Re: Glutamine, a neurotoxin?

[Guest guest]

Hi,

That is such a great question and it comes up every now and then because people

read books talking about one function of a molecule and get the feeling that

this is all that molecule is going to do.

Actually glutamine comprises 71% of the total amino acid count in the cerebral

spinal fluid...so it is basically bathing the brain and is highly PROTECTIVE of

the brain! It ends up being a fuel for the brain and important for making the

brain's glutathione.

I answered a similar question years ago on this list when someone was asking

about urinary glutamate, but the answer I gave then should help you now, I hope.

I've put it below.

If you have any questions, just ask!

HTH,

I feel a duty to bring to your attention and to the attention of others that

glutamate being elevated in urine has nothing to do with glutamate being

elevated in the brain or at synapses (which is where the GABA to glutamate ratio

might be important). Can I help you understand why I'm saying that?

Notice that in the first article below, when someone found that glutamate was

elevated in the urine in someone with cerebellar difficulties, that they learned

that glutamate was actually very deficient at the same time in the cerebral

spinal fluid. The raised level in urine reflected a transport problem, which is

a big part of the function of the kidney. The second article tells you where

urinary ammonia is coming from.

The amount of glutamate in urine is regulated by transporters that reabsorb back

what the body needs to retain. One article below says that 99.87% of the

endogenous glutamate that was filtered in the kidney was reabsorbed back into

the body so it didn't show up in the urine. This means that getting that

glutamate back in the body instead of leaving it in urine is REALLY important

and the greater danger may be losing the glutamate into the urine. Considering

that, why would the tiny fraction of glutamate left behind in the urine be

thought to have anything to do with what happens with glutamate in synapses in

the brain?

It is a hard thing to remember, but the brain is only 3 pounds in an adult, and

all of these amino acids have jobs to do in the rest of the body. By weight,

the rest of the body outnumbers the brain 98 to one in an adult! Most likely

most of the glutamate in your body is already part of proteins or it is on the

way to becoming part of a protein! In fact, when some scientists looked at the

proteins that cows eat, they found that 14-21% of the amino acids in the food

were glutamate. In fact, it was by far the most abundant amino acid in their

food. The " excitatory " amino acid, aspartic acid took second place in this test

of relative abundance in food protein, but still, it was at a distance from the

clear winner, glutamate. (The Amino Acid Composition of Protein Feedstuffs

Before and After Ruminal Incubation and After Subsequent PassageThrough the

Intestines of Dairy Cows1F. P. O'Mara*,2, J. J. *, and M. Rath†)

Completely in line with those ratios, in a study of fetal pig,

glutamate+glutamine comprised 14% of the amino acids in the pig, but GABA was

only 0.17%.(Amino Acid Composition of the Fetal Pig 1Guoyao Wu,2 Troy L. Ott,3

Darrell A. Knabe and Fuller W. Bazer)

Like all of us, amino acids wear many hats. Maybe you have a special position in

your child's PTA and it might be really important part of what you do when you

are at the school. In fact, your presence at the school might have a high

correlation to doing PTA activity, but I dare say if someone runs into you at

the dentist's office, that your being there on PTA duty is not very likely.

One thing I have majored on emphasizing in the DAN! community for all the years

I've been there (many years, for I started being involved with DAN! in 1995) is

that you HAVE to think of compartmentation [where something is being observed

and the rules at that location] when you measure anything in blood or urine, or

even CSF.

Measuring glutamate in the urine tells you mostly about the kidney. Measuring

ammonia in the urine tells you about a kidney function designed to protect the

body against acidosis. Urinary ammonia is not the same ammonia that can be

troubling to brain function.

The huge world of things that can be made out of glutamate are summarized here:

http://www.genome.jp/kegg/pathway/map/map00251.html

Glutamine can easily be converted into glutamate. Keeping that in mind, look at

the difference in the relative proportions that glutamate is of the total amino

acids in CSF, blood plasma and urine that I've put below. Why would glutamate

be showing up in these different places in such reduced quantity compared to its

relative composition in proteins? Glutamate is also a third of glutathione!

After you consider how easily glutamine and glutamate interconvert in the kidney

and all over the body, then look at how extremely low glutamate is in these

three compartments compared to glutamine. Do you see that almost 72% of the

free amino acids in CSF is glutamine, but glutamate is only a fourth of a

percent? Nothing else is even close to glutamine. When there are glutaminases

in the brain that make glutamate easily from glutamine and when it can be easily

converted back, then why would anyone think that urinary glutamate could

represent anything relevant to GABA and glutamate ratios or levels in the

synapses of the brain?

csf urine plasma

Glutamine 71.741% 11.100% 24.160%

Glycine 0.703% 29.736% 8.568%

Alanine 3.594% 6.991% 9.781%

Histidine 1.777% 14.727% 3.136%

Serine 4.449% 7.641% 4.709%

Taurine 0.789% 10.375% 2.094%

Valine 2.341% 1.518% 7.995%

Lysine 2.486% 2.972% 5.732%

Threonine 3.110% 2.714% 3.859%

Leucine 1.372% 0.645% 4.416%

Tyrosine 0.935% 3.052% 2.212%

Arginine 2.168% 0.253% 3.081%

Proline 0.000% 0.258% 5.242%

Asparagine 0.776% 2.506% 1.710%

Phenylalanine 0.935% 0.878% 1.967%

Isoleucine 0.530% 0.635% 2.157%

Ornithine 0.716% 0.600% 1.501%

Cystine 0.245% 0.719% 1.754%

Tryptophan 0.338% 0.000% 2.283%

Methionine 0.464% 1.121% 0.814%

Glutamic Acid 0.252% 0.417% 1.485%

Citrulline 0.199% 0.268% 1.185%

Aspartic Acid 0.080% 0.873% 0.158%

I've put some articles below to help in thinking about these concepts. Always

be sure when you are learning something that the rules you are learning apply to

the place where something is being measured and not elsewhere! This is SO

important with lab testing.

Acta Neurol Scand. 1991 Jul;84(1):70-2. Related Articles, Links

Cerebellar ataxia with glutamic aciduria.

Sawada H, Seriu N, Udaka F, Kameyama M, Sugiyama H.

Department of Neurology, Sumitomo Hospital, Osaka, Japan.

We report a case of cystinuria and glutamic aciduria, presenting with

progressive cerebellar manifestations. She had cerebellar type dysarthria and

limb ataxia. Head MRI revealed cerebellar atrophy. Urinary amino acid analysis

showed excessive excretion of glutamate and the dibasic amino acids (cystine,

arginine, lysine, and ornithine). Cystine and glutamic acid are thought to be

transported in a common membrane transport system. Reduction of glutamic acid

and cystine in the cerebrospinal fluid was revealed. A relationship between

cystinuria and cerebellar manifestation was discussed.

Publication Types:

Case Reports

PMID: 1681667 [PubMed - indexed for MEDLINE]

Klin Wochenschr. 1986 Sep 15;64(18):862-70. Related Articles, Links

Formation and excretion of NH3----NH4+. New aspects of an old problem.

Silbernagl S, Scheller D.

The proximal tubule cell is the major site of renal ammoniagenesis. Glutamine is

the major substrate. Deamidation by mitochondrial glutaminase yields glutamate-

and NH4+ (not NH3, as traditionally taught). A second NH4+ ion is obtained by

deamination of glutamate- to 2-oxo-glutarate2-. NH4+ preferentially enters the

tubule lumen primarily, but probably not exclusively, by non-ionic diffusion of

NH3. For each NH3 formed in the cell one H+ ion is left behind. H+ and NH3 are

secreted on separate routes, but recombine in the lumen to NH4+ and reach the

final urine in this form. This process per se does not net-remove H+ from the

organism. For this purpose, the anionic products of ammoniagenesis

(2-oxo-glutarate2- and others) have to be converted into neutral compounds (CO2,

glucose). This metabolism again takes place usually in the tubule cell. For each

negative charge one HCO3- is formed which enters the peritubular blood. Luminal

gamma-glutamyl transferase-mediated ammoniagenesis contributes to NH4+

accumulation in the proximal tubule to a small extent. The endproximal NH4+

delivery exceeds the filtered load by a factor of 9. Only 1/3 of it reaches the

distal convoluted tubule mainly because NH+4 as such is reabsorbed from the

thick ascending limb of Henle's loop by secondary active transport or

electrodiffusion. Both processes are energized by the active Na+ transport in

this segment. Thereby NH3----NH4+ is accumulated in the medullary interstitium,

which establishes the chemical gradient for non-ionic diffusion of NH3 into the

lumen of the collecting ducts. This is favoured by the acidic disequilibrium pH

in the lumen of this segment.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 2430135 [PubMed - indexed for MEDLINE]

Pflugers Arch. 1983 Mar 1;396(3):218-24. Related Articles, Links

Kinetics and localization of tubular resorption of " acidic " amino acids. A

microperfusion and free flow micropuncture study in rat kidney.

Silbernagl S.

The unidirectional resorption rates of L-glutamate (initial concentrations of

0.07, 0.66, 2.0 or 20.0 mmol X 1(-1)), D-glutamate (0.66 mmol X 1(-1) in the

presence or absence of 20 mmol X 1(-1) L-glutamate), and of L-aspartate (0.073,

0.3, 0.66, 2.0 or 5.0 mmol X 1(-1)) were determined in the rat proximal

convolution. L-Glutamate resorption was saturable. A permeability coefficient

(P) of less than or equal to 20 microns2 X S-1, and a maximum resorption rate

(Jmax) of 0.15 +/- 0.015 (SEM) nmol X S-1 X m-1 at a Km of 0.17 +/- 0.025 (SEM)

mmol X 1(-1) was obtained for L-glutamate. For L-aspartate, Jmax was 0.13 +/-

0.005 at a Km of 0.1 +/- 0.013. A free flow glutamate concentration profile

along the proximal convolution was (I) predicted from these constants and (II)

actually measured by means of free flow micropuncture. The data agree very well

and show that more than 90% of the filtered load is resorbed within the first

third of the proximal convolution. The late proximal and early distal free flow

recoveries of L-glutamate amounted to 5.3 +/- 1.7% (SEM) and 6.6 +/- 1.4% of the

filtered load, respectively. In contrast to this, unidirectional resorption

during the microperfusion of the same tubule section was high: fractional

resorption amounted to ca. 96% at 2 mmol X 1(-1) initial L-glutamate. It fell to

35 or 33% respectively if the initial L-glutamate concentration was 20 mmol X

1(-1) or if the resorption of 0.66 mmol X 1(-1) D-glutamate in presence of 20

mmol X 1(-1) L-glutamate was measured. The fractional excretion of endogenous

L-glutamate in the final urine amounted to 0.13 +/- 0.012% of the filtered load.

It is concluded that L-glutamate and L-aspartate are quickly resorbed in early

parts of the proximal convolution (low Km). Saturation already occurs when there

is a small increase in the filtered load (low Jmax). The nephron section between

the late proximal and early distal nephron sites also reabsorbs " acidic " amino

acids. Normally, however, the back leak cancels this out, and net flux becomes

zero. Deep nephrons seem to handle amino acids somewhat differently than

superficial nephrons do.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 6133264 [PubMed - indexed for MEDLINE]

J Am Soc Nephrol. 1992 Jan;2(7):1171-7. Related Articles, Links

Growth hormone and renal glutamine and glutamate handling.

Welbourne TC, Horton K, Cronin MJ.

Department of Physiology, Louisiana State University Medical Center, Shreveport

33932.

Growth hormone administration effects a positive nitrogen balance in part by

recycling glutamine nitrogen as glutamate at the expense of ureagenesis. The

study presented here focuses on the response of the isolated perfused

hypophysectomized rat kidney to acute growth hormone administration during

infusions of either glutamine or glutamate. Growth hormone at 50 nM acutely

decreases the renal utilization of both glutamine and glutamate while enhancing

reabsorption of the latter. During glutamine infusions of either 1,000 or 500

nmol/min, growth hormone markedly reduced net glutamine utilization by 55% at

the high loads and reversed utilization to release at the lower load; associated

with decreased glutamine utilization was reduced ammonium production and

increased glutamate release. Although glutamine reabsorption was unchanged,

glutamate reabsorption increased and NH4+ excretion decreased. During glutamate

infusion of 180 nmol/min, growth hormone reduced glutamate utilization 66%, the

residual utilization matching increased glutamate reabsorption was associated

with enhanced bicarbonate reabsorption and a redistribution of NH4+ release into

the urine; all three responses were eliminated by amiloride. These responses to

growth hormone are consonant with reduced glutamate oxidation underlying

decreased glutamine utilization and accelerated luminal Na+-H+ exchange

mediating luminal transport, events that are conceivably interrelated.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 1350468 [PubMed - indexed for MEDLINE]

>

> Hi! Does anyone have an opinion about Glutamine and whether our kids need it.

I heard it is bad, it turns into Glutamate, which is an excitotoxin in people

with neurodegenerative disease. I guess for neurotypical people

Glutamine/Glutamate supplementation is fine. I read some debates online about

this amino acid. And in appears to be in numerous amino acid complete

supplements, like mine, by Klaires. What are your thoughts about this?

>

[Guest guest]

Hi,

That is such a great question and it comes up every now and then because people

read books talking about one function of a molecule and get the feeling that

this is all that molecule is going to do.

Actually glutamine comprises 71% of the total amino acid count in the cerebral

spinal fluid...so it is basically bathing the brain and is highly PROTECTIVE of

the brain! It ends up being a fuel for the brain and important for making the

brain's glutathione.

I answered a similar question years ago on this list when someone was asking

about urinary glutamate, but the answer I gave then should help you now, I hope.

I've put it below.

If you have any questions, just ask!

HTH,

I feel a duty to bring to your attention and to the attention of others that

glutamate being elevated in urine has nothing to do with glutamate being

elevated in the brain or at synapses (which is where the GABA to glutamate ratio

might be important). Can I help you understand why I'm saying that?

Notice that in the first article below, when someone found that glutamate was

elevated in the urine in someone with cerebellar difficulties, that they learned

that glutamate was actually very deficient at the same time in the cerebral

spinal fluid. The raised level in urine reflected a transport problem, which is

a big part of the function of the kidney. The second article tells you where

urinary ammonia is coming from.

The amount of glutamate in urine is regulated by transporters that reabsorb back

what the body needs to retain. One article below says that 99.87% of the

endogenous glutamate that was filtered in the kidney was reabsorbed back into

the body so it didn't show up in the urine. This means that getting that

glutamate back in the body instead of leaving it in urine is REALLY important

and the greater danger may be losing the glutamate into the urine. Considering

that, why would the tiny fraction of glutamate left behind in the urine be

thought to have anything to do with what happens with glutamate in synapses in

the brain?

It is a hard thing to remember, but the brain is only 3 pounds in an adult, and

all of these amino acids have jobs to do in the rest of the body. By weight,

the rest of the body outnumbers the brain 98 to one in an adult! Most likely

most of the glutamate in your body is already part of proteins or it is on the

way to becoming part of a protein! In fact, when some scientists looked at the

proteins that cows eat, they found that 14-21% of the amino acids in the food

were glutamate. In fact, it was by far the most abundant amino acid in their

food. The " excitatory " amino acid, aspartic acid took second place in this test

of relative abundance in food protein, but still, it was at a distance from the

clear winner, glutamate. (The Amino Acid Composition of Protein Feedstuffs

Before and After Ruminal Incubation and After Subsequent PassageThrough the

Intestines of Dairy Cows1F. P. O'Mara*,2, J. J. *, and M. Rath†)

Completely in line with those ratios, in a study of fetal pig,

glutamate+glutamine comprised 14% of the amino acids in the pig, but GABA was

only 0.17%.(Amino Acid Composition of the Fetal Pig 1Guoyao Wu,2 Troy L. Ott,3

Darrell A. Knabe and Fuller W. Bazer)

Like all of us, amino acids wear many hats. Maybe you have a special position in

your child's PTA and it might be really important part of what you do when you

are at the school. In fact, your presence at the school might have a high

correlation to doing PTA activity, but I dare say if someone runs into you at

the dentist's office, that your being there on PTA duty is not very likely.

One thing I have majored on emphasizing in the DAN! community for all the years

I've been there (many years, for I started being involved with DAN! in 1995) is

that you HAVE to think of compartmentation [where something is being observed

and the rules at that location] when you measure anything in blood or urine, or

even CSF.

Measuring glutamate in the urine tells you mostly about the kidney. Measuring

ammonia in the urine tells you about a kidney function designed to protect the

body against acidosis. Urinary ammonia is not the same ammonia that can be

troubling to brain function.

The huge world of things that can be made out of glutamate are summarized here:

http://www.genome.jp/kegg/pathway/map/map00251.html

Glutamine can easily be converted into glutamate. Keeping that in mind, look at

the difference in the relative proportions that glutamate is of the total amino

acids in CSF, blood plasma and urine that I've put below. Why would glutamate

be showing up in these different places in such reduced quantity compared to its

relative composition in proteins? Glutamate is also a third of glutathione!

After you consider how easily glutamine and glutamate interconvert in the kidney

and all over the body, then look at how extremely low glutamate is in these

three compartments compared to glutamine. Do you see that almost 72% of the

free amino acids in CSF is glutamine, but glutamate is only a fourth of a

percent? Nothing else is even close to glutamine. When there are glutaminases

in the brain that make glutamate easily from glutamine and when it can be easily

converted back, then why would anyone think that urinary glutamate could

represent anything relevant to GABA and glutamate ratios or levels in the

synapses of the brain?

csf urine plasma

Glutamine 71.741% 11.100% 24.160%

Glycine 0.703% 29.736% 8.568%

Alanine 3.594% 6.991% 9.781%

Histidine 1.777% 14.727% 3.136%

Serine 4.449% 7.641% 4.709%

Taurine 0.789% 10.375% 2.094%

Valine 2.341% 1.518% 7.995%

Lysine 2.486% 2.972% 5.732%

Threonine 3.110% 2.714% 3.859%

Leucine 1.372% 0.645% 4.416%

Tyrosine 0.935% 3.052% 2.212%

Arginine 2.168% 0.253% 3.081%

Proline 0.000% 0.258% 5.242%

Asparagine 0.776% 2.506% 1.710%

Phenylalanine 0.935% 0.878% 1.967%

Isoleucine 0.530% 0.635% 2.157%

Ornithine 0.716% 0.600% 1.501%

Cystine 0.245% 0.719% 1.754%

Tryptophan 0.338% 0.000% 2.283%

Methionine 0.464% 1.121% 0.814%

Glutamic Acid 0.252% 0.417% 1.485%

Citrulline 0.199% 0.268% 1.185%

Aspartic Acid 0.080% 0.873% 0.158%

I've put some articles below to help in thinking about these concepts. Always

be sure when you are learning something that the rules you are learning apply to

the place where something is being measured and not elsewhere! This is SO

important with lab testing.

Acta Neurol Scand. 1991 Jul;84(1):70-2. Related Articles, Links

Cerebellar ataxia with glutamic aciduria.

Sawada H, Seriu N, Udaka F, Kameyama M, Sugiyama H.

Department of Neurology, Sumitomo Hospital, Osaka, Japan.

We report a case of cystinuria and glutamic aciduria, presenting with

progressive cerebellar manifestations. She had cerebellar type dysarthria and

limb ataxia. Head MRI revealed cerebellar atrophy. Urinary amino acid analysis

showed excessive excretion of glutamate and the dibasic amino acids (cystine,

arginine, lysine, and ornithine). Cystine and glutamic acid are thought to be

transported in a common membrane transport system. Reduction of glutamic acid

and cystine in the cerebrospinal fluid was revealed. A relationship between

cystinuria and cerebellar manifestation was discussed.

Publication Types:

Case Reports

PMID: 1681667 [PubMed - indexed for MEDLINE]

Klin Wochenschr. 1986 Sep 15;64(18):862-70. Related Articles, Links

Formation and excretion of NH3----NH4+. New aspects of an old problem.

Silbernagl S, Scheller D.

The proximal tubule cell is the major site of renal ammoniagenesis. Glutamine is

the major substrate. Deamidation by mitochondrial glutaminase yields glutamate-

and NH4+ (not NH3, as traditionally taught). A second NH4+ ion is obtained by

deamination of glutamate- to 2-oxo-glutarate2-. NH4+ preferentially enters the

tubule lumen primarily, but probably not exclusively, by non-ionic diffusion of

NH3. For each NH3 formed in the cell one H+ ion is left behind. H+ and NH3 are

secreted on separate routes, but recombine in the lumen to NH4+ and reach the

final urine in this form. This process per se does not net-remove H+ from the

organism. For this purpose, the anionic products of ammoniagenesis

(2-oxo-glutarate2- and others) have to be converted into neutral compounds (CO2,

glucose). This metabolism again takes place usually in the tubule cell. For each

negative charge one HCO3- is formed which enters the peritubular blood. Luminal

gamma-glutamyl transferase-mediated ammoniagenesis contributes to NH4+

accumulation in the proximal tubule to a small extent. The endproximal NH4+

delivery exceeds the filtered load by a factor of 9. Only 1/3 of it reaches the

distal convoluted tubule mainly because NH+4 as such is reabsorbed from the

thick ascending limb of Henle's loop by secondary active transport or

electrodiffusion. Both processes are energized by the active Na+ transport in

this segment. Thereby NH3----NH4+ is accumulated in the medullary interstitium,

which establishes the chemical gradient for non-ionic diffusion of NH3 into the

lumen of the collecting ducts. This is favoured by the acidic disequilibrium pH

in the lumen of this segment.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 2430135 [PubMed - indexed for MEDLINE]

Pflugers Arch. 1983 Mar 1;396(3):218-24. Related Articles, Links

Kinetics and localization of tubular resorption of " acidic " amino acids. A

microperfusion and free flow micropuncture study in rat kidney.

Silbernagl S.

The unidirectional resorption rates of L-glutamate (initial concentrations of

0.07, 0.66, 2.0 or 20.0 mmol X 1(-1)), D-glutamate (0.66 mmol X 1(-1) in the

presence or absence of 20 mmol X 1(-1) L-glutamate), and of L-aspartate (0.073,

0.3, 0.66, 2.0 or 5.0 mmol X 1(-1)) were determined in the rat proximal

convolution. L-Glutamate resorption was saturable. A permeability coefficient

(P) of less than or equal to 20 microns2 X S-1, and a maximum resorption rate

(Jmax) of 0.15 +/- 0.015 (SEM) nmol X S-1 X m-1 at a Km of 0.17 +/- 0.025 (SEM)

mmol X 1(-1) was obtained for L-glutamate. For L-aspartate, Jmax was 0.13 +/-

0.005 at a Km of 0.1 +/- 0.013. A free flow glutamate concentration profile

along the proximal convolution was (I) predicted from these constants and (II)

actually measured by means of free flow micropuncture. The data agree very well

and show that more than 90% of the filtered load is resorbed within the first

third of the proximal convolution. The late proximal and early distal free flow

recoveries of L-glutamate amounted to 5.3 +/- 1.7% (SEM) and 6.6 +/- 1.4% of the

filtered load, respectively. In contrast to this, unidirectional resorption

during the microperfusion of the same tubule section was high: fractional

resorption amounted to ca. 96% at 2 mmol X 1(-1) initial L-glutamate. It fell to

35 or 33% respectively if the initial L-glutamate concentration was 20 mmol X

1(-1) or if the resorption of 0.66 mmol X 1(-1) D-glutamate in presence of 20

mmol X 1(-1) L-glutamate was measured. The fractional excretion of endogenous

L-glutamate in the final urine amounted to 0.13 +/- 0.012% of the filtered load.

It is concluded that L-glutamate and L-aspartate are quickly resorbed in early

parts of the proximal convolution (low Km). Saturation already occurs when there

is a small increase in the filtered load (low Jmax). The nephron section between

the late proximal and early distal nephron sites also reabsorbs " acidic " amino

acids. Normally, however, the back leak cancels this out, and net flux becomes

zero. Deep nephrons seem to handle amino acids somewhat differently than

superficial nephrons do.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 6133264 [PubMed - indexed for MEDLINE]

J Am Soc Nephrol. 1992 Jan;2(7):1171-7. Related Articles, Links

Growth hormone and renal glutamine and glutamate handling.

Welbourne TC, Horton K, Cronin MJ.

Department of Physiology, Louisiana State University Medical Center, Shreveport

33932.

Growth hormone administration effects a positive nitrogen balance in part by

recycling glutamine nitrogen as glutamate at the expense of ureagenesis. The

study presented here focuses on the response of the isolated perfused

hypophysectomized rat kidney to acute growth hormone administration during

infusions of either glutamine or glutamate. Growth hormone at 50 nM acutely

decreases the renal utilization of both glutamine and glutamate while enhancing

reabsorption of the latter. During glutamine infusions of either 1,000 or 500

nmol/min, growth hormone markedly reduced net glutamine utilization by 55% at

the high loads and reversed utilization to release at the lower load; associated

with decreased glutamine utilization was reduced ammonium production and

increased glutamate release. Although glutamine reabsorption was unchanged,

glutamate reabsorption increased and NH4+ excretion decreased. During glutamate

infusion of 180 nmol/min, growth hormone reduced glutamate utilization 66%, the

residual utilization matching increased glutamate reabsorption was associated

with enhanced bicarbonate reabsorption and a redistribution of NH4+ release into

the urine; all three responses were eliminated by amiloride. These responses to

growth hormone are consonant with reduced glutamate oxidation underlying

decreased glutamine utilization and accelerated luminal Na+-H+ exchange

mediating luminal transport, events that are conceivably interrelated.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 1350468 [PubMed - indexed for MEDLINE]

>

> Hi! Does anyone have an opinion about Glutamine and whether our kids need it.

I heard it is bad, it turns into Glutamate, which is an excitotoxin in people

with neurodegenerative disease. I guess for neurotypical people

Glutamine/Glutamate supplementation is fine. I read some debates online about

this amino acid. And in appears to be in numerous amino acid complete

supplements, like mine, by Klaires. What are your thoughts about this?

>

[Guest guest]

Hi,

That is such a great question and it comes up every now and then because people

read books talking about one function of a molecule and get the feeling that

this is all that molecule is going to do.

Actually glutamine comprises 71% of the total amino acid count in the cerebral

spinal fluid...so it is basically bathing the brain and is highly PROTECTIVE of

the brain! It ends up being a fuel for the brain and important for making the

brain's glutathione.

I answered a similar question years ago on this list when someone was asking

about urinary glutamate, but the answer I gave then should help you now, I hope.

I've put it below.

If you have any questions, just ask!

HTH,

I feel a duty to bring to your attention and to the attention of others that

glutamate being elevated in urine has nothing to do with glutamate being

elevated in the brain or at synapses (which is where the GABA to glutamate ratio

might be important). Can I help you understand why I'm saying that?

Notice that in the first article below, when someone found that glutamate was

elevated in the urine in someone with cerebellar difficulties, that they learned

that glutamate was actually very deficient at the same time in the cerebral

spinal fluid. The raised level in urine reflected a transport problem, which is

a big part of the function of the kidney. The second article tells you where

urinary ammonia is coming from.

The amount of glutamate in urine is regulated by transporters that reabsorb back

what the body needs to retain. One article below says that 99.87% of the

endogenous glutamate that was filtered in the kidney was reabsorbed back into

the body so it didn't show up in the urine. This means that getting that

glutamate back in the body instead of leaving it in urine is REALLY important

and the greater danger may be losing the glutamate into the urine. Considering

that, why would the tiny fraction of glutamate left behind in the urine be

thought to have anything to do with what happens with glutamate in synapses in

the brain?

It is a hard thing to remember, but the brain is only 3 pounds in an adult, and

all of these amino acids have jobs to do in the rest of the body. By weight,

the rest of the body outnumbers the brain 98 to one in an adult! Most likely

most of the glutamate in your body is already part of proteins or it is on the

way to becoming part of a protein! In fact, when some scientists looked at the

proteins that cows eat, they found that 14-21% of the amino acids in the food

were glutamate. In fact, it was by far the most abundant amino acid in their

food. The " excitatory " amino acid, aspartic acid took second place in this test

of relative abundance in food protein, but still, it was at a distance from the

clear winner, glutamate. (The Amino Acid Composition of Protein Feedstuffs

Before and After Ruminal Incubation and After Subsequent PassageThrough the

Intestines of Dairy Cows1F. P. O'Mara*,2, J. J. *, and M. Rath†)

Completely in line with those ratios, in a study of fetal pig,

glutamate+glutamine comprised 14% of the amino acids in the pig, but GABA was

only 0.17%.(Amino Acid Composition of the Fetal Pig 1Guoyao Wu,2 Troy L. Ott,3

Darrell A. Knabe and Fuller W. Bazer)

Like all of us, amino acids wear many hats. Maybe you have a special position in

your child's PTA and it might be really important part of what you do when you

are at the school. In fact, your presence at the school might have a high

correlation to doing PTA activity, but I dare say if someone runs into you at

the dentist's office, that your being there on PTA duty is not very likely.

One thing I have majored on emphasizing in the DAN! community for all the years

I've been there (many years, for I started being involved with DAN! in 1995) is

that you HAVE to think of compartmentation [where something is being observed

and the rules at that location] when you measure anything in blood or urine, or

even CSF.

Measuring glutamate in the urine tells you mostly about the kidney. Measuring

ammonia in the urine tells you about a kidney function designed to protect the

body against acidosis. Urinary ammonia is not the same ammonia that can be

troubling to brain function.

The huge world of things that can be made out of glutamate are summarized here:

http://www.genome.jp/kegg/pathway/map/map00251.html

Glutamine can easily be converted into glutamate. Keeping that in mind, look at

the difference in the relative proportions that glutamate is of the total amino

acids in CSF, blood plasma and urine that I've put below. Why would glutamate

be showing up in these different places in such reduced quantity compared to its

relative composition in proteins? Glutamate is also a third of glutathione!

After you consider how easily glutamine and glutamate interconvert in the kidney

and all over the body, then look at how extremely low glutamate is in these

three compartments compared to glutamine. Do you see that almost 72% of the

free amino acids in CSF is glutamine, but glutamate is only a fourth of a

percent? Nothing else is even close to glutamine. When there are glutaminases

in the brain that make glutamate easily from glutamine and when it can be easily

converted back, then why would anyone think that urinary glutamate could

represent anything relevant to GABA and glutamate ratios or levels in the

synapses of the brain?

csf urine plasma

Glutamine 71.741% 11.100% 24.160%

Glycine 0.703% 29.736% 8.568%

Alanine 3.594% 6.991% 9.781%

Histidine 1.777% 14.727% 3.136%

Serine 4.449% 7.641% 4.709%

Taurine 0.789% 10.375% 2.094%

Valine 2.341% 1.518% 7.995%

Lysine 2.486% 2.972% 5.732%

Threonine 3.110% 2.714% 3.859%

Leucine 1.372% 0.645% 4.416%

Tyrosine 0.935% 3.052% 2.212%

Arginine 2.168% 0.253% 3.081%

Proline 0.000% 0.258% 5.242%

Asparagine 0.776% 2.506% 1.710%

Phenylalanine 0.935% 0.878% 1.967%

Isoleucine 0.530% 0.635% 2.157%

Ornithine 0.716% 0.600% 1.501%

Cystine 0.245% 0.719% 1.754%

Tryptophan 0.338% 0.000% 2.283%

Methionine 0.464% 1.121% 0.814%

Glutamic Acid 0.252% 0.417% 1.485%

Citrulline 0.199% 0.268% 1.185%

Aspartic Acid 0.080% 0.873% 0.158%

I've put some articles below to help in thinking about these concepts. Always

be sure when you are learning something that the rules you are learning apply to

the place where something is being measured and not elsewhere! This is SO

important with lab testing.

Acta Neurol Scand. 1991 Jul;84(1):70-2. Related Articles, Links

Cerebellar ataxia with glutamic aciduria.

Sawada H, Seriu N, Udaka F, Kameyama M, Sugiyama H.

Department of Neurology, Sumitomo Hospital, Osaka, Japan.

We report a case of cystinuria and glutamic aciduria, presenting with

progressive cerebellar manifestations. She had cerebellar type dysarthria and

limb ataxia. Head MRI revealed cerebellar atrophy. Urinary amino acid analysis

showed excessive excretion of glutamate and the dibasic amino acids (cystine,

arginine, lysine, and ornithine). Cystine and glutamic acid are thought to be

transported in a common membrane transport system. Reduction of glutamic acid

and cystine in the cerebrospinal fluid was revealed. A relationship between

cystinuria and cerebellar manifestation was discussed.

Publication Types:

Case Reports

PMID: 1681667 [PubMed - indexed for MEDLINE]

Klin Wochenschr. 1986 Sep 15;64(18):862-70. Related Articles, Links

Formation and excretion of NH3----NH4+. New aspects of an old problem.

Silbernagl S, Scheller D.

The proximal tubule cell is the major site of renal ammoniagenesis. Glutamine is

the major substrate. Deamidation by mitochondrial glutaminase yields glutamate-

and NH4+ (not NH3, as traditionally taught). A second NH4+ ion is obtained by

deamination of glutamate- to 2-oxo-glutarate2-. NH4+ preferentially enters the

tubule lumen primarily, but probably not exclusively, by non-ionic diffusion of

NH3. For each NH3 formed in the cell one H+ ion is left behind. H+ and NH3 are

secreted on separate routes, but recombine in the lumen to NH4+ and reach the

final urine in this form. This process per se does not net-remove H+ from the

organism. For this purpose, the anionic products of ammoniagenesis

(2-oxo-glutarate2- and others) have to be converted into neutral compounds (CO2,

glucose). This metabolism again takes place usually in the tubule cell. For each

negative charge one HCO3- is formed which enters the peritubular blood. Luminal

gamma-glutamyl transferase-mediated ammoniagenesis contributes to NH4+

accumulation in the proximal tubule to a small extent. The endproximal NH4+

delivery exceeds the filtered load by a factor of 9. Only 1/3 of it reaches the

distal convoluted tubule mainly because NH+4 as such is reabsorbed from the

thick ascending limb of Henle's loop by secondary active transport or

electrodiffusion. Both processes are energized by the active Na+ transport in

this segment. Thereby NH3----NH4+ is accumulated in the medullary interstitium,

which establishes the chemical gradient for non-ionic diffusion of NH3 into the

lumen of the collecting ducts. This is favoured by the acidic disequilibrium pH

in the lumen of this segment.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 2430135 [PubMed - indexed for MEDLINE]

Pflugers Arch. 1983 Mar 1;396(3):218-24. Related Articles, Links

Kinetics and localization of tubular resorption of " acidic " amino acids. A

microperfusion and free flow micropuncture study in rat kidney.

Silbernagl S.

The unidirectional resorption rates of L-glutamate (initial concentrations of

0.07, 0.66, 2.0 or 20.0 mmol X 1(-1)), D-glutamate (0.66 mmol X 1(-1) in the

presence or absence of 20 mmol X 1(-1) L-glutamate), and of L-aspartate (0.073,

0.3, 0.66, 2.0 or 5.0 mmol X 1(-1)) were determined in the rat proximal

convolution. L-Glutamate resorption was saturable. A permeability coefficient

(P) of less than or equal to 20 microns2 X S-1, and a maximum resorption rate

(Jmax) of 0.15 +/- 0.015 (SEM) nmol X S-1 X m-1 at a Km of 0.17 +/- 0.025 (SEM)

mmol X 1(-1) was obtained for L-glutamate. For L-aspartate, Jmax was 0.13 +/-

0.005 at a Km of 0.1 +/- 0.013. A free flow glutamate concentration profile

along the proximal convolution was (I) predicted from these constants and (II)

actually measured by means of free flow micropuncture. The data agree very well

and show that more than 90% of the filtered load is resorbed within the first

third of the proximal convolution. The late proximal and early distal free flow

recoveries of L-glutamate amounted to 5.3 +/- 1.7% (SEM) and 6.6 +/- 1.4% of the

filtered load, respectively. In contrast to this, unidirectional resorption

during the microperfusion of the same tubule section was high: fractional

resorption amounted to ca. 96% at 2 mmol X 1(-1) initial L-glutamate. It fell to

35 or 33% respectively if the initial L-glutamate concentration was 20 mmol X

1(-1) or if the resorption of 0.66 mmol X 1(-1) D-glutamate in presence of 20

mmol X 1(-1) L-glutamate was measured. The fractional excretion of endogenous

L-glutamate in the final urine amounted to 0.13 +/- 0.012% of the filtered load.

It is concluded that L-glutamate and L-aspartate are quickly resorbed in early

parts of the proximal convolution (low Km). Saturation already occurs when there

is a small increase in the filtered load (low Jmax). The nephron section between

the late proximal and early distal nephron sites also reabsorbs " acidic " amino

acids. Normally, however, the back leak cancels this out, and net flux becomes

zero. Deep nephrons seem to handle amino acids somewhat differently than

superficial nephrons do.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 6133264 [PubMed - indexed for MEDLINE]

J Am Soc Nephrol. 1992 Jan;2(7):1171-7. Related Articles, Links

Growth hormone and renal glutamine and glutamate handling.

Welbourne TC, Horton K, Cronin MJ.

Department of Physiology, Louisiana State University Medical Center, Shreveport

33932.

Growth hormone administration effects a positive nitrogen balance in part by

recycling glutamine nitrogen as glutamate at the expense of ureagenesis. The

study presented here focuses on the response of the isolated perfused

hypophysectomized rat kidney to acute growth hormone administration during

infusions of either glutamine or glutamate. Growth hormone at 50 nM acutely

decreases the renal utilization of both glutamine and glutamate while enhancing

reabsorption of the latter. During glutamine infusions of either 1,000 or 500

nmol/min, growth hormone markedly reduced net glutamine utilization by 55% at

the high loads and reversed utilization to release at the lower load; associated

with decreased glutamine utilization was reduced ammonium production and

increased glutamate release. Although glutamine reabsorption was unchanged,

glutamate reabsorption increased and NH4+ excretion decreased. During glutamate

infusion of 180 nmol/min, growth hormone reduced glutamate utilization 66%, the

residual utilization matching increased glutamate reabsorption was associated

with enhanced bicarbonate reabsorption and a redistribution of NH4+ release into

the urine; all three responses were eliminated by amiloride. These responses to

growth hormone are consonant with reduced glutamate oxidation underlying

decreased glutamine utilization and accelerated luminal Na+-H+ exchange

mediating luminal transport, events that are conceivably interrelated.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 1350468 [PubMed - indexed for MEDLINE]

>

> Hi! Does anyone have an opinion about Glutamine and whether our kids need it.

I heard it is bad, it turns into Glutamate, which is an excitotoxin in people

with neurodegenerative disease. I guess for neurotypical people

Glutamine/Glutamate supplementation is fine. I read some debates online about

this amino acid. And in appears to be in numerous amino acid complete

supplements, like mine, by Klaires. What are your thoughts about this?

>

[Guest guest]

Thanks for the info !

> >

> > Hi! Does anyone have an opinion about Glutamine and whether our kids need

it. I heard it is bad, it turns into Glutamate, which is an excitotoxin in

people with neurodegenerative disease. I guess for neurotypical people

Glutamine/Glutamate supplementation is fine. I read some debates online about

this amino acid. And in appears to be in numerous amino acid complete

supplements, like mine, by Klaires. What are your thoughts about this?

> >

>