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MSU Researchers Find How ‘Extraordinary Cofactor’ Is Made

Robert Hausinger

Researchers at Michigan State University have made new progress in understanding how microbial cells manufacture a recently discovered ‘cofactor,’ an unusually complex molecule that is attached to a protein and allows it to complete a simple biological process. The results are published in a paper Monday in the Proceedings of the National Academy of Sciences.

Enzymes, the biological molecules that accelerate the complex chemical reactions occurring everywhere in our lives, often require additional components in order to function. These ‘cofactors’ can either be inorganic, organic, or a combination of both. MSU researchers had previously discovered what Bob Hausinger, a professor of microbiology and molecular genetics and of biochemistry and molecular biology, termed an ‘extraordinary cofactor.’

“Our new work goes a long way in solving the puzzle of how several bacteria make this complex molecule,” said Hausinger, director of the lab at MSU where the research was conducted.

The cofactor is a nonprotein chemical compound containing nickel plus nicotinic acid (vitamin B3), called an (SCS)Ni(II) pincer complex, where “SCS” means that the nickel ion is coordinated by two sulfur atoms and one carbon atom. The earlier discovery showed the fundamental work by inorganic chemists on pincer compounds had real applications in nature, but it generated questions about how exactly this complex is made in living cells.

“All cells synthesize essential compounds derived from nicotinic acid, but we discovered a common intermediate in this pathway is hijacked by previously uncharacterized enzymes to create the (SCS)Ni(II) pincer complex,” Hausinger said.

One of these enzymes adds carbon dioxide to a modified nicotinic acid, forming a previously unknown compound with two carboxyl groups. Such addition of carboxyl groups to aromatic (ring-containing) compounds is of great interest in organic chemistry.

The second enzyme uses one of its own sulfur atoms to replace an oxygen atom in one of the carboxyl groups of the nicotinic acid derivative. This reaction has an unusual twist because the enzyme becomes inactivated during this sacrificial sulfur insertion reaction, so the enzyme is used just once. A second copy of this enzyme is needed to add sulfur to the second carboxyl group and complete synthesis of the pincer species. Another protein donates the nickel atom to the cofactor, and somehow the completed complex is attached to the final enzyme.

With the overall pathway for (SCS)Ni(II) pincer synthesis now established, the investigators can turn to other concerns such as understanding the detailed biochemistry of each step of the biosynthesis and determining how the cofactor is used in different enzyme reactions.

This research was carried out by Benoit Desguin, a postdoctoral scholar at MSU who has now returned to his home at Université catholique de Louvain in Belgium. Desguin played a key role in the discovery of the previously unknown cofactor in an enzyme called lactate racemase. In the current research, Desguin used sophisticated methods of mass spectrometry to establish the biosynthetic pathway for this cofactor.

“We learned the synthesis of this novel cofactor includes several fascinating steps, such as an unprecedented addition of carbon dioxide to an aromatic compound and a sacrificial sulfur insertion system, both of which may have further applications in biology and synthetic chemistry,” Hausinger said.

– Mark Kuykendall, Robert Hausinger via MSU Today

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