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COVER STORY
May 21, 2001
Volume 79, Number 21
CENEAR 79 21 pp. 27-34
ISSN 0009-2347
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BIOCATALYSIS
Chemical and pharmaceutical makers seek more efficient and often cleaner routes to making old and new products

ANN M. THAYER, C&EN HOUSTON

Millions of years of evolution have created thousands of microorganisms containing enzymes known to catalyze almost every chemical reaction. Nature's exquisite enzymatic chemistry tends toward the highly selective, efficient, temperate, and environmentally benign. Scientists have the ability today not only to identify organisms and their enzymes, but to accelerate normal evolutionary processes and engineer biocatalysts for improved performance.

BIOPROCESS BASF produces vitamin B-2 with the aid of the fungus Ashbya gossypii. In a collaboration with the University of Salamanca, researchers at the company have succeeded in increasing the productivity of the microorganism by 20%.
BASF PHOTO
Challenges exist, however, in coercing nature to work on the industrial scale. With a few exceptions, most applications have been for low-volume, high-value products, such as drugs and fine chemicals. Exceptions include ethanol and fructose produced by fermentation at more than a million tons per year and costing less than $1.00 per kg. But for bulk chemical production, whole cells or enzymes need further engineering to raise productivity and stability and to lower the cost of production.

Several factors are making it both desirable and possible to overcome these hurdles. Under the Clinton Administration, biobased material and process R&D recieved increased emphasis and funding. The National Research Council (NRC) weighed in with a report in 2000 on research and commercialization priorities and needs for biobased industrial products.

Chemical producers are seeking new and renewable feedstocks in the face of escalating raw material prices. They also are looking for environmentally friendly and sustainable production processes, but they want interesting new chemistry and products as well. Simultaneously, scientists have made major strides in manipulating enzymes to the desired end.

"Until a few years ago, we were pretty much restricted to those enzymes that could be captured from nature," explains Clyde Payn, chief executive officer of the Catalyst Group, a consulting firm. "What's changed is that we can apply mutagenesis and recombinant technologies to have a major impact on the activity, selectivity, and thus yield, and actually obtain economically viable chemical and polymer processes."

Major chemical companies--including Dow Chemical, DuPont, BASF, Degussa, and Celanese--are investing heavily to explore the opportunities, often through alliances with small technology firms that offer specific expertise.

BASF is among the leaders in biocatalysis as a major producer of vitamin B-2 and the amino acid lysine. Vitamin B-2 production began shifting toward biocatalytic routes about 15 years ago. Simple fermentations have replaced all but a small amount of production that uses what is now considered an uncompetitive multistep chemical route, BASF says.

Bioprocesses continue to be optimized by understanding and controlling metabolic pathways. BASF recently achieved a 20% productivity increase from the vitamin B-2-producing fungus, Ashbya gossypii, through a collaboration with the University of Salamanca, in Spain, that identified the key enzymes involved.  

Biocatalysis
Pros and cons compared with
chemical synthesis
ADVANTAGES

Mild reaction conditions (T, P, aqueous)

Highly stereo-, regio-, and
chemoselective

Unique and varied chemistry

Environmentally friendly

DISADVANTAGES

Poor operational stability

Unwanted reactions with impure
preparations

Low volumetric productivity

High cost

SIMILARLY, BASF and its collaborator Integrated Genomics recently deciphered the genome of the lysine-producing bacterium, Corynebacterium glutamicum, and will use the enzyme and metabolic pathway information to further optimize lysine production.

Integrated Genomics has signed similar genome analysis deals with Roche for vitamin production, as well as with Dow Chemical, Genencor, Maxygen, and agricultural processors Cargill and Archer Daniels Midland. At the same time, enzyme developers such as Genencor, Maxygen, and Diversa are working with chemical and drug producers on developing new enzyme-based processes.

Last year, Chevron Research & Technology signed a three-year agreement with Maxygen to discover bioprocesses for specific petrochemical products. One area of focus will be the bioconversion of methane to methanol. Overall, the work will look to replace "costly chemical processes with cheaper, more environmentally friendly bioprocesses," the firms say.

Maxygen set up another four-year collaboration in late 2000 with Hercules. Their focus is on high-value specialty chemicals for water treatment, pulp and paper, and areas using water-soluble polymers. Hercules' interest stems from the fact that many of its existing products are derived from natural materials.

Maxygen believes that $50 billion of the $800 billion global commodity, specialty, and fine chemicals markets are readily addressable by bioprocesses. Another $200 billion, it says, has been identified as potentially addressable by biological approaches in the next 10 to 20 years.

Although most companies won't share information on the products they've targeted for R&D, more is available about those nearing the marketplace.

ONE EXAMPLE is a biocatalytic process for ascorbic acid developed by Eastman Chemical and Genencor. The new process--which is entirely aqueous and consists of only two steps, compared with several in traditional chemical routes--is in the pilot phase, the companies say. Believing that it is the lowest cost route yet developed, they say they intend to formulate a commercial plan this year.

BASF has created a new business group to focus on the biocatalytic production of chiral intermediates under the tradename ChiPros. Production is to start this year at two new plants. A unit in Geismar, La., will produce 2,500 metric tons annually of methoxy isopropyl amine, an intermediate for BASF's Frontier corn herbicide. A multipurpose plant in Ludwigshafen, Germany, will supply up to 1,000 metric tons of different chiral intermediates.

"We have chosen enzymes for several reasons," explains Bernhard Hauer, vice president for research with responsibility for BASF's biocatalysis efforts. "First of all, they are highly active at room temperature and gave us access to new chiral building blocks--amines, alcohols, hydroxy carboxylic acids--where we had no access before.

"We looked for the most economically and ecologically feasible production route," he continues, "and it was the enzymes in this case."

Isolated enzymes are gaining attention for their specificity and selectivity. Older bioprocesses, such as fermentation, typically use whole cells and require separating the product from reaction batches. Enzymes can be treated more like traditional heterogeneous chemical catalysts--purified, immobilized, and stabilized to improve performance and work in continuous processes.

"The more stable an enzyme is, the more you can look into making bulk products," Hauer explains. "We now have all the molecular and biological tools to make enzymes more stable and even to discover more stable enzymes. So, in the next five to 10 years, I believe we will see more bulk chemical products from enzymatic processes."

Enzyme-yielding microbes are being found in environments where they have adapted to unusual conditions or high concentrations of chemicals, such as solvents. "Only recently has the technology been available to design biocatalysts on the basis of selecting microorganisms from extreme environments and changing their catalytic profiles by genetic modification, if necessary," says Christian Weitemeyer, head of research in Degussa's care specialties business unit.

"TOGETHER WITH high-throughput screening methods, it is possible to adapt biocatalysts in a relatively short time to the conditions needed in chemical synthesis," he explains. "And this is especially important if reactions are not run under aqueous conditions, which is an enzyme's natural environment."

Degussa is seeking biocatalysts with a broad use profile for groups of industrial chemicals, Weitemeyer says. The company has several thousand tons per year of biocatalytic acrylamide production in Perm, Russia, for water treatment applications. Its care specialties unit uses biocatalysis to produce fatty acid-derived esters and ceramides for personal care applications, and its oligomers/silicones unit produces silicone acrylates as paint additives.

One of Degussa's newest enzymatic processes turned out to be the only feasible means of making a polyglycerine ester that it will use as an active ingredient in deodorant applications. "This ester is chemically attainable only by a multistep process using protecting groups," Weitemeyer says, an option that's too difficult and expensive to be worthwhile.

About 10% of Degussa's nearly $450 million annual R&D budget is spent on biotech research, Weitemeyer says. The company's Project House Biotechnology biocatalyst initiative has about $18 million to spend over three years. And the company is acquiring the biocatalysis and catalyst research activities of Aventis Research & Technologies.

Care specialties and oligomers/silicones began a five-year alliance with Protéus, Nîmes, France, last year to develop biocatalytic processes. Some of the projects are directed toward extending or improving existing enzymatic processes for organomodified silicones and oleochemicals, whereas others will look at new chemistries.

Areas of interest to Degussa include coupling hydrophilic molecules to hydrophobic ones to build surfactant-type products, Weitemeyer says. Another is studying how enzymes can react with only one site on multifunctional molecules containing several possible reaction sites.

"Many of our products are derived from sensitive raw materials such as naturally derived building blocks like fats, sugars, glycerine, amino acid derivatives, or very reactive ones like acrylates," Weitemeyer explains. With these starting materials and, for example, high reaction temperatures, there are often by-products with color or smell that have to be removed.

LOWER TEMPERATURE enzymatic processes can help avoid by-products and other problems from the beginning, so they don't have to be fixed later, Weitemeyer says. "At the same time, the enzymatic reactions often use less energy and produce less waste than chemical processes, and biocatalysts might be used repeatedly," he adds. "Therefore, these processes tend to be environmentally friendly, but still comparable in cost."

For similar reasons, Celanese is exploring a biocatalytic route to acetic acid, one of its largest volume products, through a collaboration with Diversa. Celanese believes a biocatalytic process could be more specific while saving on energy and catalyst costs. Next year, the company expects to have a pilot plant to test the technology, Chairman Claudio Sonder said recently.

"We are looking mainly at the cost of the production process itself," explains company spokesman Carsten Henschel. "We have huge plants for acetic acid that have good economics and make us the cost leader. But we think biotechnology opens up the possibility for smaller units with the same or even better economics."

Whereas the Diversa collaboration is looking broadly at basic chemicals, Celanese has set up an internal venture called Protos to identify, develop, and market new products and processes based on microorganisms. Its focus now is on polyunsaturated fatty acids and nondigestible starch for food and other applications.

CELANESE IS developing applications for polylactic acid (PLA) polymer, Henschel says. Cargill Dow is supplying the polymer, which is derived from renewable sources. Lactic acid raw material is produced via fermentation of corn sugars. The Cargill Dow joint venture is building a 140,000-metric-ton-per-year PLA plant in Blair, Neb., and intends to expand lactic acid production there as well by 2002.

By substituting corn feedstocks for petroleum, PLA production uses 20 to 50% less fossil fuel than conventional plastics, Cargill Dow says. The company has a $2.3 million Department of Energy grant for continued R&D in fermentation processes using renewable resources. Dow also has an $18 million deal with Diversa to develop biocatalysts for chemical production.

Using corn or other crops as the source of fermentable sugars for high-volume chemical and polymer production is appealing, but it raises questions about costs and the ability to fuel market growth and meet long-term demand with these feedstocks. For its part, Cargill Dow says other sugar sources will ultimately be used in its PLA technology.

There are sufficient biological wastes--as much as 280 million metric tons per year in the U.S. from sources such as paper, tree, crop, and wood processing residues--to more than satisfy the carbon needed for all 100 million metric tons of organic chemicals consumed annually in the U.S., according to the NRC report.

Chemical companies haven't made it this far, but as a first step, DuPont recently announced that it had made 1,3-propanediol (PDO) from corn sugar instead of petroleum feedstocks. PDO is a key component of DuPont's new Sorona 3GT polymer. The biobased PDO was produced at a pilot plant at partner Tate & Lyle's Decatur, Ill., site, where they will build a full-scale plant by 2003.

DuPont developed the biocatalytic PDO technology with Genencor, and the two have since expanded their collaboration for further metabolic pathway engineering and process efficiencies. Earlier work led to a more than 500-fold gain in productivity through combining DNA from three different organisms into one production strain.  

THIS FEBRUARY, DuPont dedicated a 3GT polymerization plant in Kinston, N.C. The plant can switch from petroleum-based to biobased PDO "once process economics and market demand justify the change," DuPont says.

Sorona was developed in the company's biobased materials business unit, which serves as its center for applying biology to industrial markets. DuPont added a major research effort on biomaterials and bioprocesses in January 2000 through a five-year, $35 million alliance with Massachusetts Institute of Technology.

Ethel Noland Jackson, who leads the microbial and industrial biotechnology group within DuPont's central R&D function, says her group has sequenced the genome of Methylomonas, one of a common class of microbes that use methane as a food source. Now that DuPont understands the microbe's metabolic pathways, it can manipulate them to make a variety of products, hopefully at commercial levels, Jackson says.

"The metabolic pathways are somewhat different than in microbes that grow on glucose, and so it will be convenient to engineer for certain types of products, such as aromatics," she says. Based on experience using the microbe as a protein source for animal feed, it can be grown very inexpensively at industrial scale under mild conditions.

Methane also is considered a promising alternative feedstock. "Methane is very widely available," Jackson says, often found in remote parts of the world where it is burned rather than used in chemical production. "In those situations, this would be a way to transform the waste methane that's an environmental cost into something that would be transportable and of value."

Jackson's group also has been discovering interesting microbes living in DuPont's wastewater biotreatment facilities. "We have a collection of these bacteria categorized with respect to the chemistries they perform," she explains. "When we want to look for a particular biosynthetic route, we can go back to these microbes, look for the genes and pathways of interest, and then move them into an organism well suited for our particular production process."

Microbes have been found, for example, that synthesize terephthalic and adipic acids. But, Jackson adds, these are not likely to be commercially competitive with DuPont's existing chemical processes.

Ultimately, observers say, the selection of a biocatalytic production process won't depend on any single factor, such as its "greenness" or the use of renewable raw materials. In the end, it's simple market economics that determine which products and processes succeed.

"The true interest is in the chemistry, whether it's synthetic or biocatalytic," Catalyst Group's Payn says. "Industry is very pragmatic in the way it views manufacturing technology."

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BIOMASS
Technology Advances To Tap Fuel And Feedstock Source

One of the largest volume chemicals produced biocatalytically is ethanol. More than 1.5 billion gal per year is made this way for fuel in the U.S., the American Bioenergy Association reports. "Bioethanol" comes from fermenting sugars, which are often generated by breaking down starches from corn, potatoes, beets, sugarcane, or wheat.

New processes are being developed to produce ethanol from biomass or, more specifically, the cellulosic material in wood, grasses, and agricultural waste. Cellulose can be enzymatically broken down by cellulases into simple sugars, and thus might serve as a more plentiful and cheaper raw material for the biocatalytic production of ethanol and other chemicals than today's food starches.

However, there is a catch in making biomass a cost-effective feedstock. "The cost of the enzymes needed to convert biomass to sugars remains one of the most significant technical barriers to commercialization," Dan W. Reicher, then-assistant secretary for energy efficiency and renewable energy at the Department of Energy, said in early January.

If enzyme costs were less than 10 cents per gal of ethanol, compared with 45 cents today, then the cost of production would drop enough to make it economically feasible to use biomass wastes, enzyme producer Novozymes says.

Among the goals of the Biomass R&D Act of 2000 is making biomass competitive with petroleum feedstocks for energy and chemical production. The act is helping to support biomass conversion projects. Novozymes and enzymes competitor Genencor have received DOE grants, each totaling about $15 million over three years, to develop inexpensive cellulase systems.

Genencor and academic collaborators recently reported the structure of what the company calls a "commercially important fungal cellulase." Knowing the structure will enable the firm to design improved cellulases to increase the efficiency of industrial processes, Genencor says. The company intends to modify and optimize such enzymes.

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