Glutamine: Synthesized in the Brain... If You Breathe Correctly
Glutamine is the most abundant and most required amino acid in the human organism (hence, its popularity for bodybuilding). It is also the amino acid most required for tissue repair. However, “since the supply of glutamic acid from the circulating blood is insufficient for the formation of additional amount of glutamine, the dicarboxylic acid has to be synthesized in the brain.” (Berl et al, 1962) This last substance is a CO2 derivative and its production depends on CO2 levels in the brain and our breathing patterns.
Many normal people - and all people with chronic diseases - have low body-oxygen levels due to deep automatic breathing (chronic hyperventilation) 24/7. Why is it so?
Overbreathing, as shown in dozens of studies, leads to reduced oxygen transport to brain cells and cells of other vital organs in the human body. This leads to anaerobic acidic environment and generation of free radicals causing oxidative damage to the brain and other tissues and organs. As a result, people experience increased glutamine demands for cell repair and insufficient glutamine synthesis due to low levels of CO2 in body cells. Why could CO2 levels matter?
A review of numerous research studies devoted to this subject was given by Waelsch and colleagues (1964) in an article entitled “Quantitative aspects of CO2 fixation in mammalian brain in vivo”. They found that aspartic and glutamic amino acids and glutamine were the substances chemically synthesized in mammalian brains. But CO2 is used to synthesize glutamine (Rossi et al, 1962; Waelsch et al, 1964; Pincus, 1968; Pincus et al, 1969; Cheng, 1971; Konitzer et al, 1977; Cheng et al, 1978; Tachiki & Baxter, 1980; Lockwood & Finn, 1982; Martin et al, 1992; Oz et al, 2004). You can read abstracts of some of these studies at the bottom of this page.
All these studies suggest that the gas we exhale plays the crucial role in glutamine synthesis, while many other studies have found that cell hypocapnia (low CO2) causes generation of free radicals, oxidative stress, chronic inflammation, poor repair of injuries and many other negative effects (see CO2 links below).
Thus, CO2 can be fixed by the human organism to rebuild nervous tissues in the brain. The rate of CO2-derived glutamine production is proportional to CO2 concentration in the brain. It follows that low CO2 in the brain not only makes the brain unreasonably excited (often causing anxiety, insomnia, fears, panic attacks, aggression, hostility, violence, or other strong emotions), but also has adverse effects on its cellular repair.
As a result, slow and light diaphragmatic nasal breathing leads to higher oxygen levels in the brain and body cells favoring effective glutamine synthesis and normalizing numerous other chemical reactions.
Reference pages: Breathing norms and medical facts:
- Breathing norms: Parameters, graph, and description of the normal breathing pattern
- 6 breathing myths: Myths and superstitions about breathing and body oxygenation (prevalence: over 90%)
- Hyperventilation: Definitions of hyperventilation: their advantages and weak points
- Hyperventilation syndrome: Western scientific evidence about prevalence of chronic hyperventilation in patients with chronic conditions (37 medical studies)
- Normal minute ventilation: Small and slow breathing at rest is enjoyed by healthy subjects (14 studies)
- Hyperventilation prevalence: Present in over 90% of normal people (24 medical studies)
- HV and hypoxia: How and why deep breathing reduces oxygenation of cells and tissues of all vital organs
- Body-oxygen test (CP test) : How to measure your own breathing and body oxygenation (two in one) using a simple DIY test
- Body oxygen in healthy: Results for the body-oxygen test for healthy people (27 medical studies)
- Body oxygen in sick : Results for the body-oxygen test for sick people (14 medical studies)
- Buteyko Table of Health Zones: Clinical description and ranges for breathing zones: from the critically ill (severely sick) up to super healthy people with maximum possible body oxygenation
- Morning hyperventilation: Why people feel worse and critically ill people are most likely to die during early morning hours
References: pages about CO2 effect:
- Vasodilation: CO2 expands arteries and arterioles facilitating perfusion (or blood supply) to all vital organs
- The Bohr effect: How and why oxygen is released by red blood cells in tissues
- Cell oxygen levels: How alveolar CO2 influences oxygen transport
- Oxygen transport: O2 transport is controlled by vasoconstriction-vasodilation and the Bohr effects, both of which rely on CO2
- Free radical generation: Reactive oxygen species are produced within cells due to anaerobic cell respiration caused by cell hypoxia
- Inflammatory response: Chronic inflammation in fueled by the hypoxia-inducible factor 1, while normal breathing reduces and eliminates inflammation
- Nerve stabilization: People remain calm due to calmative or sedative effects of carbon dioxide in neurons or nerve cells
- Muscle relaxation: Relaxation of muscle cells is normal at high CO2, while hypocapnia causes muscular tension, poor posture and, sometimes, aggression and violence
- Bronchodilation: Dilation of airways (bronchi and bronchioles) is caused by carbon dioxide, and their constriction by hypocapnia (low CO2)
- Blood pH: Regulation of blood pH due to breathing and regulation of other bodily fluids
- CO2: lung damage: Elevated carbon dioxide prevents lung injury and promotes healing of lung tissues
- CO2: Topical carbon dioxide can heal skin and tissues
- Synthesis of glutamine in the brain, CO2 fixation, and other chemical reactions
- Deep breathing myth: Ignorant and naive people promote the idea that deep breathing and breathing more air at rest is beneficial for health
- Breathing control: How is our breathing regulated? Why hypocapnia makes breathing uneven, irregular and erratic.
References: Glutamine synthesis and CO2 fixation (Titles only and then abstracts below)
Quantitative aspects of CO2 fixation in mammalian brain in vivo (Waelsch
et al, 1964)
Neuroglial metabolism in the awake rat brain: CO2 fixation increases with brain activity (Oz et al, 2004)
Carbon dioxide fixation in rat brain: Relationship to cerebral excitability (Pincus et al, 1969)
11C-carbon dioxide fixation and equilibration in rat brain: effects on acid-base measurements (Lockwood & Finn, 1982)
Role of carbon dioxide fixation, blood aspartate and glutamate in the adaptation of amphibian brain tissues to a hyperosmotic internal environment (Tachiki & Baxter, 1980)
Carbon dioxide fixation in the brain: its relation to glucose synthesis (Konitzer et al, 1977)
Release and fixation of CO2 by guinea-pig kidney tubules metabolizing aspartate (Martin et al, 1992)
CO2 fixation in the nervous tissue (Cheng, 1971)
The effect of atmospheric carbon dioxide on carbon dioxide fixation in rat brain (Pincus, 1968)
Rate of CO2 fixation in brain and liver (Rossi et al, 1962)
Effects of sodium thiopental on the tricarboxylic acid cycle metabolism in mouse brain: CO2 fixation and metabolic compartmentation (Cheng et al, 1978)
Waelsch H, Berl S, Rossi CA, Clarke DD, Purpura DP,
Quantitative aspects of CO2 fixation in mammalian brain in vivo,
J. Neurochem. Oct 1964, 11: 717-728.
New York State Psychiatric Institute and Departments of Biochemistry and Neurological Surgery, College of Physicians and Surgeons, Columbia University New York, N.Y.
The data presented in this paper support the conclusion that CO2 fixation in the mammalian brain is a process which responds to the change in the metabolic environment. The rate of CO2 fixation is increased when the tissue is exposed to a metabolic stress, such as an elevated ammonia concentration, which results in an increased synthesis of glutamine. The data show that CO2 fixation is of considerable significance in brain metabolism and not negligible. It plays an essential role in maintaining the concentration of dicarboxylic acids in the citric acid cycle. The continuous removal of oxoglutarate without replenishment would lead to a breakdown of the citric acid cycle and consequently to a deficiency in the production of ATP. Although the data suggest that CO2 fixation may well replenish the intermediates of the citric acid cycle in case of increased ammonia concentration in brain tissue, these acute experiments give no answer as to the chronic effects of ammonia on the citric acid cycle.
Oz G, Berkich DA, Henry PG, Xu Y, LaNoue K, Hutson SM, Gruetter R. .
Neuroglial metabolism in the awake rat brain: CO2 fixation increases with brain activity.
J Neurosci. 2004 Dec 15;24(50):11273-9.
Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Glial cells are thought to supply energy for neurotransmission by increasing nonoxidative glycolysis; however, oxidative metabolism in glia may also contribute to increased brain activity. To study glial contribution to cerebral energy metabolism in the unanesthetized state, we measured neuronal and glial metabolic fluxes in the awake rat brain by using a double isotopic-labeling technique and a two-compartment mathematical model of neurotransmitter metabolism. Rats (n = 23) were infused simultaneously with 14C-bicarbonate and [1-13C]glucose for up to 1 hr. The 14C and 13C labeling of glutamate, glutamine, and aspartate was measured at five time points in tissue extracts using scintillation counting and 13C nuclear magnetic resonance of the chromatographically separated amino acids. The isotopic 13C enrichment of glutamate and glutamine was different, suggesting significant rates of glial metabolism compared with the glutamate-glutamine cycle. Modeling the 13C-labeling time courses alone and with 14C confirmed significant glial TCA cycle activity (V(PDH)((g)), approximately 0.5 micromol x gm(-1) x min(-1)) relative to the glutamate-glutamine cycle (V(NT)) (approximately 0.5-0.6 micromol x gm(-1) x min(-1)). The glial TCA cycle rate was approximately 30% of total TCA cycle activity. A high pyruvate carboxylase rate (V(PC), approximately 0.14-0.18 micromol x gm(-1) x min(-1)) contributed to the glial TCA cycle flux. This anaplerotic rate in the awake rat brain was severalfold higher than under deep pentobarbital anesthesia, measured previously in our laboratory using the same 13C-labeling technique. We postulate that the high rate of anaplerosis in awake brain is linked to brain activity by maintaining glial glutamine concentrations during increased neurotransmission.
Carbon dioxide fixation in rat brain: Relationship to cerebral excitability
Experimental Neurology, Volume 24, Issue 3, July 1969, Pages 339-347
Section of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510 USA
Experiments were undertaken to determine whether CO2 fixation by cerebral tissue in the rat is increased by increasing the atmospheric concentration of CO2. The measure of CO2 fixation was considered the ratio of the specific activity of glutamate to the specific activity of CO2. This ratio in both brain and liver of animals exposed to 5% CO2 was double that of control animals exposed to room air 10, 15, and 30 min after injection. After breathing a mixture of 20% CO2 and 80% O2 for 30 min, the fixation ratio was not significantly elevated above control values. Tail blood pH in control animals was 7.44. After 30-min exposure of the animals to 5% CO2 the pH fell to 7.16, and after 30 min exposure to 20% CO2 it fell further to 6.58. After exposure to 20% CO2 three of ten animals had spontaneous seizures. These experiments indicate that CO2 fixation occurs at all tested concentrations of inspired CO2 and that a marked increase in CO2 fixation occurs during exposure to 5% CO2 but not 20% CO2. The possible relationship of the membrane stabilizing properties of CO2 and CO2 fixation was considered.
Lockwood AH, Finn RD.
11C-carbon dioxide fixation and equilibration in rat brain: effects on acid-base measurements.
Neurology. 1982 Apr;32(4):451-4.
The positron-emitting isotope 11C was used to label CO2 for studies of metabolic fixation and equilibration after a single-breath inhalation by rats. Metabolic fixation and loss of the label via exhalation caused the metabolized fraction of the label in the brain to rise to 30.1 +/- 0.7% within 30 minutes. The T12 for equilibration of the label between blood and brain was 1.95 minutes. When the label was 95% equilibrated, 12% was metabolically trapped by brain, and when only 5% was trapped, the blood-brain equilibration process was only 50% complete. Labeled CO2 thus has limited usefulness as an acid-base or metabolic tracer for positron-emission tomography.
Tachiki KH, Baxter CF.
Role of carbon dioxide fixation, blood aspartate and glutamate in the adaptation of amphibian brain tissues to a hyperosmotic internal environment.
Neurochem Res. 1980 Sep;5(9):993-1010.
Mechanisms have been examined by which hyperosmotic blood plasma might elevate the levels of aspartate and glutamate in the brain of the toad Bufo boreas. CO2 fixation was assessed by two in vivo methods using [2-14 C]glucose injected intracisternally. Thirty minutes after injection, the 14C labeling of glutamate and aspartate was more than 100 times greater in brain than in liver. In brain tissues, 40 + % of 14C atoms appeared to be incorporated into aspartate via the pyruvate carboxylase pathway. Brain tissues of control toads and toads adapting or adapted to hyperosmotic plasma osmolality revealed no differences in the rate of CO2 fixation as related to glucose utilization or tissue pool sizes of glutamate and aspartate. Elevated levels of these amino acids in blood plasma preceded increases in brain tissues. Carbon atoms required during hyperosmotic adaptation for expansion of amino acid pools in brain tissues may, in part, originate from amino acids in blood but apparently not from CO2 fixation in brain.
Konitzer K, Voigt S, Hetey L.
Carbon dioxide fixation in the brain: its relation to glucose synthesis.
Acta Biol Med Ger. 1977; 36(2):147-56.
The incorporation in vivo of radiocarbon from 14C-bicarbonate in blood into relevant metabolites in rat brain is described. The animals, partially hepatectomized and nephrectomized, received the tracer bicarbonate via the intravenous route. The time course of label was followed in CO2 of blood and brain, in the anionic and cationic fractions of brain extract, in aspartate, glutamate, glutamine and in free glucose and in glycogen. From the tracer kinetic data a flux of 0.08 microgram atom fixed carbon min-1.g-1 brain tissue was calculated. Substantial amounts of 14C were found in free glucose, only a few percent in glycogen. The flux of newly synthetized glucose was approximated to 0.5--1.0 percent of the steady state level of glucose in brain tissue. In special experiments the localization of 14C in the carbon chain of aspartate and glucose was examined. 5 min following the tracer injection a practically total randomization of 14C between C-1 and C-4 aspartate was seen. From the radioactivity in glucose 94 percent were found in C-3 and C-4, only 6 percent in residual carbon. This 14C-pattern is typical for the labelling of glucose by CO2 fixation and retrograde Embden-Meyerhof pathway.
Martin G, Michoudet C, Vincent N, Baverel G.
Release and fixation of CO2 by guinea-pig kidney tubules metabolizing aspartate.
Biochem J. 1992 Jun 15; 284 (Pt 3): 697-703.
Laboratoire de Physiologie Rénale et Métabolique, CNRS URA 1177, Faculté de Médecine Alexis Carrel, Lyon, France.
1. The metabolism of L-[U-14C]aspartate, L-[1-14C]aspartate and L-[4-14C]aspartate was studied in isolated guinea-pig kidney tubules. 2. Oxidation of C-1 plus that of C-4 of aspartate accounted for 90-92% of the CO2 released from aspartate, whereas oxidation of the inner carbon atoms of aspartate (which occurs beyond the 2-oxoglutarate dehydrogenase step) represented only 8-10% of aspartate carbon oxidation. 3. The formation of [1-14C]glutamine and [1-14C]glutamate from [1-14C]aspartate and [4-14C]aspartate indicated that about one-third of the oxaloacetate synthesized from aspartate underwent randomization at the level of fumarate. 4. With [U-14C]aspartate as substrate, the percentage of the C-1 of glutamate and glutamine found radiolabelled after 60 min of incubation was 92.7% and 47.5% in the absence and the presence of bicarbonate respectively. 5. That CO2 fixation occurred at high rates in the presence of bicarbonate was demonstrated by incubating tubules with aspartate plus [14C]bicarbonate; under this condition, the label fixed was found in C-1 of glutamate, glutamine and aspartate, as well as in C-4 of aspartate, demonstrating not only randomization of aspartate carbon but also aspartate resynthesis secondary to oxaloacetate cycling via phosphoenolpyruvate carboxykinase, pyruvate kinase and pyruvate carboxylase. 6. The importance of CO2 fixation in glutamine synthesis from aspartate is discussed in relation to the possible role of the guinea-pig kidney in systemic acid-base regulation in vivo.
CO2 fixation in the nervous tissue.
Int Rev Neurobiol. 1971;14:125-57.
The effect of atmospheric carbon dioxide on carbon dioxide fixation in rat brain.
Neurology. 1968 Mar;18(3):293.
Rossi, CA, Berl, S., Clark, DD, Purpura, DP, and Waelsch, H.
Rate of CO2 fixation in brain and liver.
Life Sci. 1962 Oct;1:533-9.
Cheng SC, Naruse H, Brunner EA.
Effects of sodium thiopental on the tricarboxylic acid cycle metabolism in mouse brain: CO2 fixation and metabolic compartmentation
J Neurochem. 1978 Jun;30(6):1591-3.
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