez M, Myronovskyi M, Rosenkränzer B, et al. Novel fredericamycin variant overproduced by a streptomycin-resistant Streptomyces albus subsp. Chlorinus Strain. Mar Drugs. 2020;18:18–16.
  • Franz L, Kazmaier U, Truman AW, et al. Bottromycins-biosynthesis, synthesis and activity. Nat Prod Rep. 2021;38:1659–1683. doi: 10.1039/d0np00097c.
  • Becerril A, Alvarez S, Brana AF, et al. Uncovering production of specialized metabolites by Streptomyces argillaceus: activation of cryptic biosynthesis gene clusters using nutritional and genetic approaches. PLoS One. 2018;13:e0198145. doi: 10.1371/journal.pone.0198145.
  • Liu Z, Zhao Y, Huang C, et al. Recent advances in silent gene cluster activation in streptomyces. Front Bioeng Biotechnol. 2021;9:632230. doi: 10.3389/fbioe.2021.632230.
  • Liu Y, Zhou H, Shen Q, et al. Discovery of polycyclic macrolide shuangdaolides by heterologous expression of a cryptic trans-AT PKS gene cluster. Org Lett. 2021;23:6967–6971. doi: 10.1021/acs.orglett.1c02589.
  • Liu J, Wang X, Dai G, et al. Microbial chassis engineering drives heterologous production of complex secondary metabolites. Biotechnol Adv. 2022;59:107966. doi: 10.1016/j.biotechadv.2022.107966.
  • Pait IGU, Kitani S, Roslan FW, et al. Discovery of a new diol-containing polyketide by heterologous expression of a silent biosynthetic gene cluster from Streptomyces lavendulae FRI-5. J Ind Microbiol Biotechnol. 2018;45:77–87. doi: 10.1007/s10295-017-1997-x.
  • De BC, Zhang W, Zhang G, et al. Host-dependent heterologous expression of berninamycin gene cluster leads to linear thiopeptide antibiotics. Org Biomol Chem. 2021;19:8940–8946. doi: 10.1039/d1ob01759d.
  • Stevenson LJ, Bracegirdle J, Liu L, et al. Metathramycin, a new bioactive aureolic acid discovered by heterologous expression of a metagenome derived biosynthetic pathway. RSC Chem Biol. 2021;2:556–567. doi: 10.1039/d0cb00228c.
  • Galagan JE, Calvo SE, Cuomo C, et al. Sequencing of Aspergillus nidulans and comparative analysis with A-fumigatus and A-oryzae. Nature. 2005;438:1105–1115. doi: 10.1038/nature04341.
  • Romsdahl J, Wang CCC. Recent advances in the genome mining of Aspergillus secondary metabolites (covering 2012-2018). Medchemcomm. 2019;10:840–866. doi: 10.1039/c9md00054b.
  • He T, Wang Y, Du L, et al. Overexpression of global regulator laea induced secondary metabolite production in Aspergillus versicolor 0312. Rec.Nat.Prod. 2020;14:387–394. doi: 10.25135/rnp.183.20.03.1593.
  • Li H, Shu S, Kalaitzis JA, et al. Genome mining of Aspergillus hancockii unearths cryptic polyketide hancockinone a featuring a prenylated 6/6/6/5 carbocyclic skeleton. Org Lett. 2021;23:8789–8793. doi: 10.1021/acs.orglett.1c03283.
  • Oikawa H. Reconstitution of biosynthetic machinery of fungal natural products in heterologous hosts. Biosci Biotechnol Biochem. 2020;84:433–444. doi: 10.1080/09168451.2019.1690976.
  • Yan D, Matsuda Y. Genome mining-driven discovery of 5-methylorsellinate-derived meroterpenoids from Aspergillus funiculosus. Org Lett. 2021;23:3211–3215. doi: 10.1021/acs.orglett.1c00951.
  • Guo J, Cai Y-S, Cheng F, et al. Genome mining reveals a multiproduct sesterterpenoid biosynthetic gene cluster in Aspergillus ustus. Org Lett. 2021;23:1525–1529. doi: 10.1021/acs.orglett.0c03996.
  • Kim D-C, Tran Hong Q, Nguyen Thuy T, et al. Anti-neuroinflammatory effect of oxaline, isorhodoptilometrin, and 5-hydroxy-7-(2 ‘-hydroxypropyl)-2-methyl-chromone obtained from the marine fungal strain Penicillium oxalicum CLC-MF05. Arch Pharm Res. 2022;45:90–104. doi: 10.1007/s12272-022-01370-w.
  • Wei Q, Bai J, Yan D, et al. Genome mining combined metabolic shunting and OSMAC strategy of an endophytic fungus leads to the production of diverse natural products. Acta Pharm Sin B. 2021;11:572–587. doi: 10.1016/j.apsb.2020.07.020.
  • Kato N, Nogawa T, Takita R, et al. Control of the stereochemical course of 4 + 2 cycloaddition during trans-decalin formation by fsa2-family enzymes. Angew. Chem. Int. Ed. 2018;57:9754–9758. doi: 10.1002/anie.201805050.
  • LI, L, Yu P, Tang M-C, Zou, M., et al. Biochemical characterization of a eukaryotic decalin-forming diels-alderase. J Am Chem Soc. 2016;138:15837–15840. doi: 10.1021/jacs.6b10452.
  • Tan D, Jamieson CS, Ohashi M, et al. Genome-mined diels-alderase catalyzes formation of the cis-octahydrodecalins of varicidin A and B. J Am Chem Soc. 2019;141:769–773. doi: 10.1021/jacs.8b12010.
  • Panter F, Bader CD, Müller R. The sandarazols are cryptic and structurally unique plasmid-encoded toxins from a rare myxobacterium**. Angew Chem Int Ed Engl. 2021;60:8081–8088. doi: 10.1002/anie.202014671.
  • Sbaraini N, Hu JY, Roux I, et al. Polyketides produced by the entomopathogenic fungus Metarhizium anisopliae induce Candida albicans growth. Fungal Genet Biol. 2021;152:103568.
  • Zhu Y, Wang J, Mou P, et al. Genome mining of cryptic tetronate natural products from a PKS-NRPS encoding gene cluster in Trichoderma harzianum t-22. Org Biomol Chem. 2021;19:1985–1990. doi: 10.1039/d0ob02545c.
  • Fu Z-H, Wen C, Ye Q-M, et al. An efficient strategy for the glycosylation of total Bufadienolides in Venenum bufonis. ACS Omega. 2019;4:6819–6825. doi: 10.1021/acsomega.9b00386.
  • Luo SL, Dang LZ, Zhang KQ, et al. Cloning and heterologous expression of UDP-glycosyltransferase genes from Bacillus subtilis and its application in the glycosylation of ginsenoside Rh1. Lett Appl Microbiol. 2015;60:72–78. doi: 10.1111/lam.12339.
  • Chen K, He J, Hu Z, et al. Enzymatic glycosylation of oleanane-type triterpenoids. J Asian Nat Prod Res. 2018;20:615–623. doi: 10.1080/10286020.2018.1478818.
  • Wang C, Tang D, Xu W, et al. Glycosylation of the polyphenols from Resina draconis by glycosyltransferase YjiC1. Nat Prod Res. 2022; 36:1–8. doi: 10.1080/14786419.2022.2066100.
  • Li K, Feng J, Kuang Y, et al. Enzymatic synthesis of bufadienolide o-glycosides as potent antitumor agents using a microbial glycosyltransferase. Adv Synth. Catal. 2017;359:3765–3772. doi: 10.1002/adsc.201700777.
  • Zheng S, Zeng T, Li C, et al. Deep learning driven biosynthetic pathways navigation for natural products with BioNavi-NP. Nat Commun. 2022;13:3342. doi: 10.1038/s41467-022-30970-9.
  • Zhang M, Li F-D, Li K, et al. Functional characterization and structural basis of an efficient di-c-glycosyltransferase from Glycyrrhiza glabra. J Am Chem Soc. 2020;142:3506–3512. doi: 10.1021/jacs.9b12211.
  • Li C, Zhang R, Wang J, et al. Protein engineering for improving and diversifying natural product biosynthesis. Trends Biotechnol. 2020;38:729–744. doi: 10.1016/j.tibtech.2019.12.008.
  • Yang D, Park SY, Park YS, et al. Metabolic engineering of escherichia coli for natural product biosynthesis. Trends Biotechnol. 2020;38:745–765. doi: 10.1016/j.tibtech.2019.11.007.
  • Arnold FH. Directed evolution: bringing new chemistry to life. Angew Chem Int Ed Engl. 2018;57:4143–4148. doi: 10.1002/anie.201708408.
  • Widersten M. Engineering aldolases for asymmetric synthesis. In Enzyme Engineering and Evolution: specific Enzyme Applications, Tawfik, D. S., Ed. 2020;644:149–167.
  • Xu N, Liu Y, Jiang H, et al. Combining protein and metabolic engineering to construct efficient microbial cell factories. Curr Opin Biotechnol. 2020;66:27–35. doi: 10.1016/j.copbio.2020.06.001.
  • Ravikumar A, Arzumanyan GA, Obadi MKA, et al. Scalable, continuous evolution of genes at mutation rates above genomic error thresholds. Cell. 2018;175:1946–1957.e13. +. doi: 10.1016/j.cell.2018.10.021.
  • Jiang Y, Qu G, Sun Z. Machine learning-assisted enzyme directed evolution. J Biol. 2020;37:1–11.
  • Zhang M, Yi Y, Gao B-H, et al. Functional characterization and protein engineering of a triterpene 3-/6-/2’-O-Glycosyltransferase reveal a conserved residue critical for the regiospecificity. Angew Chem Int Ed Engl. 2022;61:e202113587. doi: 10.1002/anie.202113587.
  • Ma N, Fang W, Liu C, et al. Switching an artificial P450 peroxygenase into peroxidase via mechanism-guided protein engineering. ACS Catal. 2021;11:8449–8455. doi: 10.1021/acscatal.1c02698.
  • Xing H, Zou G, Liu C, et al. Improving the thermostability of a GH11 xylanase by directed evolution and rational design guided by B-factor analysis. Enzyme Microb Tech. 2021;143:109720.
  • Luo Y, Jiang G, Yu T, et al. ECNet is an evolutionary context-integrated deep learning framework for protein engineering. Nat Commun. 2021;12:5743. doi: 10.1038/s41467-021-25976-8.
  • Tao H, Lauterbach L, Bian G, et al. Discovery of non-squalene triterpenes. Nature. 2022;606:414–419. doi: 10.1038/s41586-022-04773-3.
  • Buel GR, Walters KJ. Can AlphaFold2 predict the impact of missense mutations on structure? Nat Struct Mol Biol. 2022;29:1–2. doi: 10.1038/s41594-021-00714-2.
  • Alley EC, Khimulya G, Biswas S, et al. Unified rational protein engineering with sequence-based deep representation learning. Nat Methods. 2019;16:1315–1322. doi: 10.1038/s41592-019-0598-1.
  • Dhakal A, McKay C, Tanner JJ, et al. Artificial intelligence in the prediction of protein-ligand interactions: recent advances and future directions. Briefings Bioinf. 2022;23:1–23 doi: 10.1093/bib/bbab476.
  • Mazurenko S, Prokop Z, Damborsky J. Machine learning in enzyme engineering. ACS Catal. 2020;10:1210–1223. doi: 10.1021/acscatal.9b04321.
  • Ma EJ, Siirola E, Moore C, et al. Machine-directed evolution of an imine reductase for activity and stereoselectivity. ACS Catal. 2021;11:12433–12445. doi: 10.1021/acscatal.1c02786.
  • Lovelock SL, Crawshaw R, Basler S, et al. The road to fully programmable protein catalysis. Nature. 2022;606:49–58. doi: 10.1038/s41586-022-04456-z.
  • Chen W, Yao J, Meng J, et al. Promiscuous enzymatic activity-aided multiple-pathway network design for metabolic flux rearrangement in hydroxytyrosol biosynthesis. Nat Commun. 2019;10:960. doi: 10.1038/s41467-019-08781-2.
  • Yeom S-J, Kim M, Kwon KK, et al. A synthetic microbial biosensor for high-throughput screening of lactam biocatalysts. Nat Commun. 2018;9:5053. doi: 10.1038/s41467-018-07488-0.
  • Garst AD, Bassalo MC, Pines G, et al. Genome-wide mapping of mutations at single-nucleotide resolution for protein, metabolic and genome engineering. Nat Biotechnol. 2017;35:48–55. doi: 10.1038/nbt.3718.
  • Biswas S, Khimulya G, Alley EC, et al. Low-N protein engineering with data-efficient deep learning. Nat Methods. 2021;18:389–396. doi: 10.1038/s41592-021-01100-y.
  • Zhang S, Zhu J, Fan S, et al. Directed evolution of a cyclodipeptide synthase with new activities via label-free mass spectrometric screening. Chem Sci. 2022;13:7581–7586. doi: 10.1039/d2sc01637k.
  • Yang Y, Hussain N, Zhang L, et al. Kadsura coccinea: a rich source of structurally diverse and biologically important compounds. Chin Herb Med. 2020;12:214–223. doi: 10.1016/j.chmed.2020.03.006.
  • Wang XJ, Xie Q, Liu Y, et al. Panax japonicus and chikusetsusaponins: a review of diverse biological activities and pharmacology mechanism. Chin Herb Med. 2021;13:64–77. doi: 10.1016/j.chmed.2020.12.003.
  • Han S, Shi S, Zou Y, et al. Chemical constituents from acid hydrolyzates of Panax quinquefolius total saponins and their inhibition activity to alpha-glycosidase and protein tyrosine phosphatase 1B. Chin Herb Med. 2020;12:195–199. doi: 10.1016/j.chmed.2020.03.003.
  • Kavya NM, Adil L, Senthilkumar P. A review on saponin biosynthesis and its transcriptomic resources in medicinal plants. Plant Mol Biol Rep. 2021;39:833–840. doi: 10.1007/s11105-021-01293-8.
  • Yan M, Sun Y, Ding L, et al. Three new triterpenoid saponins from Aralia echinocaulis. Chin Herb Med. 2022;14:337–341. doi: 10.1016/j.chmed.2022.02.002.
  • Yao L, Zhang H, Liu Y, et al. Engineering of triterpene metabolism and overexpression of the lignin biosynthesis gene PAL promotes ginsenoside Rg3 accumulation in ginseng plant chassis. J Integr Plant Biol. 2022;64:1739–1754. doi: 10.1111/jipb.13315.
  • Yao L, Wang J, He J, et al. Endophytes, biotransforming microorganisms, and engineering microbial factories for triterpenoid saponins production. Crit Rev Biotechnol. 2021;41:249–272. doi: 10.1080/07388551.2020.1869691.
  • Rahimi S, Kim J, Mijakovic I, et al. Triterpenoid-biosynthetic UDP-glycosyltransferases from plants. Biotechnol Adv. 2019;37:107394. doi: 10.1016/j.biotechadv.2019.04.016.
  • Dai LH, Li J, Yang JG, et al. Use of a promiscuous glycosyltransferase from Bacillus subtilis 168 for the enzymatic synthesis of novel protopanaxatriol-type ginsenosides. J Agric Food Chem. 2018;66:943–949. doi: 10.1021/acs.jafc.7b03907.
  • Dai L, Liu C, Li J, et al. One-pot synthesis of ginsenoside rh2 and bioactive unnatural ginsenoside by coupling promiscuous glycosyltransferase from Bacillus subtilis 168 to sucrose synthase. J Agric Food Chem. 2018;66:2830–2837. doi: 10.1021/acs.jafc.8b00597.
  • Zhang T-T, Gong T, Hu Z-F, et al. Enzymatic synthesis of unnatural ginsenosides using a promiscuous UDP-glucosyltransferase from Bacillus subtilis. Molecules. 2018;23:2797. doi: 10.3390/molecules23112797.
  • Atopkina LN, Malinovskaya GV, Elyakov GB, et al. Cytotoxicity of natural ginseng glycosides and semisynthetic analogues. Planta Med. 1999;65:30–34. doi: 10.1055/s-1999-13957.
  • Liang H, Hu Z, Zhang T, et al. Production of a bioactive unnatural ginsenoside by metabolically engineered yeasts based on a new UDP-glycosyltransferase from Bacillus subtilis. Metab Eng. 2017;44:60–69. doi: 10.1016/j.ymben.2017.07.008.
  • Wang DD, Kim YJ, Baek NI, et al. Glycosyltransformation of ginsenoside Rh2 into two novel ginsenosides using recombinant glycosyltransferase from Lactobacillus rhamnosus and its in vitro applications. J Ginseng Res. 2021;45:48–57. doi: 10.1016/j.jgr.2019.11.004.
  • Li J, Yang JG, Mu S, et al. Efficient O-glycosylation of triterpenes enabled by protein engineering of plant glycosyltransferase UGT74AC1. ACS Catal. 2020;10:3629–3639. doi: 10.1021/acscatal.9b05232.
  • Dai LH, Liu C, Zhu YM, et al. Functional characterization of cucurbitadienol synthase and triterpene glycosyltransferase involved in biosynthesis of mogrosides from Siraitia grosvenorii. Plant Cell Physiol. 2015;56:1172–1182. doi: 10.1093/pcp/pcv043.
  • Xian D, Guo M, Xu J, et al. Current evidence to support the therapeutic potential of flavonoids in oxidative stress-related dermatoses. Redox Rep. 2021;26:134–146. doi: 10.1080/13510002.2021.1962094.
  • Jia J, Zang E, Lv L, et al. Flavonoids in myocardial ischemia-reperfusion injury: therapeutic effects and mechanisms. Chin Herb Med. 2021;13:49–63. doi: 10.1016/j.chmed.2020.09.002.
  • Lee HS, Selvaraj B, Yoo KY, et al. Flavonoids as anti-inflammatory and neuroprotective agents. Int J Oral Biol. 2020;45:31–41.
  • Slika H, Mansour H, Wehbe N, et al. Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomed Pharmacother. 2022;146:112442. doi: 10.1016/j.biopha.2021.112442.
  • Sun J, Sun W, Zhang G, et al. High efficient production of plant flavonoids by microbial cell factories: challenges and opportunities. Metab Eng. 2022;70:143–154. doi: 10.1016/j.ymben.2022.01.011.
  • Wang AM, Zhang FK, Huang LF, et al. New progress in biocatalysis and biotransformation of flavonoids. J Med Plants Res. 2010;4:847–856.
  • Dai Y, Zhang S, Liu D-C, et al. Enzymatic biosynthesis of novel bavachin glucosides via Bacillus UDP-glycosyltransferase. Phytochem Lett. 2018;23:9–14. doi: 10.1016/j.phytol.2017.11.005.
  • Xie K, Zhang X, Sui S, et al. Exploring and applying the substrate promiscuity of a C-glycosyltransferase in the chemo-enzymatic synthesis of bioactive C-glycosides. Nat Commun. 2020;11:5162. doi: 10.1038/s41467-020-18990-9.
  • Fan Z, Jaisi A, Chen Y, et al. Discovery and biosynthesis of ascorbylated securinega alkaloids. ACS Catal. 2021;11:8818–8828. doi: 10.1021/acscatal.1c01514.
  • Xie K, Zhang Y, Chen R, et al. Enzymatic glucosylation of unnatural naphthols by a promiscuous glycosyltransferase from Aloe arborescens. Tetrahedron Lett. 2017;58:2118–2121. doi: 10.1016/j.tetlet.2017.04.041.
  • Chen R, Gao B, Liu X, et al. Molecular insights into the enzyme promiscuity of an aromatic prenyltransferase. Nat Chem Biol. 2017;13:226–234. doi: 10.1038/nchembio.2263.
  • Wang M, Carver JJ, Phelan VV, et al. Sharing and community curation of mass spectrometry data with global natural products social molecular networking. Nat Biotechnol. 2016;34:828–837. doi: 10.1038/nbt.3597.
  • Handayani I, Saad H, Ratnakomala S, et al. Mining indonesian microbial biodiversity for novel natural compounds by a combined genome mining and molecular networking approach. Mar Drugs. 2021;19:316.
  • Bracegirdle J, Hou P, Nowak VV, et al. Skyllamycins D and E, non-ribosomal cyclic depsipeptides from lichen-sourced Streptomyces anulatus. J Nat Prod. 2021;84:2536–2543. doi: 10.1021/acs.jnatprod.1c00547.
  • Ho S-T, Ho Y-N, Lin C, et al. Integrated omics strategy reveals cyclic lipopeptides empedopeptins from Massilia sp. YMA4 and their biosynthetic pathway. Mar Drugs. 2021;19:209.
  • Saad H, Aziz S, Gehringer M, et al. Nocathioamides, uncovered by a tunable metabologenomic approach, define a novel class of chimeric lanthipeptides. Angew Chem Int Ed Engl. 2021;60:16472–16479. doi: 10.1002/anie.202102571.
  • Kim LJ, Ohashi M, Zhang Z, et al. Prospecting for natural products by genome mining and microcrystal electron diffraction. Nat Chem Biol. 2021;17:872–877. doi: 10.1038/s41589-021-00834-2.

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