D.J. Ferguson

Education

Ph.D. Biochemistry, The Ohio State University (2000)

Research Interests

Anaerobic One-Carbon Metabolism in Methanogens and Gram-Positive Bacteria

• The role of microbial metabolism of quaternary amines in cardiovascular disease - Cardiovascular disease is the leading cause of death worldwide. In recent years, studies have shown a clear link between consumption of foods rich in quaternary amine compounds such as choline and carnitine and the development of atherosclerosis. This association is due to the action of gut microbiota that can cleave quaternary amines in a way that yields a product called trimethylamine (TMA). TMA then travels through the blood to the liver where it becomes oxidized to a compound called trimethylamine N-oxide (TMAO). TMAO then acts as a direct precursor to the development of atherosclerosis, or deposition of plaques along in the inside of blood vessels. The conversion of quaternary amines to TMA is strictly dependent on gut microbiota and yet not all gut microbiota contribute to heart disease in this manner. Our research has shown that some gut microbiota, including those that are plentiful in the gut, possess the ability to demethylate quaternary amines rather than cleave them, and thus do not generate TMA. Therefore, many gut microbes appear to catabolize quaternary amines in ways that would lessen the risk of atherosclerosis rather than heighten that risk. We are interested in learning more about this form of microbial metabolism.
• Quaternary amine metabolism in Desulfitobacterium hafniense - We recently reported that an organism called Desulfitobacterium hafniense, a known gut inhabitant, is capable of demethylation of the quaternary amine glycine betaine. Furthermore, this organism does so using an enzyme (MtgB) closely related to the TMA methyltransferase enzymes (MttB) of methanogenic archaea. One key difference between the D. hafniense MtgB enzyme and the MttB enzymes of methanogens is the lack of the rare pyrrolysine residue in MtgB that is critical for the activity of the TMA methyltransferases. MtgB is part of the large MttB superfamily (COG5598) and, interestingly, the majority of the members of this superfamily also lack pyrrolysine. Therefore, it is likely that the majority of the members of this widespread superfamily actually function as quaternary amine methyltransferases.
• Quaternary amine dependent methanogenesis - We are also interested in the metabolism of methylotrophic methanogens. Methanogens generate methane (natural gas) as the end product of their metabolism. Methane is both an important fuel source and potent greenhouse gas. We hypothesized that some strains of methylotrophic methanogens are able to use quaternary amines as substrates and this led us to the successful isolation of two novel strains of methanogens capable of quaternary amine dependent methanogenesis. We are currently investigating the genomes of these organisms and elucidating the pathways by which they convert quaternary amines to methane. We are also working towards the isolation of more novel strains of both methanogens and bacteria capable of growth on and demethylation of quaternary amines. Our work has ecological, evolutionary, and human health significance.

Selected Publications

• Kashyap JS, Ringiesn JR, Schwab N, and DJ Ferguson Jr. Isolation and characterization of a novel choline degrading Citrobacter amalonaticus strain from the human gut. 2022. Curr. Res. Microb. Sci.  3: 100157. https://www.sciencedirect.com/science/article/pii/S2666517422000542
• Creighbaum AJ, Ticak T, Shinde S, Wang X, and DJ Ferguson Jr. 2019. Examination of the glycine betaine-dependent methylotrophic methanogenesis pathway: insights into anaerobic quaternary amine methylotrophy. Front. Microbiol. 10:2572. https://www.frontiersin.org/articles/10.3389/fmicb.2019.02572/full
• Ticak T, Kuntz, D, Girosky K, Krzycki JA, and DJ Ferguson Jr. 2014. A nonpyrrolysine member of the widely distributed trimethylamine methyltransferase family is a glycine betaine methyltransferase. Proc Nat Acad Sci (USA). Oct 28; 111(43):E4668-76.
• Ticak T, Hariraju D, Bayron M, Arivett BA, Fiester SE, andDJ Ferguson Jr. 2014. Isolation and characterization of a tetramethylammonium degrading Methanococcoides strain and a novel glycine betaine utilizing Methanolobus strain. Arch Microbiol. 197(2): 97-209.
• Ferguson, DJ Jr., DG Longstaff and JA Krzycki. 2011. Assay of methylotrophicmethyltransferases from methanogenic archaea. Meth Enzymol. vol 494. pp. 139-158.
• Gong W, Hao B, Wei Z, Ferguson DJ Jr., Tallant T, Krzycki JA, and Chan M. Structure of the a2e2 Ni-CODH component of the Methanosarcina barkeri ACDS complex. Proc Nat Acad Sci (USA). 2008 Jul 15;105(28):9558-63.
• Ferguson DJ Jr, Gorlatova N, Grahame D.A., Krzycki JA. Reconstitution of dimethylamine:coenzyme M methyl transfer with a discrete corrinoid protein and two methyltransferases purified from Methanosarcina barkeri. J Biol Chem. 2000 Sep 15;275(37):29053-60.
• Ferguson D.J. Jr, Krzycki J.A.. Reconstitution of trimethylamine-dependent coenzyme M methylation with the trimethylamine corrinoid protein and the isozymes of methyltransferase II from Methanosarcina barkeri. J Bacteriol. 1997 Feb;179(3):846-52.
• Ferguson D.J. Jr, Krzycki J.A., Grahame D.A.. Specific roles of methylcobamide:coenzyme M methyltransferase isozymes in metabolism of methanol and methylamines in Methanosarcina barkeri. J Biol Chem. 1996 Mar 1;271(9):5189-94