Thiaville2016 - Folate pathway model (PanB overexpression)
This model is described in the article:
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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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.
Submitter of this revision: administrator
Modellers: administrator, Christopher Henry
Metadata information
isDescribedBy (2 statements)
hasTaxon (1 statement)
hasProperty (1 statement)
hasPart (2 statements)
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000689_url.xml | SBML L2V4 representation of Thiaville2016 - Folate pathway model (PanB overexpression) | 66.28 KB | Preview | Download |
Additional files |
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| BIOMD0000000689-biopax2.owl | Auto-generated BioPAX (Level 2) | 31.76 KB | Preview | Download |
| BIOMD0000000689-biopax3.owl | Auto-generated BioPAX (Level 3) | 44.07 KB | Preview | Download |
| 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
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Version: 3
- Submitted on: Mar 13, 2018 5:15:45 PM
- Submitted by: administrator
- With comment: Model name updated using online editor.
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Version: 2
- 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
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Version: 1
- 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
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: Variable used inside SBML models
| 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 | 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 |
(added: 12 Mar 2018, 15:07:45, updated: 12 Mar 2018, 15:07:45)