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UCLA researchers develop synthetic biocatalytic pathway for more efficient conversion of methanol to longer-chain fuels

Researchers at the UCLA Henry Samueli School of Engineering and Applied Science led by Dr. James Liao have developed a more efficient way to turn methanol into useful chemicals, such as liquid fuels, and that would also reduce carbon dioxide emissions. The UCLA team constructed a synthetic biocatalytic pathway that efficiently converts methanol under room temperature and ambient atmospheric pressures to higher-chain alcohols or other higher carbon compounds without carbon loss or ATP expenditure.

Building off their previous work in creating a new synthetic metabolic pathway for breaking down glucose that could lead to a 50% increase in the production of biofuels (earlier post), the researchers modified the non-oxidative glycolysis pathway to utilize methanol instead of sugar. An open-access paper on the research was published in the 11 Nov. edition of the Proceedings of the National Academy of Sciences.

Methanol is an important intermediate in the utilization of natural gas for synthesizing other feedstock chemicals. Typically, chemical approaches for building C–C bonds from methanol require high temperature and pressure. Biological conversion of methanol to longer carbon chain compounds is feasible; however, the natural biological pathways for methanol utilization involve carbon dioxide loss or ATP expenditure.

Here we demonstrated a biocatalytic pathway, termed the methanol condensation cycle (MCC), by combining the non-oxidative glycolysis with the ribulose monophosphate pathway to convert methanol to higher-chain alcohols or other acetyl-CoA derivatives using enzymatic reactions in a carbon-conserved and ATP-independent system. We investigated the robustness of MCC and identified operational regions. We confirmed that the pathway forms a catalytic cycle through 13C-carbon labeling. With a cell-free system, we demonstrated the conversion of methanol to ethanol or n-butanol. The high carbon efficiency and low operating temperature are attractive for transforming natural gas-derived methanol to longer-chain liquid fuels and other chemical derivatives.

—Bogorad et al.

Methanol, which is a product of natural gas, is a feedstock chemical that can be processed into gasoline and other chemicals such as solvents, adhesives, paints and plastics. Using current methods, that processing requires high temperatures, high pressures, expensive catalysts, and typically results in the release of the greenhouse gas carbon dioxide into the atmosphere.

Although there are natural pathways to assimilate methanol to form metabolites that could, in principle, be used to form higher-chain alcohols, inherent pathway limitations prevent complete carbon conservation.

The first step in the synthetic MCC is the oxidation of methanol to formaldehyde. The core portion of MCC is then the biochemical condensation of two formaldehydes with a CoA to form acetyl-CoA and water. The final phase in MCC involves the reduction of acetyl-CoA to alcohols.

The … results demonstrate that MCC is indeed functional, although kinetics of the cycle needs to be tuned to avoid the kinetic trap. We expect that with some moderate protein engineering, the activities of Mdh, Fpk, and PduP could be improved to enable substantially higher fluxes. Because MCC is completely redox balanced and independent of ATP, a cell-free system could be a viable application for larger-scale production after optimizing the conditions for enzyme and intermediates stability. Unlike microbial systems, cell-free conversion can achieve high theoretical yields, achieve high productivity, and are easier to control. Alternatively, MCC could be engineered into a variety of hosts because all of the enzymes are oxygen tolerant.

—Bogorad et al.

Tung-Yun (Tony) Wu, a project scientist with Liao’s metabolic engineering and synthetic biology laboratory, was a co-author and manager of the research. Other contributing authors included Igor Bogorad, Chang-Ting Chen, Matthew Theisen, Alicia Schlenz and Albert Lam.

While this research addresses a major step in converting methanol to liquid fuels, another major challenge remains in the conversion of methane (the major component in natural gas) to methanol.

The research was supported by the ARPA-e REMOTE (Reducing Emissions using Methanotrophic Organisms for Transportation Energy) program. (Earlier post.)


  • Igor W. Bogorad, Chang-Ting Chen, Matthew K. Theisen, Tung-Yun Wu, Alicia R. Schlenz, Albert T. Lam, and James C. Liao (2014) “Building carbon–carbon bonds using a biocatalytic methanol condensation cycle,” PNAS 111 (45) 15928-15933 doi: 10.1073/pnas.1413470111



"Methanol, which is a product of natural gas..."

It can also be synthesized from gasified biomass.

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