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2,4-dihydroxybutyric acid (DHB) and 2-keto-4-hydroxybutyrate (OHB) are non-natural molecules obtained through synthetic pathways from renewable carbon source. As they are structurally similar to lactate and pyruvate respectively, they could possibly interfere with the metabolic network of Escherichia coli. In fact, we showed that DHB can be easily oxidized by the membrane associated L and D-lactate dehydrogenases encoded by lldD, dld and ykgF into OHB, and the latter being cleaved into pyruvate and formaldehyde by several pyruvate-dependent aldolases, with YagE being the most effective. While formaldehyde was readily detoxified into formate, Escherichia coli K12 MG1655 strain failed to grow on DHB despite of the production of pyruvate. To find out the reason for this failure, we constructed a mutant strain whose growth was rendered dependent on DHB and subjected this strain to adaptive evolution. Genome sequencing of the adapted strain revealed an essential role for ygbI encoding a transcriptional repressor of the threonate operon in this DHB-dependent growth. This critical function was attributed to the derepression of ygbN encoding a putative threonate transporter, which was found to exclusively transport the D form of DHB. A subsequent laboratory evolution was carried out with E. coli K12 MG1655 deleted for ΔygbI to adapt for growth on DHB as sole carbon source. Remarkably, only two additional mutations were disclosed in the adapted strain, which were demonstrated by reverse engineering to be necessary and sufficient for robust growth on DHB. One mutation was in nanR encoding the transcription repressor of sialic acid metabolic genes, causing 140-fold increase in expression of nanA encoding N-acetyl neuraminic acid lyase, a pyruvate-dependent aldolase, and the other was in the promoter of dld leading to 14-fold increase in D-lactate dehydrogenase activity on DHB. Taken together, this work illustrates the importance of promiscuous enzymes in underground metabolism and moreover, in the frame of synthetic pathways aiming at producing non-natural products, these underground reactions could potentially penalize yield and title of these bio-based products.

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Daptomycin is a cyclic lipodepsipeptide antibiotic used to treat infections caused by Gram-positive pathogens, including multi-drug resistant strains such as methicillin-resistant Staphylococcus au-reus (MRSA) and vancomycin-resistant enterococci (VRE). The emergence of daptomycin-resistant bacterial strains has renewed interest in generating daptomycin analogs. Previous studies have shown that replacing the tryptophan of daptomycin with aromatic groups can generate analogs with enhanced potency. Additionally, we have demonstrated that aromatic prenyltransferases can attach diverse groups to the tryptophan of daptomycin. Here, we report the use of the prenyltransferase CdpNPT to derivatize the tryptophan of daptomycin with a library of benzylic and heterocyclic pyrophosphates. An analytical-scale study revealed that CdpNPT can transfer various aromatic groups onto daptomycin. Subsequent scaled-up and purified reactions indicated that the enzyme can attach aromatic groups to N1, C2, C5 and C6 positions of Trp1 of daptomycin. In vitro antibacterial activity assays using six of these purified compounds identified aromatic substituted daptomycin analogs show potency against both daptomycin-susceptible and resistant strains of Gram-positive bacteria. These findings suggest that installing aromatic groups on the Trp1 of daptomycin can lead to the generation of potent daptomycin analogs.

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Enzymes are nature's ultimate machinery to catalyze complex reactions. Though enzymes are evolved to catalyze specific reactions, they also show significant promiscuity in reactions and substrate selection. Metalloenzymes contain a metal ion or metal cofactor in their active site, which is crucial in their catalytic activity. Depending on the metal and its coordination environment, the metal ion or cofactor may function as a Lewis acid or base and a redox center and thus can catalyze a plethora of natural reactions. In fact, the versatility in the oxidation state of the metal ions provides metalloenzymes with a high level of catalytic adaptability and promiscuity. In this chapter, we discuss different aspects of promiscuity in metalloenzymes by using several recent experimental and theoretical works as case studies. We start our discussion by introducing the concept of promiscuity and then we delve into the mechanistic insight into promiscuity at the molecular level.

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Enzymatic malonylation of natural glycosides provides a promising alternative method for drug-like malonylated glycosides supply. However, the catalytic potential and structural basis of plant malonyltransferase are far from being fully elucidated. This work identified a new malonyltransferase CtMaT1 from Cistanche tubulosa. It displayed unprecedented mono- and/or di-malonylation activity toward diverse glucosides with different aglycons. A "one-pot" system by CtMaT1 and a malonyl-CoA synthetase was established to biosynthesize nine new malonylated glucosides. Structural investigations revealed that CtMaT1 possesses an adequately spacious acyl-acceptor pocket capable of accommodating diverse glucosides. Additionally, it recognizes malonyl-CoA through strong electrotactic and hydrogen interactions. QM/MM calculation revealed the H167-mediated SN2 reaction mechanism of CtMaT1, while dynamic simulations detected the formation of stable hydrogen bonds between the glucose-6-OH group and H167, resulting in its high malonylation regiospecificity. Calculated energy profiles of two isomeric glycosides highlighted lower reaction energy barriers towards glucoside substrates, emphasizing CtMaT1's preference for glucosides. Furthermore, a mutant CtMaT1H36A with notably increased di-malonylation activity was obtained. The underlying molecular mechanism was illuminated through MM/GBSA binding free energy calculation. This study significantly advances the understanding of plant acyltransferases from both functional and protein structural perspectives, while also providing a versatile tool for enzymatic malonylation applications in pharmacology.

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In this present study, characteristics and structure-function relationship of an organophosphate-degrading enzyme from Bacillus sp. S3wahi were described. S3wahi metallohydrolase, designated as S3wahi-MH (probable metallohydrolase YqjP), featured the conserved αß/ßα metallo-ß-lactamase-fold (MBL-fold) domain and a zinc bimetal at its catalytic site. The metal binding site of S3wahi-MH also preserves the H-X-H-X-D-H motif, consisting of specific amino acids at Zn1 (Asp69, His70, Asp182, and His230) and Zn2 (His65, His67, and His137). The multifunctionality of S3wahi-MH was demonstrated through a steady-state kinetic study, revealing its highest binding affinity (KM) and catalytic efficiency (kcat/KM) for OP compound, paraoxon, with values of 8.09 × 10-6 M and 4.94 × 105 M-1 s-1, respectively. Using OP compound, paraoxon, as S3wahi-MH native substrate, S3wahi-MH exhibited remarkable stability over a broad temperature range, 20 °C - 60 °C and a broad pH tolerance, pH 6-10. Corresponded to S3wahi-MH thermal stability characterization, the estimated melting temperature (Tm) was found to be 72.12 °C. S3wahi-MH was also characterized with optimum catalytic activity at 30 °C and pH 8. Additionally, the activity of purified S3wahi-MH was greatly enhanced in the presence of 1 mM and 5 mM of manganese (Mn2+), showing relative activities of 1323.68 % and 2073.68 %, respectively. The activity of S3wahi-MH was also enhanced in the presence of DMSO and DMF, showing relative activities of 270.37 % and 307.41 %, respectively. The purified S3wahi-MH retained >60 % residual activity after exposure to non-ionic Tween series surfactants. Nevertheless, the catalytic activity of S3wahi-MH was severely impacted by the treatment of SDS, even at low concentrations. Considering its enzymatic properties and promiscuity, S3wahi-MH emerges as a promising candidate as a bioremediation tool in wide industrial applications, including agriculture industry.

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The screening of enzymes for catalyzing specific substrate-product pairs is often constrained in the realms of metabolic engineering and synthetic biology. Existing tools based on substrate and reaction similarity predominantly rely on prior knowledge, demonstrating limited extrapolative capabilities and an inability to incorporate custom candidate-enzyme libraries. Addressing these limitations, we have developed the Substrate-product Pair-based Enzyme Promiscuity Prediction (SPEPP) model. This innovative approach utilizes transfer learning and transformer architecture to predict enzyme promiscuity, thereby elucidating the intricate interplay between enzymes and substrate-product pairs. SPEPP exhibited robust predictive ability, eliminating the need for prior knowledge of reactions and allowing users to define their own candidate-enzyme libraries. It can be seamlessly integrated into various applications, including metabolic engineering, de novo pathway design, and hazardous material degradation. To better assist metabolic engineers in designing and refining biochemical pathways, particularly those without programming skills, we also designed EnzyPick, an easy-to-use web server for enzyme screening based on SPEPP. EnzyPick is accessible at http://www.biosynther.com/enzypick/.

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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.

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Dehydrosqualene synthase (CrtM), as a squalene synthase-like enzyme from Staphylococcus aureus, can naturally utilize farnesyl diphosphate to produce dehydrosqualene (C30H48). However, no study has documented the natural production of squalene (C30H50) by CrtM. Here, based on an HPLC-Q-Orbitrap-MS/MS study, we report that the expression of crtM in vitro or in Bacillus subtilis 168 both results in the output of squalene, dehydrosqualene, and phytoene (C40H64). Notably, wild-type CrtM exhibits a significantly higher squalene yield compared to squalene synthase (SQS) from Bacillus megaterium with an approximately 2.4-fold increase. Moreover, the examination of presqualene diphosphate's stereostructures in both CrtM and SQS enzymes provides further understanding into the presence of multiple identified terpenoids. In summary, this study not only provides insights into the promiscuity demonstrated by squalene synthase-like enzymes but also highlights a new strategy of utilizing CrtM as a potential replacement for SQS in cell factories, thereby enhancing squalene production.

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BACKGROUND: Flavonoids are plant specialised metabolites, which derive from phenylalanine and acetate metabolism. They possess a variety of beneficial characteristics for plants and humans. Several modification steps in the synthesis of tricyclic flavonoids cause for the amazing diversity of flavonoids in plants. The 2-oxoglutarate-dependent dioxygenases (2-ODDs) flavanone 3-hydroxylase (F3H, synonym FHT), flavonol synthase (FLS) and anthocyanidin synthase (ANS, synonym leucoanthocyanidin dioxygenase (LDOX)), catalyse oxidative modifications to the central C ring. They are highly similar and have been shown to catalyse, at least in part, each other's reactions. FLS and ANS have been identified as bifunctional enzymes in many species, including Arabidopsis thaliana, stressing the capability of plants to bypass missing or mutated reaction steps on the way to flavonoid production. However, little is known about such bypass reactions and the flavonoid composition of plants lacking all three central flavonoid 2-ODDs. RESULTS: To address this issue, we generated a f3h/fls1/ans mutant, as well as the corresponding double mutants and investigated the flavonoid composition of this mutant collection. The f3h/fls1/ans mutant was further characterised at the genomic level by analysis of a nanopore DNA sequencing generated genome sequence assembly and at the transcriptomic level by RNA-Seq analysis. The mutant collection established, including the novel double mutants f3h/fls1 and f3h/ans, was used to validate and analyse the multifunctionalities of F3H, FLS1, and ANS in planta. Metabolite analyses revealed the accumulation of eriodictyol and additional glycosylated derivatives in mutants carrying the f3h mutant allele, resulting from the conversion of naringenin to eriodictyol by flavonoid 3'-hydroxylase (F3'H) activity. CONCLUSIONS: We describe the in planta multifunctionality of the three central flavonoid 2-ODDs from A. thaliana and identify a bypass in the f3h/fls1/ans triple mutant that leads to the formation of eriodictyol derivatives. As (homo-)eriodictyols are known as bitter taste maskers, the annotated eriodictyol (derivatives) and in particular the observations made on their in planta production, could provide valuable insights for the creation of novel food supplements.

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The new farnesyl pyrophosphate (FPP) derivative with a shifted olefinic double bond from C6-C7 to C7-C8 is accepted and converted by the sesquiterpene cyclases protoilludene synthase (Omp7) as well as viridiflorene synthase (Tps32). In both cases, a so far unknown germacrene derivative was found to be formed, which we name "germacrene F". Both cases are examples in which a modification around the central olefinic double bond in FPP leads to a change in the mode of initial cyclization (from 1→11 to 1→10). For Omp7 a rationale for this behaviour was found by carrying out molecular docking studies. Temperature-dependent NMR experiments, accompanied by NOE studies, show that germacrene F adopts a preferred mirror-symmetric conformation with both methyl groups oriented in the same directions in the cyclodecane ring.

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BACKGROUND: Secondary metabolites such as benzylisoquinoline alkaloids (BIA) have attracted considerable attention because of their pharmacological properties and potential therapeutic applications. Methyltransferases (MTs) can add methyl groups to alkaloid molecules, altering their physicochemical properties and bioactivity, stability, solubility, and recognition by other cellular components. Five types of O-methyltransferases and two types of N-methyltransferases are involved in BIA biosynthesis. OBJECTIVE: Since MTs may be the source for the discovery and development of novel biomedical, agricultural, and industrial compounds, we performed extensive molecular and phylogenetic analyses of O- and N-methyltransferases in BIA-producing plants. METHODS: MTs involved in BIA biosynthesis were isolated from transcriptomes of Berberis koreana and Caulophyllum robustum. We also mined the methyltransferases of Coptis japonica, Papaver somniferum, and Nelumbo nucifera from the National Center for Biotechnology Information protein database. Then, we analyzed the functional motifs and phylogenetic analysis. RESULT: We mined 42 O-methyltransferases and 8 N-methyltransferases from the five BIA-producing plants. Functional motifs for S-adenosyl-L-methionine-dependent methyltransferases were retained in most methyltransferases, except for the three O-methyltransferases from N. nucifera. Phylogenetic analysis revealed that the methyltransferases were grouped into four clades, I, II, III and IV. The clustering patterns in the phylogenetic analysis suggested a monophyletic origin of methyltransferases and gene duplication within species. The coexistence of different O-methyltransferases in the deep branch subclade might support some cases of substrate promiscuity. CONCLUSIONS: Methyltransferases may be a source for the discovery and development of novel biomedical, agricultural, and industrial compounds. Our results contribute to further understanding of their structure and reaction mechanisms, which will require future functional studies.

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Metallo-ß-lactamase (MBL) is an enzyme produced by clinically important bacteria that can inactivate many commonly used antibiotics, making them a significant concern in treating bacterial infections and the risk of having high antibiotic resistance issues among the community. This review presents a bibliometric and patent analysis of MBL worldwide research trend based on the Scopus and World Intellectual Property Organization databases in 2013-2022. Based on the keywords related to MBL in the article title, abstract, and keywords, 592 research articles were retrieved for further analysis using various tools such as Microsoft Excel to determine the frequency analysis, VOSviewer for bibliometric networks visualization, and Harzing's Publish or Perish for citation metrics analysis. Standard bibliometric parameters were analysed to evaluate the field's research trend, such as the growth of publications, topographical distribution, top subject area, most relevant journal, top cited documents, most relevant authors, and keyword trend analysis. Within 10 years, MBL discovery has shown a steady and continuous growth of interest among the community of researchers. United States of America, China, and the United Kingdom are the top 3 countries contribute high productivity to the field. The patent analysis also shows several impactful filed patents, indicating the significance of development research on the structural and functional relationship of MBL for an effective structure-based drug design (SBDD). Developing new MBL inhibitors using SBDD could help address the research gap and provide new successful therapeutic options for treating MBL-producing bacterial infections.

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Promiscuous enzymes have shown their synthetic abilities in generating various organic compounds with high selectively and efficiency under mild conditions. Therefore, the design and development of conditions to raise promiscuity to the enzymes have been under the spotlight in recent years. Flavin reductase, that reduces flavins by using NADH as a cofactor, has not been studied in promiscuous reactions. In the present study, it was aimed to develop a catalytic promiscuous activity in the recombinant E.coli flavin reductase by removing its cofactor. The flavin reductase demonstrated a promiscuous activity for Knoevenagel condensation and Michael addition reactions individually. The cofactor-independent promiscuous activity of the flavin reductase was further enhanced by altering the reaction conditions to proceed a Knoevenagel-Michael addition cascade for tetraketone synthesis. Yet, the presence of the cofactor blocked the promiscuous Knoevenagel condensation, Michael addition, and therefore the cascade reaction, demonstrating that the removal of NADH was pivotal in inducing the promiscuous activity. Furthermore, molecular docking and MD simulations were performed to obtain more structural and mechanistic details of the transformation. The computational studies identified the most likely catalytic sites of the flavin reductase in the reaction. Additionally, a truncated variant of the enzyme that lacked 28 residues from the C-terminus displayed comparable activity to the wild-type enzyme, indicating the robustness of the enzyme in performing the cascade reaction. In brief, the cofactor-elimination method presented in this work could be considered as a straightforward and economical approach for inducing enzyme promiscuity in promoting organic transformations.

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The Candidate Phyla Radiation (CPR) was found to harbor a vast repertoire of genes encoding for enzymes with potential antibiotic resistance activity. Among these, as many as 3349 genes were predicted in silico to contain a metallo-beta-lactamase-like (MBL-like) fold. These proteins were subject to an in silico functional characterization by comparing their protein profiles (presence/absence of conserved protein domains) to other MBLs, including 24 already expressed in vitro, along with those of the beta-lactamase database (BLDB) (n = 761). The sequence similarity network (SSN) was then used to predict the functional clusters of CPR MBL-like sequences. Our findings showed that CPR MBL-like sequences were longer and more diverse than bacterial MBL sequences, with a high content of functional domains. Most CPR MBL-like sequences did not show any SSN connectivity with expressed MBLs, indicating the presence of many potential, yet unidentified, functions in CPR. In conclusion, CPR was shown to have many protein functions and a large sequence variability of MBL-like folds, exceeding all known MBLs. Further experimental and evolutionary studies of this superfamily of hydrolyzing enzymes are necessary to illustrate their functional annotation, origin, and expansion for adaptation or specialization within a given niche or compared to a specific substrate.

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Enzyme promiscuity is evolutionarily advantageous to plants for gaining new enzyme functions when adapting to environmental challenges. However, this promiscuity can negatively affect the expression of genes encoding for plant enzymes in microorganisms. Here, we show that refining the promiscuity of flavonoid 3'-hydroxylase (F3'H) and 4'-O-methyltransferase (F4'OMT) improves (2S)-hesperetin production in Escherichia coli. First, we employed inverse molecular docking to screen a highly substrate-specific ThF3'H from Tricyrtis hirta, which could selectively convert 100 mg L-1 (2S)-naringenin to (2S)-eriodictyol but not (2S)-isosakuranetin, with a cytochrome P450 reductase from Arabidopsis thaliana. Second, we employed a directed evolution approach to restrict the promiscuity of MpOMT from Mentha × piperita. The strain harboring the MpOMTS142V mutant presented a remarkably increased preference for (2S)-eriodictyol. Finally, 27.5 mg L-1 (2S)-hesperetin was produced, while only minor amounts of (2S)-eriodictyol and (2S)-isosakuranetin accumulated as byproducts. This value represents a 14-fold increase in (2S)-hesperetin compared to the parental strain, along with a dramatic reduction in side products. Our work highlights the benefit of alleviating the promiscuity of plant enzymes when engineering production of natural products by microbial cell factories.

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Traditional psychedelics are undergoing a transformation from recreational drugs, to promising pharmaceutical drug candidates with the potential to provide an alternative treatment option for individuals struggling with mental illness. Sustainable and economic production methods are thus needed to facilitate enhanced study of these drug candidates to support future clinical efforts. Here, we expand upon current bacterial psilocybin biosynthesis by incorporating the cytochrome P450 monooxygenase, PsiH, to enable the de novo production of psilocybin as well as the biosynthesis of 13 psilocybin derivatives. The substrate promiscuity of the psilocybin biosynthesis pathway was comprehensively probed by using a library of 49 single-substituted indole derivatives, providing biophysical insights to this understudied metabolic pathway and opening the door to the in vivo biological synthesis of a library of previously unstudied pharmaceutical drug candidates.

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The plethora of biological functions that sustain life is rooted in the remarkable evolvability of proteins. An emerging view highlights the importance of a protein's initial state in dictating evolutionary success. A deeper comprehension of the mechanisms that govern the evolvability of these initial states can provide invaluable insights into protein evolution. In this review, we describe several molecular determinants of protein evolvability, unveiled by experimental evolution and ancestral sequence reconstruction studies. We further discuss how genetic variation and epistasis can promote or constrain functional innovation and suggest putative underlying mechanisms. By establishing a clear framework for these determinants, we provide potential indicators enabling the forecast of suitable evolutionary starting points and delineate molecular mechanisms in need of deeper exploration.

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Hydroxytyrosol, a valuable plant-derived phenolic compound, is increasingly produced from microbial fermentation. However, the promiscuity of the key enzyme HpaBC, the two-component flavin-dependent monooxygenase from Escherichia coli, often leads to low yields. To address this limitation, we developed a novel strategy utilizing microbial consortia catalysis for hydroxytyrosol production. We designed a biosynthetic pathway using tyrosine as the substrate and selected enzymes and overexpressing glutamate dehydrogenase GdhA to realize the cofactor cycling by coupling reactions catalyzed by the transaminase and the reductase. Additionally, the biosynthetic pathway was divided into two parts and performed by separate E. coli strains. Furthermore, we optimized the inoculation time, strain ratio, and pH to maximize the hydroxytyrosol yield. Glycerol and ascorbic acid were added to the co-culture, resulting in a 92% increase in hydroxytyrosol yield. Using this approach, the production of 9.2 mM hydroxytyrosol was achieved from 10 mM tyrosine. This study presents a practical approach for the microbial production of hydroxytyrosol that can be promoted to produce other value-added compounds.

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BACKGROUND: Biochemical reaction prediction tools leverage enzymatic promiscuity rules to generate reaction networks containing novel compounds and reactions. The resulting reaction networks can be used for multiple applications such as designing novel biosynthetic pathways and annotating untargeted metabolomics data. It is vital for these tools to provide a robust, user-friendly method to generate networks for a given application. However, existing tools lack the flexibility to easily generate networks that are tailor-fit for a user's application due to lack of exhaustive reaction rules, restriction to pre-computed networks, and difficulty in using the software due to lack of documentation. RESULTS: Here we present Pickaxe, an open-source, flexible software that provides a user-friendly method to generate novel reaction networks. This software iteratively applies reaction rules to a set of metabolites to generate novel reactions. Users can select rules from the prepackaged JN1224min ruleset, derived from MetaCyc, or define their own custom rules. Additionally, filters are provided which allow for the pruning of a network on-the-fly based on compound and reaction properties. The filters include chemical similarity to target molecules, metabolomics, thermodynamics, and reaction feasibility filters. Example applications are given to highlight the capabilities of Pickaxe: the expansion of common biological databases with novel reactions, the generation of industrially useful chemicals from a yeast metabolome database, and the annotation of untargeted metabolomics peaks from an E. coli dataset. CONCLUSION: Pickaxe predicts novel metabolic reactions and compounds, which can be used for a variety of applications. This software is open-source and available as part of the MINE Database python package ( https://pypi.org/project/minedatabase/ ) or on GitHub ( https://github.com/tyo-nu/MINE-Database ). Documentation and examples can be found on Read the Docs ( https://mine-database.readthedocs.io/en/latest/ ). Through its documentation, pre-packaged features, and customizable nature, Pickaxe allows users to generate novel reaction networks tailored to their application.

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The immense structural diversity of products and intermediates of plant specialized metabolism (specialized metabolites) makes them rich sources of therapeutic medicine, nutrients, and other useful materials. With the rapid accumulation of reactome data that can be accessible on biological and chemical databases, along with recent advances in machine learning, this review sets out to outline how supervised machine learning can be used to design new compounds and pathways by exploiting the wealth of said data. We will first examine the various sources from which reactome data can be obtained, followed by explaining the different machine learning encoding methods for reactome data. We then discuss current supervised machine learning developments that can be employed in various aspects to help redesign plant specialized metabolism.