Industrialization of Biology A Roadmap to Accelerate the Advanced Manufacturing of Chemicals (2015) / Chapter Skim
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3 Vision of the Future: What New Chemicals Could Be Made?
3 Vision of the Future: What New Chemicals Could Be Made?
Pages 53-66
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From page 53... ...
As discussed in the preceding chapter, a large degree of chemical space is already known to be available for chemical manufacturing. The vision of the future put forth herein is one where biological synthesis and engineering and chemical synthesis and engineering are on par with one another for chemical manufacturing.
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From page 54... ...
and can include preexisting high-volume chemicals, biologically sourced BIO LOGY C H EMISTRY RATIONAL DE SIGN F E E DSTOCK Areas that enable Areas that enable chemical transformations chemical transformations -Fermentation -Heterogeneous -Processing catalysis -Organism P RE- P ROCE SS ING -Homogeneous -Chassis catalysis -Pathways -Enzyme-mediated -"Cell-free systems" ONE OR M ORE reactions T RANS F ORM AT IONS POST- P ROCESS ING External Factors -Scalability -Infrastructure -Environment P RODUCT FIGURE 3-1 Chemical manufacturing flowchart, showing the report's conceptual schema of the chemical manufacturing process and highlighting the techniques of both biology and chemistry that enable chemical transformations.
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From page 55... ...
In general, synthetic compounds are ultimately derived from petrochemical sources with substitution patterns controlled by the selectivity of chemical reagents but can take advantage of a broader coverage of elemental composition, functional groups, and reaction space. In contrast, large classes of biological metabolites often share a biosynthetic logic in their assembly but can utilize the selectivity of enzymes to produce highly complex structures.
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From page 56... ...
They represent a significant portion of new chemical entities while also playing an important role in the identification of druggable targets and pathways for development of synthetic compounds.77 Their success as pharmaceutical agents is likely derived from their natural evolution toward structures optimized to bind macromolecular biological targets, which requires a high structural complexity that can be oftentimes difficult to replicate in a synthetic compound. As such, it is estimated that it is several orders of magnitude more likely that a natural product will bind a cellular target compared to a synthetic compound.
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From page 57... ...
Tapping New Structural Diversity Beyond the exploration of natural products classes with known genetic signatures, such as polyketides, nonribosomal peptides, and isoprenoids, there are many structural cores that have yet to be identified or genetically annotated. Among these are nitrogen-rich compounds of varied structure, including alkaloids, which are needed to augment our pool of compounds, as the more well-characterized classes of natural products tend to be oxygen rich (e.g., polyketides and isoprenoids)
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From page 58... ...
In this case, both the intermediate and the target compounds are natural products and synthetic chemistry is used to scale up a biologically difficult reaction that ultimately opens access to a low-cost antimalarial drug. A different type of advancement in this area can be illustrated in the commercial synthesis of oseltamivir (Tamiflu)
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From page 59... ...
, where a partnership between enzyme engineering and chemical synthesis led to the insertion of a transaminase-catalyzed step, thereby reducing the step count in its preparation.80 Currently, we are limited to a select group of enzyme families that are known to be naturally accommodating to wide ranges of substrates, which correspondingly limits the scope of transformations that are targeted for this approach. Thus, the identification and implementation of new target enzyme families and transformations could greatly accelerate advances in this area.
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From page 60... ...
They are derived from biological sources, such as natural r ubber, silk, and cellulose, as well as synthetic origins, such as olyethylene, p p olystyrene, nylon, silicone, and polyvinyl chloride. Polymer properties are controlled by many variables, including monomer structure, bonding between monomers, tacticity, average molecular weight, polydispersity, and branching for homopolymers.
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From page 61... ...
In general, many commercial polymers have been developed from readily available petrochemical feedstocks and optimized for their intended application by controlling various parameters as discussed above. As such, compounds falling into the same chemical class as known monomer feedstocks, but with different substitution patterns, could be funneled into the same polymerization pipeline but impart altered properties to homo- and co-polymers.
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From page 62... ...
Because small structural changes in monomer structure, such as stereochemistry, substitution patterns, or spacing between functional groups, can greatly affect polymer performance, these monomers could be explored for their behavior in homo- and co-polymers. The biosynthesis of some of these monomers could then be directly engineered from existing pathways or could also be greatly diversified by engineering pathways to accommodate greater structural diversity.
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From page 63... ...
Protein polymers offer a key example of how precise control over sequence and chain length can impart key material properties. There are many examples of polypeptide-based materials, such as silks, wool, or collagen, which are genetically encoded and synthesized via the ribosome.
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From page 64... ...
In this future, the industrial biotechnology industry is comparable to the PC industry of the 1990s in which different companies manufactured the hardware components, assembled the computers, wrote the operating system, and developed the software applications.93 The term "centralized production" is used to describe a future in which the biomanufacturing of chemicals occurs in a handful of verylarge-capacity biorefineries that take advantage of economies of scale to eliminate inefficiency and produce chemicals with razor-thin cost margins and at volumes sufficient to meet world demand. In this future, chemical biomanufacturing looks similar to the oil and petrochemical industry in which there has been a persistent trend toward ever fewer and ever larger oil refineries over the past two decades.94, iii iii In 1994, the United States had 179 operable crude oil refineries capable of distilling just over 1.5 million barrels per day.
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From page 65... ...
Centralized Production Distributed Production Biomanufacturing occurs in a Biomanufacturing occurs in handful of very large capacity many local, small-scale facilities, facilities that take advantage of potentially using geographically economies of scale to eliminate co-localized feedstocks and inefficiency and produce chemi- producing only enough product to cals with thin margins and at meet local demand. volumes sufficient to meet world The home brewing or micro demand brewery industry is a contem The petroleum industry is a con- porary example of distributed temporary example of centralized production.
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From page 66... ...
As a particularly relevant case in point, DNA sequencing began as a highly distributed technology that was largely performed by individual researchers and labs. Then, driven in part by the Human Genome Project and the desire to push down the cost per base pair of sequencing DNA, there was a move to sequencing centers such as the Broad Institute of MIT and Harvard, the Sanger Centre, the Beijing Genome Institute, and the Department of Energy Joint Genome Institute.
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