3 ms·

It is always delightful to me when people look more closely at well-understood pathways and make new discoveries that change our understanding. This is one such

It is always delightful to me when people look more closely at well-understood pathways and make new discoveries that change our understanding. This is one such occasion. Basically, it appears that they discovered a feed-forward loop in the synthesis of phosphoenolpyruvate, the penultimate product of glycolysis. Though this wasn't mentioned in the news article, I wonder if this helps to explain the Warburg effect. Anyways, this doesn't exactly jump out to me with applications since the research seems so early stage. True, discovery of novel pathways implies that inhibition of these pathways could be useful for treating cancer. But until some research is actually done in that vein, I'm hesitant to read too deeply. I'll review the manuscript itself, but I don't think we know for sure that this "cancer-only" pathway is not at play in important, rapidly-growing non-cancerous tissues, which would be my main concern.

enjo 16y ago
The article did mention the research was already doing some sort of drug trial with mice. So hopefully they're already heading in that direction.
carbocation 16y ago
OK, I've read the manuscript now. Very interesting work. I didn't realize this initially, but they are also saying that the transient phosphorylation of PGAM1 is a mechanism by which PEP is converted to pyruvate at a meaningful rate! Reason for the exclamation point: the conversion of PEP -> pyruvate is is considered the last of 3 rate-limiting steps in glycolysis. They propose an end-run around this rate-limiting step. In their model, PEP donates its phosphate to PGAM1. Thus, PEP becomes pyruvate. Normally I wouldn't expect this to be a meaningful way to produce pyruvate--but their data appear to support the notion that PGAM1 becomes dephosphorylated at a high enough rate that this process can repeat itself fast enough to sustain pyruvate production. Oh, and phosphorylated PGAM1 isn't just a temporary phosphate holder--they hypothesize (relying on other studies) that it helps shunt carbons into biosynthetic pathways (which you need if you are a proliferating cancer). It's not every day that someone figures out how living cells bypass a canonical rate-limiting step in the fundamental metabolic process shared by all living things.
- tptacek 16y ago
  Please keep writing comments like these.
- noonespecial 16y ago
  It took me about 20 minutes to google all of the terms in your response and figure out why this is really important, but I feel like I might actually get some of this this now and feel the excitement. Thanks for this as the paper itself was more or less unapproachable for me. Biohacking still seems to me like this great big unexplored space filled with new terms and exciting ideas that I'm just beginning to get acquainted with.
rsheridan6 16y ago
>Anyways, this doesn't exactly jump out to me with applications since the research seems so early stage. The first thing I thought was that starving the cells of sugar could be an effective treatment. Maybe feeding patients something like the ketogenic diet for epileptics (ie lots and lots of heavy cream and not much else esp. not many carbs) would help. A quick pub med search turns up a little bit of work in this area but there might be room for more.

enjo 16y ago

The article did mention the research was already doing some sort of drug trial with mice. So hopefully they're already heading in that direction.

carbocation 16y ago

OK, I've read the manuscript now. Very interesting work. I didn't realize this initially, but they are also saying that the transient phosphorylation of PGAM1 is a mechanism by which PEP is converted to pyruvate at a meaningful rate! Reason for the exclamation point: the conversion of PEP -> pyruvate is is considered the last of 3 rate-limiting steps in glycolysis. They propose an end-run around this rate-limiting step. In their model, PEP donates its phosphate to PGAM1. Thus, PEP becomes pyruvate. Normally I wouldn't expect this to be a meaningful way to produce pyruvate--but their data appear to support the notion that PGAM1 becomes dephosphorylated at a high enough rate that this process can repeat itself fast enough to sustain pyruvate production. Oh, and phosphorylated PGAM1 isn't just a temporary phosphate holder--they hypothesize (relying on other studies) that it helps shunt carbons into biosynthetic pathways (which you need if you are a proliferating cancer). It's not every day that someone figures out how living cells bypass a canonical rate-limiting step in the fundamental metabolic process shared by all living things.

tptacek 16y ago
Please keep writing comments like these.
noonespecial 16y ago
It took me about 20 minutes to google all of the terms in your response and figure out why this is really important, but I feel like I might actually get some of this this now and feel the excitement. Thanks for this as the paper itself was more or less unapproachable for me. Biohacking still seems to me like this great big unexplored space filled with new terms and exciting ideas that I'm just beginning to get acquainted with.

rsheridan6 16y ago

>Anyways, this doesn't exactly jump out to me with applications since the research seems so early stage. The first thing I thought was that starving the cells of sugar could be an effective treatment. Maybe feeding patients something like the ketogenic diet for epileptics (ie lots and lots of heavy cream and not much else esp. not many carbs) would help. A quick pub med search turns up a little bit of work in this area but there might be room for more.