Limits...
A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction.

Watterson S, Guerriero ML, Blanc M, Mazein A, Loewe L, Robertson KA, Gibbs H, Shui G, Wenk MR, Hillston J, Ghazal P - Biochimie (2012)

Bottom Line: Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus or treated with IFNγ, we show that, under these assumptions, coordinate down-regulation of enzyme activity imparts a graduated reduction in flux along the pathway.The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions.We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathway Medicine, University of Edinburgh Medical School, Chancellor's Building, 49 Little France Crescent, Edinburgh, Scotland, United Kingdom. s.watterson@ed.ac.uk

Show MeSH

Related in: MedlinePlus

A) The effect of a statin-like inhibitor on pathway activity. The profile of flux at 0 and 12 h following mCMV infection and IFNγ treatment together with the profile of flux in an unperturbed cell following the introduction of a statin-like inhibitor which targets the enzyme HMGCR. The effect of a statin-like inhibitor is to step down the flux through the interactions catalysed by HMGCR. This impacts upon the pathway significantly upstream of the point of cholesterol synthesis and creates a flux profile dramatically different to that which arises from the biological response to mCMV infection or IFNγ treatment. B) The profile of flux achieved along the pathway when inhibitor concentrations are chosen so that each interaction contributes equally to the regulation of flux (inhibitor levels listed in Supplementary section 9).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3585962&req=5

fig4: A) The effect of a statin-like inhibitor on pathway activity. The profile of flux at 0 and 12 h following mCMV infection and IFNγ treatment together with the profile of flux in an unperturbed cell following the introduction of a statin-like inhibitor which targets the enzyme HMGCR. The effect of a statin-like inhibitor is to step down the flux through the interactions catalysed by HMGCR. This impacts upon the pathway significantly upstream of the point of cholesterol synthesis and creates a flux profile dramatically different to that which arises from the biological response to mCMV infection or IFNγ treatment. B) The profile of flux achieved along the pathway when inhibitor concentrations are chosen so that each interaction contributes equally to the regulation of flux (inhibitor levels listed in Supplementary section 9).

Mentions: Fig. 4A shows the profile of flux obtained in the unperturbed pathway and the profiles at 12 h following IFNγ treatment and mCMV infection. Fig. 4A also shows the profile of flux obtained when the statin-like inhibitor is introduced with a concentration sufficient to suppress cholesterol production to the mean of the production rates for IFNγ treatment and mCMV infection at 12 h. Here we can see that the profile takes a very different form, impacting dramatically upon the interactions upstream of Squa. The profile corresponding to statin-like inhibition is less graduated than in the physiological responses both in terms of the dominant interactions and the non-dominant interactions, and such a flat profile arises because the single HMGCR inhibited interaction takes the entire regulatory burden of reducing the flux along the pathway with the other interactions contributing no more flux reduction than in the unperturbed case.


A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction.

Watterson S, Guerriero ML, Blanc M, Mazein A, Loewe L, Robertson KA, Gibbs H, Shui G, Wenk MR, Hillston J, Ghazal P - Biochimie (2012)

A) The effect of a statin-like inhibitor on pathway activity. The profile of flux at 0 and 12 h following mCMV infection and IFNγ treatment together with the profile of flux in an unperturbed cell following the introduction of a statin-like inhibitor which targets the enzyme HMGCR. The effect of a statin-like inhibitor is to step down the flux through the interactions catalysed by HMGCR. This impacts upon the pathway significantly upstream of the point of cholesterol synthesis and creates a flux profile dramatically different to that which arises from the biological response to mCMV infection or IFNγ treatment. B) The profile of flux achieved along the pathway when inhibitor concentrations are chosen so that each interaction contributes equally to the regulation of flux (inhibitor levels listed in Supplementary section 9).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585962&req=5

fig4: A) The effect of a statin-like inhibitor on pathway activity. The profile of flux at 0 and 12 h following mCMV infection and IFNγ treatment together with the profile of flux in an unperturbed cell following the introduction of a statin-like inhibitor which targets the enzyme HMGCR. The effect of a statin-like inhibitor is to step down the flux through the interactions catalysed by HMGCR. This impacts upon the pathway significantly upstream of the point of cholesterol synthesis and creates a flux profile dramatically different to that which arises from the biological response to mCMV infection or IFNγ treatment. B) The profile of flux achieved along the pathway when inhibitor concentrations are chosen so that each interaction contributes equally to the regulation of flux (inhibitor levels listed in Supplementary section 9).
Mentions: Fig. 4A shows the profile of flux obtained in the unperturbed pathway and the profiles at 12 h following IFNγ treatment and mCMV infection. Fig. 4A also shows the profile of flux obtained when the statin-like inhibitor is introduced with a concentration sufficient to suppress cholesterol production to the mean of the production rates for IFNγ treatment and mCMV infection at 12 h. Here we can see that the profile takes a very different form, impacting dramatically upon the interactions upstream of Squa. The profile corresponding to statin-like inhibition is less graduated than in the physiological responses both in terms of the dominant interactions and the non-dominant interactions, and such a flat profile arises because the single HMGCR inhibited interaction takes the entire regulatory burden of reducing the flux along the pathway with the other interactions contributing no more flux reduction than in the unperturbed case.

Bottom Line: Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus or treated with IFNγ, we show that, under these assumptions, coordinate down-regulation of enzyme activity imparts a graduated reduction in flux along the pathway.The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions.We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzyme regulation.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathway Medicine, University of Edinburgh Medical School, Chancellor's Building, 49 Little France Crescent, Edinburgh, Scotland, United Kingdom. s.watterson@ed.ac.uk

Show MeSH
Related in: MedlinePlus