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232 10 Perspectives on Multienzyme Process Technology

reactions. Likewise, in nature we find enzymes not only as primary catalysts for
synthesis but also ancillary helpers (for cofactor recycling and to shift equilibrium,
for example), which we term here secondary catalysts. Here too organic synthesis
can follow an analogous path to that in industry. Together these two concepts have
spawned the development of multienzyme processes [5–8]. Although historically
such systems have been used for assay and analysis [9], their role in chemical
synthesis is potentially even more powerful. Indeed, there are many benefits from
reaction chemistry, biocatalysis, and process, as listed in Table 10.1. In addition,
the option of using multiple enzymes to make entirely new pathways or routes
becomes possible. Such a concept builds on what nature has already provided
[10]. However, although this can provide inspiration, new pathways are required
to build the necessary products of the future and attention will need to be paid
not only to kinetics but also to the thermodynamics of such de novo pathways.
Nature normally allows for this with large negative ΔG values at the start and end
of a pathway. In addition, several fascinating scientific issues are now raised by
these developments, such as what format these multiple enzyme systems should
take, what types of reactors should be used and whether reagents should be added
or intermediates removed. Many of the other chapters in this text discuss the
chemistry that can be possible with such systems. However, in this chapter, we
focus on the considerations required to develop a suitable process. In this way, we

Table 10.1 Potential benefits of adopting multienzyme processes.

Reaction benefits ∙ Opportunity to create new pathways to products
∙ Pathways optimized toward product, minimizing by-products
∙ Opportunity to shift the equilibrium of a desired reaction by
integrating in a cascade
∙ Secondary enzymes can be combined to assist primary reactions
∙ Potential solution for cofactor dependent reactions
Biocatalyst benefits ∙ Dependent on format, downstream processes can be simplified
∙ Renewable catalyst
∙ Cells can be modified
∙ Enzymes can be designed
Process benefits ∙ Flexibility for process control
∙ Reduced separation of intermediates
∙ Better reaction control
∙ Opportunities to exploit modeling and rapid development methods
∙ Novel reactor options
∙ Possible to run processes under more productive conditions (e.g.,
higher concentrations and organic solvents).
∙ Green processes running under mild conditions
Economic benefits ∙ Reduction in unit operations (including downstream)
∙ More compact process units
∙ Cofactor regeneration
∙ Biocatalyst recycling