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Chalmers team engineers synthetic enzymes for bio-production of fuel alternatives

Researchers at Chalmers University and their colleagues have engineered synthetic fatty acid synthases (FASs) that enable yeast to produce short/medium-chain fatty acids and methyl ketones for use in fuels and chemicals. A paper on their work is published in the journal Nature Chemical Biology.

FASs normally synthesize long chain fatty acids, but the Chalmers team developed a new method to modify FAS by inserting heterologous enzymes into the FAS reaction compartments to synthesize the medium-chain fatty acids and methyl ketones—components in currently used transportation fuels, said Zhiwei Zhu, post-doc and first author of the study. “In other words: We are now able to produce petrol and jet fuel alternatives in yeast cell factories,” he said.

Fungal type I fatty acid synthase (FAS) complexes, encoded by one or two polypeptides that typically consist of seven distinct catalytic enzyme domains and one acyl carrier protein (ACP) domain, are barrel-shaped hollow particles separated by a central wheel at the equator to form two identical reaction chambers, each containing three complete catalytic centers. The ACP domain is located inside the compartmented chamber, tethered by two flexible linkers anchored to the chamber wall and central wheel. The ACP is activated via a phosphopantetheinyl transferase (PPT)-catalyzed attachment of a prosthetic phosphopantetheine group, which provides a thiol group to link the growing fatty acyl chain, and the holo-ACP carrying the acyl cargo interacts dynamically with other catalytic domains to fulfill the complete reaction cycle of fatty acid synthesis.

As the ACP and its adjacent linkers swing in the hollow reaction chambers, we speculated that these flexible regions could be readily modified, and heterologous enzymes using acyl-ACP via direct interaction or channeling acyl-CoA released by malonyl/ palmitoyl transferase domains could be embedded into the FAS chambers to create a novel synthetic FAS, and to expand the product portfolio of the fatty acid biosynthetic machinery.

—Zhu et al.

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The structure of the FAS enzyme (left), and the foreign enzymes embedded into the chambers of FAS (right). Click to enlarge.

The important enzyme was first described by Nobel Prize winner Feodor Lynen, and many researchers have tried to modify it in recent years; however, the rigid enzyme seemed not readily amenable to manipulation, said Zhu.

The findings are in fact a result of a lucky break. A few years ago, the researchers occasionally found a fatty acid synthase which had two acyl carrier protein domains.

We first tried to change this fatty acid synthase by replacing one of its acyl carrier protein domains with a foreign enzyme to modify its properties and, surprisingly, it worked. Then we implemented such modification in other fungal fatty acid synthases and found this approach versatile.

—Zhiwei Zhu

The researchers are now focusing on using the modified enzyme to build yeast cell factories for production of chemicals and fuels from glucose. An invention patent has been applied for, and the company Biopetrolia—a spin-off from Chalmers University of Technology—is closely involved in trying to further develop the technique to make it economically viable.

Resources

  • Zhiwei Zhu, Yongjin J Zhou, Anastasia Krivoruchko, Martin Grininger, Zongbao K Zhao & Jens Nielsen (2017) “Expanding the product portfolio of fungal type I fatty acid synthases” Nature Chemical Biology doi: 10.1038/nchembio.2301

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