Tuesday, March 16, 2010

The fascinating adventures of glutamic acid and its metabolites

Okay. Leptin is intimately involved in glutamic acid metabolism. That seems to be established. Lets look at some basic glutamic acid stuff.


"Acute effect of poly-gamma-glutamic acid on calcium absorption in post-menopausal women"

A number of food constituents have a positive [13] or negative [46] effect on intestinal Ca absorption in humans. Ca solubility is increased in the small intestine of rats given poly--glutamic acid (PGA), a polymer in which a large number of glutamic acid molecules are combined by -linkages [7]. PGA is a component of natto mucilage obtained from fermented soybeans, a traditional Japanese food; estimates of natto consumption in Japan suggest that the daily intake of PGA is approximately 16 mg/day. PGA can also be produced by fermentation of Bacillus natto in a liquid medium [8] and it has been considered as a candidate compound for functional foods aimed at promoting bone health. A recent report suggests that the consumption of natto is associated with reduced bone loss in postmenopausal Japanese women [9]. We hypothesise that the mode of action of PGA is increased Ca solubility in the gut lumen [7] thereby increasing paracellular Ca absorption in the lower intestine.

Another glutamic acid calcium connection. Obviously just a coincidence, any attempt to follow the significance of glutamic acid/calcium around the body would obviously be naive.

Another coincidence. Vitamin k, which is necessary for the gamma-carboxylation of glutamic acid residues (don't worry, I don't know what that means, either), is necessary for the proper control of calcium throughout the body. For one thing, it prevents the calcification of soft tissues.

Glutamic acid is anaplerotic, which means that it feeds into the Krebs cycle. Mitochondrial respiration. One thing about the Krebs cycle-- you can't burn fat without it. So if a cell needs to burn fat, there's no way to do it without glutamic acid.

There may be a problem in this. Brain cells get excited when they see glutamate, the salt of glutamic acid.

Glutamate transporters are found in neuronal and glial membranes. They rapidly remove glutamate from the extracellular space. In brain injury or disease, they can work in reverse and excess glutamate can accumulate outside cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death, and is called excitoxicity.

That's wikipedia. Again with the calcium.


Glutamate is a main constituent of dietary protein and is also consumed in many prepared foods as an additive in the form of monosodium glutamate. Evidence from human and animal studies indicates that glutamate is a major oxidative fuel for the gut and that dietary glutamate is extensively metabolized in first pass by the intestine. Glutamate also is an important precursor for bioactive molecules, including glutathione, and functions as a key neurotransmitter. The dominant role of glutamate as an oxidative fuel may have therapeutic potential for improving function of the infant gut, which exhibits a high rate of epithelial cell turnover. Our recent studies in infant pigs show that when glutamate is fed at higher (4-fold) than normal dietary quantities, most glutamate molecules are either oxidized or metabolized by the mucosa into other nonessential amino acids. Glutamate is not considered to be a dietary essential, but recent studies suggest that the level of glutamate in the diet can affect the oxidation of some essential amino acids, namely leucine. Given that
substantial oxidation of leucine occurs in the gut, ongoing studies are investigating whether dietary glutamate affects the oxidation of leucine in the intestinal epithelial cells. Our studies also suggest that at high dietary intakes, free glutamate may be absorbed by the stomach as well as the small intestine, thus implicating the gastric mucosa in the metabolism of dietary glutamate. Glutamate is a key excitatory amino acid, and metabolism and neural sensing of dietary glutamate in the developing gastric mucosa, which is poorly developed in premature infants, may play a functional role in gastric emptying. These and other recent reports raise the question as to the metabolic role of glutamate in gastric function. The physiologic significance of glutamate as an oxidative fuel and its potential role in gastric function during infancy are discussed.

So. The tissues in the body that get the first look at glutamate dig in deep.

Here's a tidbit;


Rats received 3H-mannitol, which marks the intactness of the blood-brain barrier, and 14C glutamate or 14C-aspartate by intracardiac injection after oral gavage with water, monosodium glutamate, monosodium aspartate, or sodium chloride (doses equiosmolar to 4 g/kg monosodium glutamate). Thirty min later, various brain regions (e.g., cerebellum, cortex, hypothalamus, and striatum) were assayed for tritium and carbon-14. In most regions in most animals given monosodium glutamate or hypertonic saline, the level of the carbon-14 acidic amino acid tended to parallel the extent of damage incurred by the blood-brain barrier, as indicated by high levels of tritium-labelled mannitol. These data suggest that severe hyperosmolarity may be a prerequisite for monosodium glutamate to produce neurotoxic changes, and may explain why elective dietary consumption of enormous quantities of glutamate, by animals given free access to water, fails to induce brain lesions.

No comment, you never know what might come in useful. Edit; MSG is accused of being an asthma trigger. That "hyperosmolarity" thing may be related to that, there's a lot of stuff out there about asthma and sodium.

L-glutamic acid is oxidized by the brain to alphaketoglutaric acid, NH3 and later CO2 and H2O and is the only amino acid that on its own can maintain brain slice
(Weil-Malherbe, 1936)

Mouse. Mice aged 2 to 9 days were killed 1 to 48 hours after single subcutaneous injection of monosodium glutamate at doses from 0.5-4 µg/kg, lesions seen in the preoptic and arcuate nuclei of the hypothalamic region on the roof and floor of the third ventricle and in scattered neurons in the nuclei tuberales. No pituitary lesions were seen but sub-commissural and subfornical organs exhibited intracellular oedema and neuronal necrosis. Adult mice given subcutaneously 5-7 µg/kg monosodium L-glutamate showed similar lesions. Similar lesions were seen in another strain of mouse and in neonatal rats
(Olney, 1969b).

After a single subcutaneous injection of monosodium glutamate at 4 g/kg into neonatal mice aged 9-10 days. the animals were killed from 30 minutes to48 hours. The retinas showed an acute lesion on electron microscopy with swelling dendrites and early neuronal changes leading to necrosis followed by phagocytosis (Olney, 1969a). Sixty-five neonatal mice aged 10-12 days received single oral very high loads of monosodium glutamate at 0.5, 0.75, 1.0 and 2.0 g/kg
body-weight by gavage. 10 were controls and 54 mice received other amounts. After 3-6 hours all treated animals were killed by perfusion. Brain damage as evidenced by necrotic neurons was evident in arcuate nuclei of 51 animals. 62 per cent. at
0.5 g/kg, 81 per cent. at 0.75 g/kg, 100 per cent. at 1 g/kg and 100 per cent. at 2 g/kg. The lesions were identical both by light and electron microscopy to s.c. produced lesions. The number of necrotic neurons rose approximately with dose.


That's from a WHO toxin report on MSG. So what's wrong with MSG?

There may be a few problems. Glutamate may travel around the body more freely. Rats that drank MSG water or plain water at will in one study ate more food, but were leaner. L Glutamine causes fat cells to become insulin resistant. Glutamate and L Glutamine are both obvious precursors to Glutamic acid, which makes them precursors to several points of entry into the Krebs Cycle.

So what happens in the brain on MSG, if free access to water isn't given? Well, what if MSG has the same effect on calcium as glutamate? But suppose that the brain also can't properly metabolize MSG, perhaps into Krebs cycle metabolites, because of the sodium. Sodium and Glutamic acid have their own taste receptors, as well as regulatory hormones (aldosterone and leptin). Cells may have difficulty regulating these two substances if they are bound together. The sodium further complicates things through its effect on osmolarity. This much seems clear. Disregulation of sodium and glutamate (which means disregulation of calcium) cannot be a good idea.

Should we be looking for hormones that regulate sour and bitter substances?

That bit I highlighted in red. Glutamic acid seems to be the preferred fuel for human cells. All of them. We can't live off a diet of pure glutamic acid, of course. Much of glucose and fat metabolism is to the purpose of rationing our use of glutamic acid.

Eat glucose. Your pancreas puts out insulin, just like a yeast cell does, the purpose of the insulin as far as the pancreas is concerned is to bring it some glucose. But the pancreas isn't very good at this, and is horribly insulin resistant, so it ends up putting out enough insulin to regulate blood glucose throughout the body. Some of the glucose and insulin travels to the muscle; this has the effect of spurring glutamine production in the muscle. The thing about glutamine; it's one more step away from the various metabolites of the Krebs cycle that glutamic acid is a precursor to. So this may be a sort of safety valve, lowering free glutamic acid levels in the cell, glutamine is more inert. Being similar to glutamic acid, glutamine might interfere with enzymic actions that produce those metabolites of the Krebs cycle, as well.

Glutamine crosses the blood-brain barrier by a mediated process.

Here's something;

This study examines the effects of middle cerebral artery (MCA) occlusion in the rat on blood to brain glutamine transport, a potential marker of early endothelial cell dysfunction. It also examines whether the effects of ischemia on glutamine transport are exacerbated by hyperglycemia. In pentobarbital-anesthetized rats, 4 hours of MCA occlusion resulted in a marked decline in the influx rate constant for [14C]L-glutamine from 16.1+/-1.2 microL.g(-1).min(-1) in the contralateral hemisphere to 7.3+/-2.5 microL.g(-1).min(-1) in the ischemic core (P <>


Mess with sodium, and you mess with glutamine, which means you mess with glutamic acid. Which messes you up. They only theorize that sodium is the cause of the cell swelling. Potassium uptake is regulated directly by insulin. So obviously glucose itself must have some effect on osmalarity, necessitating that extra potassium. And in all this mess, how is the brain to be properly fed? And how is it to maintain the integrity of its tissues, if it isn't properly fed. And

L-glutamic acid ...is the only amino acid that on its own can maintain
brain slice respiration.

This is why we have leptin, which is the "insulin" for glutamic acid. It's kind of important.

Another possible place L glutamine produced by muscle might wander over to is adipose tissue. L Glutamine causes fat cells to become insulin resistant. Why are muscles insulin-resistant? Fat feeds into the Krebs cycle, lowering the need for glucose. Why are fat cells insulin-resistant? Fat feeds into the Krebs cycle, lowering the need for glucose. Somehow mediated by glutamine. Less need for glucose translates into a decrease in cell levels of glucose, and if cell levels of glucose are a rate-limiting factor for triglyceride synthesis (um, duh) then free fatty acids in the cell tend to stay... free. Which means they can be oxidized.

1 comment:

donny said...

The fat cell must be rich in the hormones necessary to break down glutamine to glutamic acid to kreb cycle metabolites... less glucose would then be needed, as glucose's only entry into Kreb's would then be oxaloacetate, no need for acetyl-CoA from glucose. Insulin resistance. Insulin resistance is actually just a lack of hunger for glucose, nothing else.