Applications of artificial intelligence to enzyme and pathway design for metabolic engineering

Jang, Woo Dae; Kim, Gi Bae; Kim, Yeji; Lee, Sang Yup

doi:10.1016/j.copbio.2021.07.024

Cited by 67 publications

(45 citation statements)

References 43 publications

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“… The development of processes for the synthesis of APIs with the use of immobilized lipases, with the appropriate studies of reuse or continuous use, and, if possible, in the absence of organic solvents: in comparative studies of ACL of biocatalysis vs. conventional process, those two aspects are some of the most critical when favoring the implementation of enzymatic processes over chemicals in the industry [ 227 , 229 , 230 ]. The expansion of lipase promiscuity and the improvement of synthetic parameters such as reaction rates, performance and industrial-scale stereoselectivity: this requires the integrated use of tools such as directed evolution, enzymatic immobilization, enzyme chemical modification, QM/MM and, recently, Machine-Learning (ML) and Artificial Intelligence (AI) [ 231 , 232 , 233 , 234 , 235 ], applied to the old but also to the new microbial lipases that the required bioprospection can offer. The experimental work will continue to be a source of knowledge in complex reaction systems such as those that normally involve immobilized lipases: an adequate experimental design for the generation of quality data will be indispensable to feed the improvement tools such as ML and AI.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

“…The expansion of lipase promiscuity and the improvement of synthetic parameters such as reaction rates, performance and industrial-scale stereoselectivity: this requires the integrated use of tools such as directed evolution, enzymatic immobilization, enzyme chemical modification, QM/MM and, recently, Machine-Learning (ML) and Artificial Intelligence (AI) [ 231 , 232 , 233 , 234 , 235 ], applied to the old but also to the new microbial lipases that the required bioprospection can offer.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

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Microbial Lipases and Their Potential in the Production of Pharmaceutical Building Blocks

Godoy

Pardo‐Tamayo

Barbosa

2022

IJMS

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Processes involving lipases in obtaining active pharmaceutical ingredients (APIs) are crucial to increase the sustainability of the industry. Despite their lower production cost, microbial lipases are striking for their versatile catalyzing reactions beyond their physiological role. In the context of taking advantage of microbial lipases in reactions for the synthesis of API building blocks, this review focuses on: (i) the structural origins of the catalytic properties of microbial lipases, including the results of techniques such as single particle monitoring (SPT) and the description of its selectivity beyond the Kazlauskas rule as the “Mirror-Image Packing” or the “Key Region(s) rule influencing enantioselectivity” (KRIE); (ii) immobilization methods given the conferred operative advantages in industrial applications and their modulating capacity of lipase properties; and (iii) a comprehensive description of microbial lipases use as a conventional or promiscuous catalyst in key reactions in the organic synthesis (Knoevenagel condensation, Morita–Baylis–Hillman (MBH) reactions, Markovnikov additions, Baeyer–Villiger oxidation, racemization, among others). Finally, this review will also focus on a research perspective necessary to increase microbial lipases application development towards a greener industry.

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Section: Perspectives and Conclusionmentioning

confidence: 99%

Section: Perspectives and Conclusionmentioning

confidence: 99%

Microbial Lipases and Their Potential in the Production of Pharmaceutical Building Blocks

Godoy

Pardo‐Tamayo

Barbosa

2022

IJMS

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“…These insights will help to prioritise positions for the directed evolution of A-domain specificity in the future. Considering the plasticity of A-domain specificity upon single mutation, we predict that screening smart, medium-sized libraries, perhaps supported by artificial intelligence, will suffice to unlock various target substrates (52, 53).…”

Section: Discussionmentioning

confidence: 99%

Defining a Nonribosomal Specificity Code for Design

Stanišić

Svensson

Ettelt

et al. 2022

Preprint

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Nonribosomal peptide synthetases (NRPSs) assemble bioactive peptides from an enormous repertoire of building blocks. How binding pocket residues of the nonribosomal adenylation domain, the so-called specificity code, determine which building block becomes incorporated has been a landmark discovery in NRPS enzymology. While specificity codes enable the prediction of substrate specificity from protein sequence, design strategies based on rewriting the specificity code have been limited in scope. An important reason for failed NRPS design has been that multispecificity has not been considered, for a lack of suitable assay formats. Here, we employ a multiplexed hydroxamate specificity assay (HAMA) to determine substrate profiles for mutant libraries of A-domain in the termination module the SrfAC of surfactin synthetase. A generalist version of SrfAC is developed and the functional flexibility of the adenylation reaction is probed by fully randomizing 15 residues in and around the active site. We identify mutations with profound impact on substrate selectivity and thus reveal a remarkable evolvability of A-domains. Statistical analysis of the specificity divergence caused by point mutations has determined the impact of each code position on specificity, which will serve as a roadmap for NRPS engineering. The shortness of evolutionary pathways between NRPS specificities explains the rich natural substrate scope and suggests directed evolution guided by A-domain promiscuity as a promising strategy.

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“…To meet this demand, valuable insights for rational structural designs and high-throughput virtual screening of SACs can be assisted by computational modeling and artificial intelligence (AI). 135 7.3. Catalytic Mechanism.…”

Section: Conclusion and Outlooksmentioning

confidence: 99%

“…These phenomena necessitate new designs of SACs with the preferable tuning of their multiple enzymelike catalytic abilities. To meet this demand, valuable insights for rational structural designs and high-throughput virtual screening of SACs can be assisted by computational modeling and artificial intelligence (AI) …”

Section: Conclusion and Outlooksmentioning

confidence: 99%

Metal–Support Interactions of Single-Atom Catalysts for Biomedical Applications

Shi

et al. 2021

ACS Appl. Mater. Interfaces

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The development of single-atom catalysts (SACs) has become a rapidly growing research field. It is a critical challenge to understand the interactions between the single-atom metal active sites and the support materials. Recently, original research reports of SACs in biomedical applications have emerged in the literature, yet this topic has seldom been reviewed. Here, this review focuses on the latest advances in single-atom catalysis for biomedical applications and highlights the keys for the design of SACs, such as understanding the interactions between metals and supports and classifying various enzyme-like activities. This review helps bridge the knowledge of multiple disciplines and provides prospects regarding the development of SACs for biomedicine.

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Applications of artificial intelligence to enzyme and pathway design for metabolic engineering

Cited by 67 publications

References 43 publications

Microbial Lipases and Their Potential in the Production of Pharmaceutical Building Blocks

Microbial Lipases and Their Potential in the Production of Pharmaceutical Building Blocks

Defining a Nonribosomal Specificity Code for Design

Metal–Support Interactions of Single-Atom Catalysts for Biomedical Applications

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