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Formaldehyde-Detoxifying Role of the Tetrahydromethanopterin-Linked Pathway in Methylobacterium extorquens AM1

Christopher J. Marx,^1, Ludmila Chistoserdova,² and Mary E. Lidstrom^1,2*

Department of Microbiology,¹ Department of Chemical Engineering, University of Washington, Seattle, Washington 98195²

Received 17 June 2003/ Accepted 17 September 2003

The facultative methylotroph Methylobacterium extorquens AM1 possesses two pterin-dependent pathways for C₁ transfer between formaldehyde and formate, the tetrahydrofolate (H₄F)-linked pathway and the tetrahydromethanopterin (H₄MPT)-linked pathway. Both pathways are required for growth on C₁ substrates; however, mutants defective for the H₄MPT pathway reveal a unique phenotype of being inhibited by methanol during growth on multicarbon compounds such as succinate. It has been previously proposed that this methanol-sensitive phenotype is due to the inability to effectively detoxify formaldehyde produced from methanol. Here we present a comparative physiological characterization of four mutants defective in the H₄MPT pathway and place them into three different phenotypic classes that are concordant with the biochemical roles of the respective enzymes. We demonstrate that the analogous H₄F pathway present in M. extorquens AM1 cannot fulfill the formaldehyde detoxification function, while a heterologously expressed pathway linked to glutathione and NAD⁺ can successfully substitute for the H₄MPT pathway. Additionally, null mutants were generated in genes previously thought to be essential, indicating that the H₄MPT pathway is not absolutely required during growth on multicarbon compounds. These results define the role of the H₄MPT pathway as the primary formaldehyde oxidation and detoxification pathway in M. extorquens AM1.

Present address: 2215 Biomedical Physical Sciences, Michigan State University, East Lansing, MI 48824-4320.

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