Thiaville2016 - Folate pathway model (PanB overexpression)

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Model Identifier
BIOMD0000000689
Short description
Henry2016 Folate pathway model with induced PanB reaction

This model is described in the article:

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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Format
SBML (L2V4)
Related Publication
  • 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
  • Frontiers in microbiology , 0/ 2016 , Volume 7 , pages: 431 , PubMed ID: 27065985
  • Department of Microbiology and Cell Science, University of Florida Gainesville, FL, USA.
  • 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.
Contributors
Submitter of the first revision: Christopher Henry
Submitter of this revision: administrator
Modellers: administrator, Christopher Henry

Metadata information

is (2 statements)
BioModels Database MODEL1602280002
BioModels Database BIOMD0000000689

isDescribedBy (2 statements)
PubMed 27065985
PubMed 27065985

hasTaxon (1 statement)
Taxonomy Escherichia coli

hasProperty (1 statement)
hasPart (2 statements)

Curation status
Curated

Tags

Connected external resources

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Model files

BIOMD0000000689_url.xml SBML L2V4 representation of Thiaville2016 - Folate pathway model (PanB overexpression) 66.28 KB Preview | Download

Additional files

BIOMD0000000689-biopax2.owl Auto-generated BioPAX (Level 2) 31.76 KB Preview | Download
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BIOMD0000000689.m Auto-generated Octave file 6.39 KB Preview | Download
BIOMD0000000689.pdf Auto-generated PDF file 165.64 KB Preview | Download
BIOMD0000000689.png Auto-generated Reaction graph (PNG) 85.53 KB Preview | Download
BIOMD0000000689.sci Auto-generated Scilab file 154.00 Bytes Preview | Download
BIOMD0000000689.svg Auto-generated Reaction graph (SVG) 23.75 KB Preview | Download
BIOMD0000000689.vcml Auto-generated VCML file 103.86 KB Preview | Download
BIOMD0000000689.xpp Auto-generated XPP file 4.50 KB Preview | Download
BIOMD0000000689_urn.xml Auto-generated SBML file with URNs 66.26 KB Preview | Download
MODEL1602280002.cps Curated and annotated model COPASI file 78.81 KB Preview | Download
MODEL1602280002.sedml SED-ML file for figure 7A of the reference publication. PanB reaction rate constant is 0.0121 and not 0.00121 as stated in table 3 of the supplementary material. Additionally, the reaction rate constant for FolC has been decreased from 6184 to 3600 to get dihydropteroate and dihydrofolate to be approximately the same value. 4.99 KB Preview | Download

  • Model originally submitted by : Christopher Henry
  • Submitted: Feb 28, 2016 9:44:36 PM
  • Last Modified: Mar 13, 2018 5:15:45 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Mar 13, 2018 5:15:45 PM
    • Submitted by: administrator
    • With comment: Model name updated using online editor.
  • Version: 2 public model Download this version
    • Submitted on: May 31, 2017 4:19:17 PM
    • Submitted by: Christopher Henry
    • With comment: Current version of Thiaville2016 - Folate pathway model with induced PanB reaction
  • Version: 1 public model Download this version
    • Submitted on: Feb 28, 2016 9:44:36 PM
    • Submitted by: Christopher Henry
    • With comment: Original import of Henry2016 Folate pathway model with induced PanB reaction

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
H2 HMPt

6-(Hydroxymethyl)-7,8-dihydropterin ; dihydropterin
3.315E-6 mmol
p ABA

4-aminobenzoate ; 4-Aminobenzoate
1.0E-5 mmol
Glycine

Glycine ; glycine
2.77E-4 mmol
DHF

dihydrofolate(2-) ; Dihydrofolate
1.0E-5 mmol
THF

Tetrahydrofolate ; tetrahydrofolate
1.69E-4 mmol
NADPH

NADPH ; NADPH
9.4E-7 mmol
AMP

AMP ; AMP
2.8E-4 mmol
H2 HMPterinPP

6-(Hydroxymethyl)-7,8-dihydropterin ; phosphorylation ; dihydropterin
1.0E-5 mmol
Reactions
Reactions Rate Parameters
=> H2_HMPt compartment*v v=1.66E-7
=> p_ABA compartment*v v=1.66E-7
THF + L_serine => CH2_THF + Glycine compartment*(k1*THF*L_serine-k2*CH2_THF*Glycine) k1=4080.0; k2=2000.0
L_Glutamate + ATP + H2_Pteroate => DHF + ADP + Phosphate compartment*k1*L_Glutamate*ATP*H2_Pteroate k1=3602.18
THF => compartment*V*THF/(Km+THF) V=1.243E-7; Km=1.571E-4
DHF + NADPH => NADP + THF compartment*k1*DHF*NADPH k1=31170.0
CH2_THF => H2_HMPt + p_ABA compartment*k1*CH2_THF k1=0.0121
ATP + H2_HMPt => AMP + H2_HMPterinPP compartment*k1*ATP*H2_HMPt k1=15.8
p_ABA + H2_HMPterinPP => PPi + H2_Pteroate compartment*k1*p_ABA*H2_HMPterinPP k1=4000.0
Curator's comment:
(added: 12 Mar 2018, 15:07:45, updated: 12 Mar 2018, 15:07:45)
Attempt at reproducing figure 7A of the reference publication. The value of the reaction rate constant for PanB was 0.0121 and not 0.00121 as stated in the supplementary material table 3. Additionally, to get dihydropteroate and dihydrofolate to be approximately the same (yellow and magenta curves, bottom curated figure) as in the publication figure, the reaction rate constant for FolC was decreased from 6184 to 3600. The simulations were performed in COPASI 4.22 (Build 170) and the figure was generated with MATLAB R2014b.