Thiaville2016 - Folate pathway model (PanB overexpression)

Henry2016 Folate pathway model with induced
PanB reaction

This model is described in the article:

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

Thiaville JJ, Frelin O,
García-Salinas C, Harrison K, Hasnain G, Horenstein NA,
Díaz de la Garza RI, Henry CS, Hanson AD, de
Crécy-Lagard V.
Front Microbiol 2016; 7: 431
Abstract:

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.

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