Brain cancer researchers have provided chemical engineers with a biological enzyme that could be key to completing a more eco-friendly manufacturing process for nylon. The Duke University team used their knowledge of cancer-related mutations to generate an enzyme that is required for the biological manufacture of adipic acid (1.4-butanedicarboxylic acid), which is a critical substrate in nylon production and one of the most produced chemicals worldwide.
Adipic acid is currently produced from fossil fuels, and chemical engineers haven’t yet been able to manufacture the compound through biological means, which presents a major roadblock in attempts to develop a complete bioproduction process for nylon. They’ve been stymied by an inability to produce 2-hydroxyadipate dehydrogenase, an enzyme that is critical for the manufacture of adipic acid from simple sugars.
Duke University Medical Center’s Zachary J. Reitman, Ph.D., Hai Yan, Ph.D., and colleagues hypothesized that insights from studies on functional mutated enzymes in cancer might help in the design and development of an enzymatic process for producing adipic acid. They focused on a previously identified mutation in brain cancers that alters the function of an enzyme known as isocitrate dehydrogenase. By engineering this gain-of-function mutation into homologous dehydrogenase isocitrate dehydrogenase enzymes found in yeast and in a distantly related thermophilic bacterium, they were able to derive an enzyme that could efficiently catalyze the conversion of 2-oxoadipate to (R)-2-hydroxyadipate, the adipic acid production step that had so far seemed intractable.
The Duke team say their achievement vividly demonstrates how enzyme mutations found in cancer can guide the design and development of industrial enzymes. “Even genetic changes that occur in only a few patients could reveal useful new enzyme functions that were not obvious before,” Dr. Reitman remarks.
They admit that gain of function activities in metabolic enzymes resulting from cancer mutations have, to date, been few and far between. Nevertheless, they stress, “sequencing cancer genomes can provide a powerful source of functional mutation diversity to mine for additional new enzyme activities.” And while computational design and directed evolution will remain the mainstay of new industrial enzyme design, “this study demonstrated that prospecting for alterations from human disease, cancer in particular, can help to rapidly address a specific problem in enzyme design.”
The Duke researchers report their achievement in Nature Chemical Biology, in a paper titled “Enzyme redesign guided by cancer-derived IDH1 mutations.”