Toward modular construction of cell-free multienzyme systems

doi:10.1016/S1872-2067(21)64002-0

Abstract

Abstract:

The implementation of multiple enzymes for chemical production in a cell-free scenario is an emerging field in biomanufacturing. It enables the redesign and reconstitution of new enzymatic routes for producing chemicals that may be hard to obtain from natural pathways. Although the construction of a cell-free multienzyme system is highly flexible and adaptable, it is challenging to make all enzymatic reactions act in concert. Recently, modular construction has been conceptualized as an effective way to harmonize diverse enzymatic reactions. In this review, we introduce the concept of a multienzyme module and exemplify representative modules found in Nature. We then categorize recent developments of synthetic multienzyme modules into main-reaction modules and auxiliary modules according to their roles in reaction routes. We highlight four main-reaction modules that can perform carbon metabolism, carbon assimilation, protein glycosylation and nonribosomal peptide synthesis, and exemplify auxiliary modules used for energy supply, protection and reinforcement for main reactions. The reactor-level modularization of multienzyme catalysis is also discussed.

Key words: Cell-free biosynthesis, In vitro synthetic biology, Multienzyme system, Modular construction, Synthetic module

Yinchen Zhang, Ning Nie, Yifei Zhang. Toward modular construction of cell-free multienzyme systems[J]. Chinese Journal of Catalysis, 2022, 43(7): 1749-1760.

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URL: https://www.cjcatal.com/EN/10.1016/S1872-2067(21)64002-0

https://www.cjcatal.com/EN/Y2022/V43/I7/1749

Figures/Tables 6

Fig. 1. Example of natural multienzyme modules. (a) A section view of pyruvate dehydrogenase complex. Reprinted with permission from Ref. [25]. Copyright 2001, National Academy of Sciences of the United States of America. (b) Schematic representation of cellulosome. CipA, cellulosome integrating protein A; OlpB, outer layer protein B; SLH, bacterial SLH domain (for S-layer homology). (c) A fluorescence image of purinosomes and the illustration of protein-protein interactions among purinosome proteins. ATIC, a bifunctional enzyme composed of aminoimidazolecarboxamide ribonucleotide transformylase and inosine monophosphate cyclohydrolase; ASL, adenylosuccinate lyase; PAICS, a bifunctional enzyme composed of carboxyaminoimidazole ribonucleotide synthase and succinoaminoimidazolecarboxamide ribonucleotide synthetase; FGAMS, formylglycinamidine ribonucleotide synthase; PPAT, phosphoribosylpyrophosphate amidotransferase; GARS, glycinamide ribonucleotide synthetase; AIRS, aminoimidazole ribonucleotide synthetase; TGART, a trifunctional enzyme composed of glycinamide ribonucleotide synthetase, GAR formyltransferase and aminoimidazole ribonucleotide synthetase; GAR Tfase, GAR transformylase. Reprinted with permission from Ref. [34]. Copyright 2013, Royal Society of Chemistry. (d) A non-ribosomal peptide synthtase for the production of surugamide A.

Fig. 2. Schematic representation of carbon metabolism pathways for hydrogen generation from biomass and the production of myo-inositol from starch. αGP, α-glucan phosphorylase; PGM, phosphoglucomutase; stav CDP, cellodextrin phosphorylase; CBP, cellobiose phosphorylase; PPGK, polyphosphate glucokinase; CTec2, Cellic CTec2 cellulase; XK, xylulokinase; IPS, inositol 1-phosphate synthase; IMP, inositol monophosphatase; G6PDH, glucose 6-phosphate dehydrogenase; 6PGDH, 6-phosphogluconate dehydrogenase; H2ase, hydrogenase; R5PI, ribose 5-phosphate isomerase; Ru5PE, ribulose 5-phosphate epimerase; TK, transketolase; TAL, transaldolase; TIM, triose phosphate isomerase; ALD, aldolase; FBP, fructose 1,6-bisphosphate; PGI, phosphoglucose isomerase.

Fig. 3. An artificial starch anabolic pathway (ASAP) that can produce starch from CO2 and H2. The pathway consists of four modules: C1, C3, C6 and Cn modules (individually colored). aox, alcohol oxidase; fls, formolase; dak, dihydroxyacetone kinase; tpi, triosephosphate isomerase; fba, fructose-1,6-bisphosphate aldolase; fbp, fructose-bisphosphatase; pgi, phosphoglucose isomerase; pgm, phosphoglucomutase; agp, ADP-glucose pyrophosphorylase; ss, starch synthase; ppa, pyrophosphatase; ppk, polyphosphate kinase. Reprinted with permission from Ref. [53]. Copyright 2021, AAAS.

Fig. 4. A platform for glycosylation pathway assembly by rapid in vitro mixing and expression (GlycoPRIME). GTs, glycosyltransferases; ApNGT, the N-linked glycosyltranferase from A. pleuropneumoniae. Reprinted with permission from Ref. [55]. Copyright 2019, Nature Publishing Group.

Fig. 5. Reprogramming NRPS systems with DNA scaffolds. (a) Gramicidin S is synthesized by two NRPS enzymes, designated GrsA and GrsB. (b) Assembling individual modules of GrsB on DNA templates can successfully produce the precursor of Gramicidin S, fPVOL.

Fig. 6. Reactor-level modularization of multienzyme systems. (a) The continuous flow system can produce a series of amines through different packed bed modules. Reprinted with permission from Ref. [92]. Copyright 2021, Wiley-VCH. (b) A three-enzyme cascade capillary bioreactor for digestion of genomic DNA strands. SVP, snake venom phosphodiesterase; ALPase, alkaline phosphatase. Reprinted with permission from Ref. [93]. Copyright 2018, American Chemical Society.

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