Experimental and Metabolic Modeling Evidence for a Folate-Cleaving Side-Activity of Ketopantoate Hydroxymethyltransferase (PanB)

Thiaville, Jennifer J.; Frelin, Océane; García-Salinas, Carolina; Harrison, Katherine; Hasnain, Ghulam; Horenstein, Nicole A.; Díaz de la Garza, Rocio I.; Henry, Christopher S.; Hanson, Andrew D.; de Crécy-Lagard, Valérie

doi:10.3389/fmicb.2016.00431

Experimental and Metabolic Modeling Evidence for a Folate-Cleaving Side-Activity of Ketopantoate Hydroxymethyltransferase (PanB)

Journal Article · Thu Mar 31 04:00:00 EDT 2016 · Frontiers in Microbiology

DOI:https://doi.org/10.3389/fmicb.2016.00431· OSTI ID:1393178

Thiaville, Jennifer J.; Frelin, Océane; García-Salinas, Carolina; Harrison, Katherine; Hasnain, Ghulam; Horenstein, Nicole A.; Díaz de la Garza, Rocio I.; Henry, Christopher S.; Hanson, Andrew D.; de Crécy-Lagard, Valérie

Tetrahydrofolate (THF) and its one-carbon derivatives, collectively termed folates, are essential cofactors, but are inherently unstable. While it is clear that chemical oxidation can cleave folates or damage their pterin precursors, very little is known about enzymatic damage to these molecules or about whether the folate biosynthesis pathway responds adaptively to damage to its end-products. The presence of a duplication of the gene encoding the folate biosynthesis enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) in many sequenced bacterial genomes combined with a strong chromosomal clustering of the folK gene with panB, encoding the 5,10-methylene-THF-dependent enzyme ketopantoate hydroxymethyltransferase, led us to infer that PanB has a side activity that cleaves 5,10-methylene-THF, yielding a pterin product that is recycled by FolK. Genetic and metabolic analyses of Escherichia coli strains showed that overexpression of PanB leads to accumulation of the likely folate cleavage product 6-hydroxymethylpterin and other pterins in cells and medium, and—unexpectedly—to a 46% increase in total folate content. In silico modeling of the folate biosynthesis pathway showed that these observations are consistent with the in vivo cleavage of 5,10-methylene-THF by a side-activity of PanB, with FolK-mediated recycling of the pterin cleavage product, and with regulation of folate biosynthesis by folates or their damage products.

Research Organization:: Argonne National Laboratory (ANL)

Sponsoring Organization:: National Science Foundation (NSF)

DOE Contract Number:: AC02-06CH11357

OSTI ID:: 1393178

Journal Information:: Frontiers in Microbiology, Journal Name: Frontiers in Microbiology Vol. 7; ISSN 1664-302X

Publisher:: Frontiers Research Foundation

Country of Publication:: United States

Language:: English

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