Saturday, 14 April 2018

How does Dimethyl fumarate work

How does dimethyl fumarate work?
Read on

Kornberg MD, Bhargava P, Kim PM, Putluri V, Snowman AM, Putluri N, Calabresi PA, Snyder SH. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science. 2018 Mar 29. pii: eaan4665. doi: 10.1126/science.aan4665. [Epub ahead of print]

Activated immune cells undergo a metabolic switch to aerobic (requiring oxygen) glycolysis.


Glycolysis breaks down glucose and forms pyruvate with the production of two molecules of ATP. The pyruvate end product of glycolysis can be used in either anaerobic respiration if no oxygen is available or in aerobic respiration via the TCA cycle which yields much more usable energy for the cell.

Dimethyl fumarate, a derivative of the Krebs cycle (see below) intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis. 

Although its therapeutic mechanism remains uncertain, it covalently modifies cysteine residues in a process termed “succination.” Here, we show that dimethyl fumarate succinates and inactivates the catalytic cysteine of the glycolytic enzyme GAPDH both in vitro and in vivo. It thereby downregulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our findings provide mechanistic insight into immune modulation by dimethyl fumarate and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.

7 comments:

  1. Where does the enzyme acid maltase fit in?

    ReplyDelete
    Replies
    1. Citric acid cycle

      "In the seventh step ,fumarate its converted to malate by the enzyme fumarase"

      Ps:See link bellow ,turn on subtitles

      Delete
    2. "Before I came here I was confused about this subject. Having listened to your lecture I am still confused. But on a higher level". Enrico Fermi


      Cellular metabolism

      https://www.youtube.com/watch?time_continue=267&v=-7FPtZm8sno



      Glycolysis

      https://www.youtube.com/watch?v=KfWkZZZjMQE&index=3&list=PLf9u4r9oMkmS259O9oHajnUCvaXfec-6U


      Citric Acid Cycle

      https://www.youtube.com/watch?v=82CplqKfw90

      The electron transport chain

      oxidative phosphorylation

      https://www.youtube.com/watch?time_continue=294&v=D6U2AVWV9iI


      Ps: Turn on subtitles


      Happy learning :)

      Obrigado

      Delete
    3. Thanks Luis, another trip down memory lane. Will there be a quiz tomorrow? Some times it’s best to be left in the dark. :-)

      Delete
  2. This is a very interesting paper

    1º Dmf exercts its efects via cellular metabolism

    (glycolisis pathway)

    2º If you are on Dmf please dont eat candies :)


    We next measured the production of IL-1β under low (0.5 mM) or high (10 mM) glucose concen-trations and found that DMF was much less effective in the presence of high glucose (Fig. 3A), suggesting that its anti-inflammatory effect can be overcome by driving glycolysis higher with saturating concentrations of glucose.

    3º Low sugar diet makes sense in modulating the immune system


    Obrigado

    ReplyDelete
  3. Work in animals suggests that targeting immune metabolism is a promising approach. In one 2015 study, immunologist Laurence Morel of the University of Florida in Gainesville and colleagues dosed mice that were genetically modified to develop a lupuslike condition with metformin and 2DG. Metformin curtails oxidative phosphorylation, whereas 2DG squelches glycolysis. Together, the molecules reversed lupus symptoms in the animals. Lupus patients, for example, pump out antibodies that attack their own DNA. But in the mice, the levels of those antibodies fell by about 50% after treatment began. The researchers detected no signs that the rodents became more vulnerable to infections.

    In another study, Rathmell and colleagues added dichloroacetate, which suppresses glycolysis, to the drinking water of mice that have a condition that mimics multiple sclerosis, in which the immune system attacks nerves' insulating myelin sheath. The compound prevented myelin destruction in the animals and reduced neurological symptoms such as muscle weakness, the scientists reported in 2014.

    Impeding cellular metabolism also could curb the immune system's attacks on transplanted organs, Powell and colleagues have found. They gave metformin, 2DG, and a third drug that blocks the metabolism of glutamine to mice that had received skin grafts or heart transplants.
    Two years ago, Argentine researchers reported fewer new brain lesions in 30 patients with multiple sclerosis who took metformin or another drug that short-circuits oxidative phosphorylation. A clinical trial by Chinese researchers is testing whether metformin can quell lupus flares. And so far, such drugs seem safe. "Metformin on its own does very little to impair immunity, for example, but can reduce chronic inflammation," Rathmell says.

    http://www.sciencemag.org/news/2018/03/treat-some-diseases-researchers-are-putting-immune-cells-diet

    ReplyDelete

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