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Using biology to improve chemical synthesis

MIT team finds a more economical way to create valuable building blocks for pharmaceuticals
Authors of the recent paper published in <i>Nature Communications</i> include (from left) Christopher Reisch, associate professor of chemical engineering Kristala Prather, Micah Sheppard and Himanshu Dhamankar.
Authors of the recent paper published in <i>Nature Communications</i> include (from left) Christopher Reisch, associate professor of chemical engineering Kristala Prather, Micah Sheppard and Himanshu Dhamankar.
Photo: Melanie Miller
Graphic courtesy of the Prather Research Group

Biological synthesis has emerged as a highly promising alternative to traditional organic synthesis for a variety of chemical compounds. One such compound, 3-hydroxyg-butyrolactone (3HBL), can be widely used in the pharmaceutical industry as a chiral building block for the statin class of cholesterol-reducing drugs such as Crestor and Lipitor, as well as the antibiotic Zyvox, and the antihyperlipidemic medication Zetia3. 3HBL is such a versatile pharmaceutical building block that the Department of Energy has listed it as one of the “top value-added chemicals from biomass.” Unfortunately, commercial synthesis of 3HBL employs hazardous processing conditions and expensive catalyst and purification processes, thus it is currently produced as a specialty chemical and sells at a wholesale cost of around $450 per kilogram.

Various other chemical and chemoenzymatic routes developed for 3HBL synthesis suffer from similar disadvantages, including the use of hazardous materials and processing conditions, expensive starting materials, reagents and catalysts, and poor yield, and difficulties in separating by-products. In a paper recently published in Nature Communications, MIT researchers have found a way to create 3HBL through biosynthesis, thus alleviating many of these issues and offering an elegant solution towards economical production of this valuable chemical.

As reported in the Feb. 4 edition of Chemical and Engineering News, an MIT team, led by Kristala Prather, the Theodore T. Miller Career Development Associate Professor in the Department of Chemical Engineering, “created a biosynthetic route to 3HBL and its hydrolyzed form, 3,4-dihydroxybutyric acid, starting with glucose and glycolate or glucose alone. Prather’s team took an existing enzymatic pathway used to make 3-hydroxybutyrate and 3-hydroxyvalerate and reengineered it to make the more structurally diverse 3-hydroxyacids. The key enzyme is the thiolase that catalyzes a C-C bond-forming Claisen condensation. The researchers acknowledge the pathway will need to be optimized if it’s going to compete with the current industrial process for making these building blocks. Even so, they note that it’s a promising demonstration of an engineered pathway that relies on C-C bond-forming reactions.”

According to Prather, “Our goal is to use biology more in order to do chemistry. We identify molecules that we’d like to make but for which we don’t have known biological pathways. Then, we try to design routes to get to these molecules. This is what we did to make 3-HBL. However, along the way, we realized the pathway can be used to make other molecules that are also of interest.”

Himanshu Dhamankar, MIT chemical engineering graduate student and one of the paper’s lead authors, states, "The key players in our novel pathways are the enzymes. Organisms in nature have evolved numerous enzymes to efficiently catalyze biochemical reactions critical for survival. We are harnessing the catalytic power of these natural enzymes in new ways to make chemicals. The challenge is selecting just the right ones to bring about the desired chemical transformations. In the construction of the 3HA platform, we explored 10 enzymes from 6 different organisms to synthesize 5 new products. There are so many more out there that can allow synthesis of other interesting products.”

Authors on this paper include Collin H. Martin, Hsien-Chung Tseng, Micah J. Sheppard and Christopher R. Reisch. The research was supported by the National Science Foundation and Shell Global Solutions (US) Inc.

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