Re: Rich: Nitric oxide and NOS SNP question?

[Guest guest]

> I took a quick skim of the material below, and without studying it

> further, I will say that she has made very clear in her

presentations

> and books that the body will use bh4 to detoxify ammonia. And its

> clear from all that follows below that BH4 is an essential cofactor

> for NOS.

This assumes her descriptions and graphs are correct, but I believe

they are wrong, as I'll point out. But first, a word on aluminum...

> You only have to view the metals chart of the son of the mom I was

> speaking to, to begin to have new respect for Dr. Yasko's

approach. IE

> she has said that aluminum suppresses bh4. And there is this boy's

> first UTM taken after adding bh4 a few weeks ago--and a huge dump

of

> aluminum.

FWIW, bh4 deficiency in autism has been documented in studies,

starting from the early 1990s, so it's not a new idea. Also,

aluminum absorption is highly dependent on acid intake. In order to

do a before and after test for aluminum excretion, you must keep the

same level of acid intake. But if the brain is being affected by

aluminum, changing aluminum absorption isn't going to help. You

would need a chelator that could cross the blood brain

barrier and be able to remove the aluminum. Because otherwise,

aluminum has a very long half-life, i.e. years.

> BH4 Cycle: Tetrahydrobiopterin (BH4) is essential for normal

central

> nervous system functioning. It is an essential factor or cofactor

for

> the enzymes in the biological pathways necessary for synthesizing

> catecholamines (dopamine, noradrenaline/norepinephrine) and

> indolamines (serotonin and melatonin), as well as for all three

> isotypes of nitric oxide synthases (NOS in the Urea cycle).

This is the question, where is NOS in the urea cycle?

> Urea Cycle: Urea is the chief nitrogenous waste of mammals. Most of

> our nitrogenous waste comes from the breakdown of amino acids.

> Breakdown of amino acids results in the production of ammonia

(NH3).

> Ammonia is a toxic compound that is converted into its safer

> counterpart urea, by enzymes in the liver. Urea is then eliminated

by

> our kidneys. Essentially the urea cycle involves the conversion of

> ammonia into urea with the help of the intermediates listed below.

> Arginine from our diet or from protein metabolism is converted to

> ornithine and urea by the enzyme Arginase. Ornithine is then

converted

> to citrulline by ornithine transcabamoylase. This is the reaction

on

> the far left side of the pathway diagram. Citrulline is converted

back

> to arginine. This cycling of Arginine through the various

> intermediates is what converts ammonia to urea.

All this is correct, but NOS is not mentioned. Also note

that this is a self-contained process in the liver. But the

following process occurs outside of this cycle.

> Arginine is also required for the production of Nitric Oxide (NO)

by

> the enzyme nitric oxide synthase (NOS or eNOS). This reaction is

> dependent on the levels of BH4 available from the BH4 cycle.

Remember

> two molecules of BH4 are needed to generate Citrulline and NO. One

> molecule of BH4 will in turn generate peroxynitrite and if there

is no

> BH4, super oxide is formed. If we do not have enough BH4 to go

around

> because of the A1298C mutation, we are going to have trouble with

> ammonia. Because ammonia is dangerous to the body, any BH4 we have

is

> going to be used to try to get rid of the ammonia rather than to be

> making neurotransmitters like serotonin and dopamine.

This conversion of arginine to nitric oxide occurs outside the

liver. It's not part of the urea cycle. As I pointed out in a

previous post, arginine in the liver is basically unaffected by

NOS. And the citrulline formed using BH4 is not used by the urea

cycle in the liver. Instead, citrulline is formed from

ornithine in the urea cycle, as mentioned above.

Thus, NOS does not appear to required for the urea cycle in the

liver, and thus neither is BH4 required.

- Mark

[Guest guest]

Hi, Mark.

" Mark London " <mrl@...> wrote:>

> FWIW, bh4 deficiency in autism has been documented in studies,

> starting from the early 1990s, so it's not a new idea. Also,

> aluminum absorption is highly dependent on acid intake. In order to

> do a before and after test for aluminum excretion, you must keep the

> same level of acid intake. But if the brain is being affected by

> aluminum, changing aluminum absorption isn't going to help. You

> would need a chelator that could cross the blood brain

> barrier and be able to remove the aluminum. Because otherwise,

> aluminum has a very long half-life, i.e. years.

***DMPS for chelation of several heavy metals can't cross the blood-brain

barrier either,

but one way in which it is thought to help rid the brain of these metals is by

the lowering

of the saturation gradient, there by creating diffusion of metals out of the

brain. So, I'm

wondering if this same effect might be in play for aluminum in the Yasko

approach for

ME/CFS/autism and changing absorption of aluminum can indeed aid elimination of

aluminum from the brain?

[Guest guest]

> ***DMPS for chelation of several heavy metals can't cross the

blood-brain barrier either,

> but one way in which it is thought to help rid the brain of these

metals is by the lowering

> of the saturation gradient, there by creating diffusion of metals

out of the brain.

That theory is fine, assuming you can significantly reduce serum

metal levels (by reducing exposure, or using a chelator), and

assuming metals are in a free state in cells, so that they can

easily pass out of the cells into the serum. Once the metals are

organically bound though, I think it's a lot harder for this method

to get them out of the cells. If that is the case, (and I think it

is with aluminum), then cell turnover becomes an important factor.

I've read that the reason that the half life of heavy metals in the

brain is so long, is likely because of the much slower cell turnover

rate in the brain.

- Mark

[Guest guest]

> " The liver contains an enzyme system that irreversibly converts

> ornithine into glutamate:

>

> ornithine->glutamate semialdehyde->glutamate

This will have to be quick answers, because I'm off to bed right

now.

The above reaction only occurs when the urea cycle has excess

ornithine:

http://www.med.unibs.it/~marchesi/aametab.html#arginine

> " Depletion of ornithine by these reactions inhibits urea synthesis

> in the liver for want of ornithine, the intermediate of the urea

> cycle that must recycle. Replenishment of ornithine is necessary

> and completely dependent on a source of blood arginine. Thus urea

> synthesis in the liver is dependent on citrulline synthesis by the

> gut and arginine synthesis by the kidney. "

>

> This being the case, it would seem to me that there may indeed be

an

> interaction between the urea cycle and epithelial nitric oxide

> synthase, since this enzyme normally utilizes arginine and produces

> citrulline, and its operation no doubt affects the blood levels of

> arginine and citrulline, at least to some degree.

First, serum citrulline is not taken up by the liver.

Secondly, urea production uses very little of the serum arginine:

Biochem. J. (1998) 336, 1±17

Arginine metabolism: nitric oxide and beyond

" Only 5% of urea production is derived from plasma arginine [62],

reflecting very low uptake of arginine by the liver and the strict

segregation of hepatic and plasma arginine pools. "

Also, arginine blood levels are very well controlled, so it's

unlikely to be affected by eNOS. For example, this is true even

when the kidneys have a reduced ability to produce arginine:

" As expected, individuals with chronic renal insufficiency have

elevated plasma levels of citrulline [116,120,121]. Surprisingly,

however, there is little or no decrease in plasma arginine in these

patients. The basis for the maintenance of plasma arginine at

normal or near-normal levels is unknown, but probably involves

a combination of factors [40,122], including increased release

of arginine by protein catabolism in skeletal muscle, increased

arginine synthesis at extrarenal sites, hypertrophy of proximal

tubules, hyperfiltration (which increases the amount of citrulline

filtered per nephron), and an increased rate of arginine synthesis

due to elevated plasma levels of citrulline. "

- Mark

[Guest guest]

>

> First, serum citrulline is not taken up by the liver.

fwiw: Here's the reference for that information:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & dop\

t=AbstractPlus & list_uids=7325229 & query_hl=22 & itool=pubmed_docsum

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed & cmd=Retrieve & do\

pt=AbstractPlus & list_uids=7325229 & query_hl=22 & itool=pubmed_docsum>

> Secondly, urea production uses very little of the serum arginine:

>

> Biochem. J. (1998) 336, 1±17

> Arginine metabolism: nitric oxide and beyond

>

> " Only 5% of urea production is derived from plasma arginine [62],

> reflecting very low uptake of arginine by the liver and the strict

> segregation of hepatic and plasma arginine pools. "

>

> Also, arginine blood levels are very well controlled, so it's

> unlikely to be affected by eNOS. For example, this is true even

> when the kidneys have a reduced ability to produce arginine:

>

> " As expected, individuals with chronic renal insufficiency have

> elevated plasma levels of citrulline [116,120,121]. Surprisingly,

> however, there is little or no decrease in plasma arginine in these

> patients. The basis for the maintenance of plasma arginine at

> normal or near-normal levels is unknown, but probably involves

> a combination of factors [40,122], including increased release

> of arginine by protein catabolism in skeletal muscle, increased

> arginine synthesis at extrarenal sites, hypertrophy of proximal

> tubules, hyperfiltration (which increases the amount of citrulline

> filtered per nephron), and an increased rate of arginine synthesis

> due to elevated plasma levels of citrulline. "

>

> - Mark

>

[Guest guest]

-- In , " rvankonynen "

<richvank@...> wrote:

> The following is from page 871 of Devlin, T.,

> Textbook of Biochemistry, fifth edition (2002):

>

> " The liver contains an enzyme system that irreversibly converts

> ornithine into glutamate:

> ornithine->glutamate semialdehyde->glutamate

>

> " Depletion of ornithine by these reactions inhibits urea synthesis

> in the liver for want of ornithine, the intermediate of the urea

> cycle that must recycle. Replenishment of ornithine is necessary

> and completely dependent on a source of blood arginine. Thus urea

> synthesis in the liver is dependent on citrulline synthesis by the

> gut and arginine synthesis by the kidney. "

These statements are incorrect. Here's the long answer, that I

found this morning. It explains why only excess ornithine is used

for the above process, so that the major urea cycle is unaffected.

Histochem Cell Biol (1999) 111:445–452 Abstract:

" High protein diet induces pericentral glutamate dehydrogenase [GDH]

and ornithine aminotransferase [OAST] to provide sufficient

glutamate

for pericentral detoxification of ammonia in rat liver lobules. "

" The major pathway responsible for detoxification of bicarbonate and

NH4+ [ammonia] is the ornithine cycle, which is mainly localized in

periportal zones of liver lobules (Jungermann and Katz 1989; Meijer

et al. 1990; Gebhardt 1992). The key enzyme involved in synthesis of

urea and the first enzyme of the ornithine cycle (carbamoylphosphate

synthase; EC 6.3.4.16; CPS) has a high capacity but low affiniy

(high Km) for NH4+ (Häussinger et al. 1984). Therefore, not all free

NH4+ can be converted into urea in the periportal zones. This is

essential because NH4+ is an important metabolite in the liver. It

is required for the synthesis of non-essential amino acids, purines,

pyrimidines, and other nitrogen-containing compounds. This means

that sufficient concentrations of NH4+ are necessary in the liver

but once the blood leaves the liver, all NH4+ should be neutralized

(Boon et al. 1991).

Glutamine synthetase (EC 6.3.1.2; GS; a high capacity, high affinity

system) prevents the remaining NH4+ from entering the circulation by

its unique localization in a small rim of hepatocytes around the

central vein (Häussinger et al. 1984; Moorman et al. 1988, 1990). "

" In order to fulfill this scavenger function, GS needs large amounts

of glutamate. In the pericentral zone, two compartments were

distinguished (Geerts et al. 1997): a two-cell-thick rim of

pericentral cells adjacent to the central vein (GS positive subzone

that contains the highest glutamate concentrations and a larger

layer of pericentral hepatocytes around the GS-positive subzone that

contains less glutamate (Fig. 3). GDH is expressed in the entire

pericentral zone. It is hypothesized that pericentral GDH is highly

active in the direction of glutamate production. The relatively low

affinity of pericentral GDH for glutamate (Jonker et al. 1996) and

the presence of GS, a glutamate-consuming system, in this zone are

in good agreement with this concept. The relatively high cellular

glutamate concentration in the GS-positive subzone shows that

glutamate availability is not limiting GS activity under normal

conditions.

In this way, NH4+ is neutralized efficiently and recirculated as

glutamine via the blood stream. However, the situation can be

different under more extreme conditions (i.e., 60% protein diet)

when GS has to detoxify large amounts of NH4+. Under these

conditions, both GDH and GS mRNA levels were increased. In addition

to this, we observed that OAT expression was strongly upregulated in

pericentral zones and may, therefore, serve as a glutamate source

for GS at the cost of ornithine (Fig. 3). Due to the unique

localization of OAT as compared with other transaminases that are

localized in periportal zones, ornithine is not degraded in the

periportal ornithine cycle. As a consequence, ornithine is the only

amino acid that is degraded pericentrally. Due to this

compartmentalization, ornithine is not degraded where it is

essential for its catalytic function in the ornithine cycle

(periportally), whereas it can be converted to glutamate as

substrate for GS in the ornithine cycle-negative zone.

The present study shows that the complex regulation of ornithine

degradation and NH4+ detoxification by the liver in the different

zones of the lobulus, as summarized in Fig. 3, ensures, on the one

hand, availability of free NH4+ in the liver for the production of

non-essential amino acids, purines, pyrimidines, and other nitrogen-

containing compounds, and, on the other hand, it guarantees

detoxification of free NH4+, even under extreme conditions, before

it can enter the circulation. "

[Guest guest]

Hi, Mark.

Thanks for posting this. I think it's really interesting. It

sounds as though the liver is well set up to deal with various

eventualities.

I guess that one question that remains in my mind is whether the

operation of the urea cycle in a person with an upregulated CBS

enzyme (I realize that you haven't agreed on the upregulated part)

would be the same as described below for the normal, healthy

person. That is, we are trying to sort out the pathophysiology,

which will differ in some respects from the normal physiology. The

normal physiology and biochemistry are certainly the right place to

start, but then I think we have to try to understand how the

physiology of the person with this disorder differs from the normal

physiology.

Concerning your earlier message about citrulline not being imported

by the liver, I actually realized that from what I had read.

However, citrulline is used by the kidneys to make arginine, which

goes back into the blood and is available for import by the liver

cells, so that's a possible connection.

It seems to me that there really is evidence for excess ammonia in

people with the CBS polymorphisms, based on their high urine ammonia

levels (I understand what the normal route of putting ammonia into

the urine is, but again, the pathophysiology in these people may

differ from the normal in this respect, also) and based on reports

of their being able to smell ammonia. I think I've also found some

with the torpor that is characteristic of high ammonia, and I've had

some reports that just cutting back on protein intake has been

beneficial for some. So I think there is excess ammonia involved in

these cases.

I've decided to go to Dr. Yasko's conference in Boston next weekend,

so maybe I'll learn some more about some of the issues you've been

raising, which are very good issues to raise, in my opinion.

Rich

> > The following is from page 871 of Devlin, T.,

> > Textbook of Biochemistry, fifth edition (2002):

> >

> > " The liver contains an enzyme system that irreversibly converts

> > ornithine into glutamate:

> > ornithine->glutamate semialdehyde->glutamate

> >

> > " Depletion of ornithine by these reactions inhibits urea

synthesis

> > in the liver for want of ornithine, the intermediate of the urea

> > cycle that must recycle. Replenishment of ornithine is

necessary

> > and completely dependent on a source of blood arginine. Thus

urea

> > synthesis in the liver is dependent on citrulline synthesis by

the

> > gut and arginine synthesis by the kidney. "

>

> These statements are incorrect. Here's the long answer, that I

> found this morning. It explains why only excess ornithine is used

> for the above process, so that the major urea cycle is unaffected.

>

> Histochem Cell Biol (1999) 111:445–452 Abstract:

> " High protein diet induces pericentral glutamate dehydrogenase

[GDH]

> and ornithine aminotransferase [OAST] to provide sufficient

> glutamate

> for pericentral detoxification of ammonia in rat liver lobules. "

>

> " The major pathway responsible for detoxification of bicarbonate

and

> NH4+ [ammonia] is the ornithine cycle, which is mainly localized

in

> periportal zones of liver lobules (Jungermann and Katz 1989;

Meijer

> et al. 1990; Gebhardt 1992). The key enzyme involved in synthesis

of

> urea and the first enzyme of the ornithine cycle

(carbamoylphosphate

> synthase; EC 6.3.4.16; CPS) has a high capacity but low affiniy

> (high Km) for NH4+ (Häussinger et al. 1984). Therefore, not all

free

> NH4+ can be converted into urea in the periportal zones. This is

> essential because NH4+ is an important metabolite in the liver. It

> is required for the synthesis of non-essential amino acids,

purines,

> pyrimidines, and other nitrogen-containing compounds. This means

> that sufficient concentrations of NH4+ are necessary in the liver

> but once the blood leaves the liver, all NH4+ should be

neutralized

> (Boon et al. 1991).

>

> Glutamine synthetase (EC 6.3.1.2; GS; a high capacity, high

affinity

> system) prevents the remaining NH4+ from entering the circulation

by

> its unique localization in a small rim of hepatocytes around the

> central vein (Häussinger et al. 1984; Moorman et al. 1988, 1990). "

>

> " In order to fulfill this scavenger function, GS needs large

amounts

> of glutamate. In the pericentral zone, two compartments were

> distinguished (Geerts et al. 1997): a two-cell-thick rim of

> pericentral cells adjacent to the central vein (GS positive

subzone

> that contains the highest glutamate concentrations and a larger

> layer of pericentral hepatocytes around the GS-positive subzone

that

> contains less glutamate (Fig. 3). GDH is expressed in the entire

> pericentral zone. It is hypothesized that pericentral GDH is

highly

> active in the direction of glutamate production. The relatively

low

> affinity of pericentral GDH for glutamate (Jonker et al. 1996) and

> the presence of GS, a glutamate-consuming system, in this zone are

> in good agreement with this concept. The relatively high cellular

> glutamate concentration in the GS-positive subzone shows that

> glutamate availability is not limiting GS activity under normal

> conditions.

>

> In this way, NH4+ is neutralized efficiently and recirculated as

> glutamine via the blood stream. However, the situation can be

> different under more extreme conditions (i.e., 60% protein diet)

> when GS has to detoxify large amounts of NH4+. Under these

> conditions, both GDH and GS mRNA levels were increased. In

addition

> to this, we observed that OAT expression was strongly upregulated

in

> pericentral zones and may, therefore, serve as a glutamate source

> for GS at the cost of ornithine (Fig. 3). Due to the unique

> localization of OAT as compared with other transaminases that are

> localized in periportal zones, ornithine is not degraded in the

> periportal ornithine cycle. As a consequence, ornithine is the

only

> amino acid that is degraded pericentrally. Due to this

> compartmentalization, ornithine is not degraded where it is

> essential for its catalytic function in the ornithine cycle

> (periportally), whereas it can be converted to glutamate as

> substrate for GS in the ornithine cycle-negative zone.

>

> The present study shows that the complex regulation of ornithine

> degradation and NH4+ detoxification by the liver in the different

> zones of the lobulus, as summarized in Fig. 3, ensures, on the one

> hand, availability of free NH4+ in the liver for the production of

> non-essential amino acids, purines, pyrimidines, and other

nitrogen-

> containing compounds, and, on the other hand, it guarantees

> detoxification of free NH4+, even under extreme conditions, before

> it can enter the circulation. "

>

[Guest guest]

> > > The following is from page 871 of Devlin, T.,

> > > Textbook of Biochemistry, fifth edition (2002):

> > >

> > > " The liver contains an enzyme system that irreversibly

converts

> > > ornithine into glutamate:

> > > ornithine->glutamate semialdehyde->glutamate

> > >

> > > " Depletion of ornithine by these reactions inhibits urea

> synthesis

> > > in the liver for want of ornithine, the intermediate of the

urea

> > > cycle that must recycle. Replenishment of ornithine is

> necessary

> > > and completely dependent on a source of blood arginine. Thus

> urea

> > > synthesis in the liver is dependent on citrulline synthesis by

> the

> > > gut and arginine synthesis by the kidney. "

> >

> > These statements are incorrect. Here's the long answer, that I

> > found this morning. It explains why only excess ornithine is

used

> > for the above process, so that the major urea cycle is

unaffected.

> >

> > Histochem Cell Biol (1999) 111:445–452 Abstract:

> > " High protein diet induces pericentral glutamate dehydrogenase

> [GDH]

> > and ornithine aminotransferase [OAST] to provide sufficient

> > glutamate

> > for pericentral detoxification of ammonia in rat liver lobules. "

> >

> > " The major pathway responsible for detoxification of bicarbonate

> and

> > NH4+ [ammonia] is the ornithine cycle, which is mainly localized

> in

> > periportal zones of liver lobules (Jungermann and Katz 1989;

> Meijer

> > et al. 1990; Gebhardt 1992). The key enzyme involved in

synthesis

> of

> > urea and the first enzyme of the ornithine cycle

> (carbamoylphosphate

> > synthase; EC 6.3.4.16; CPS) has a high capacity but low affiniy

> > (high Km) for NH4+ (Häussinger et al. 1984). Therefore, not all

> free

> > NH4+ can be converted into urea in the periportal zones. This is

> > essential because NH4+ is an important metabolite in the liver.

It

> > is required for the synthesis of non-essential amino acids,

> purines,

> > pyrimidines, and other nitrogen-containing compounds. This means

> > that sufficient concentrations of NH4+ are necessary in the

liver

> > but once the blood leaves the liver, all NH4+ should be

> neutralized

> > (Boon et al. 1991).

> >

> > Glutamine synthetase (EC 6.3.1.2; GS; a high capacity, high

> affinity

> > system) prevents the remaining NH4+ from entering the

circulation

> by

> > its unique localization in a small rim of hepatocytes around the

> > central vein (Häussinger et al. 1984; Moorman et al. 1988,

1990). "

> >

> > " In order to fulfill this scavenger function, GS needs large

> amounts

> > of glutamate. In the pericentral zone, two compartments were

> > distinguished (Geerts et al. 1997): a two-cell-thick rim of

> > pericentral cells adjacent to the central vein (GS positive

> subzone

> > that contains the highest glutamate concentrations and a larger

> > layer of pericentral hepatocytes around the GS-positive subzone

> that

> > contains less glutamate (Fig. 3). GDH is expressed in the entire

> > pericentral zone. It is hypothesized that pericentral GDH is

> highly

> > active in the direction of glutamate production. The relatively

> low

> > affinity of pericentral GDH for glutamate (Jonker et al. 1996)

and

> > the presence of GS, a glutamate-consuming system, in this zone

are

> > in good agreement with this concept. The relatively high

cellular

> > glutamate concentration in the GS-positive subzone shows that

> > glutamate availability is not limiting GS activity under normal

> > conditions.

> >

> > In this way, NH4+ is neutralized efficiently and recirculated as

> > glutamine via the blood stream. However, the situation can be

> > different under more extreme conditions (i.e., 60% protein diet)

> > when GS has to detoxify large amounts of NH4+. Under these

> > conditions, both GDH and GS mRNA levels were increased. In

> addition

> > to this, we observed that OAT expression was strongly

upregulated

> in

> > pericentral zones and may, therefore, serve as a glutamate

source

> > for GS at the cost of ornithine (Fig. 3). Due to the unique

> > localization of OAT as compared with other transaminases that

are

> > localized in periportal zones, ornithine is not degraded in the

> > periportal ornithine cycle. As a consequence, ornithine is the

> only

> > amino acid that is degraded pericentrally. Due to this

> > compartmentalization, ornithine is not degraded where it is

> > essential for its catalytic function in the ornithine cycle

> > (periportally), whereas it can be converted to glutamate as

> > substrate for GS in the ornithine cycle-negative zone.

> >

> > The present study shows that the complex regulation of ornithine

> > degradation and NH4+ detoxification by the liver in the

different

> > zones of the lobulus, as summarized in Fig. 3, ensures, on the

one

> > hand, availability of free NH4+ in the liver for the production

of

> > non-essential amino acids, purines, pyrimidines, and other

> nitrogen-

> > containing compounds, and, on the other hand, it guarantees

> > detoxification of free NH4+, even under extreme conditions,

before

> > it can enter the circulation. "

> >

>

[Guest guest]

Hi, Mark.

Thanks for the comments. I hope things go well for your wife. I

will probably be off line for the next few days, too.

Rich

> > > > The following is from page 871 of Devlin, T.,

> > > > Textbook of Biochemistry, fifth edition (2002):

> > > >

> > > > " The liver contains an enzyme system that irreversibly

> converts

> > > > ornithine into glutamate:

> > > > ornithine->glutamate semialdehyde->glutamate

> > > >

> > > > " Depletion of ornithine by these reactions inhibits urea

> > synthesis

> > > > in the liver for want of ornithine, the intermediate of the

> urea

> > > > cycle that must recycle. Replenishment of ornithine is

> > necessary

> > > > and completely dependent on a source of blood arginine.

Thus

> > urea

> > > > synthesis in the liver is dependent on citrulline synthesis

by

> > the

> > > > gut and arginine synthesis by the kidney. "

> > >

> > > These statements are incorrect. Here's the long answer, that

I

> > > found this morning. It explains why only excess ornithine is

> used

> > > for the above process, so that the major urea cycle is

> unaffected.

> > >

> > > Histochem Cell Biol (1999) 111:445–452 Abstract:

> > > " High protein diet induces pericentral glutamate dehydrogenase

> > [GDH]

> > > and ornithine aminotransferase [OAST] to provide sufficient

> > > glutamate

> > > for pericentral detoxification of ammonia in rat liver

lobules. "

> > >

> > > " The major pathway responsible for detoxification of

bicarbonate

> > and

> > > NH4+ [ammonia] is the ornithine cycle, which is mainly

localized

> > in

> > > periportal zones of liver lobules (Jungermann and Katz 1989;

> > Meijer

> > > et al. 1990; Gebhardt 1992). The key enzyme involved in

> synthesis

> > of

> > > urea and the first enzyme of the ornithine cycle

> > (carbamoylphosphate

> > > synthase; EC 6.3.4.16; CPS) has a high capacity but low

affiniy

> > > (high Km) for NH4+ (Häussinger et al. 1984). Therefore, not

all

> > free

> > > NH4+ can be converted into urea in the periportal zones. This

is

> > > essential because NH4+ is an important metabolite in the

liver.

> It

> > > is required for the synthesis of non-essential amino acids,

> > purines,

> > > pyrimidines, and other nitrogen-containing compounds. This

means

> > > that sufficient concentrations of NH4+ are necessary in the

> liver

> > > but once the blood leaves the liver, all NH4+ should be

> > neutralized

> > > (Boon et al. 1991).

> > >

> > > Glutamine synthetase (EC 6.3.1.2; GS; a high capacity, high

> > affinity

> > > system) prevents the remaining NH4+ from entering the

> circulation

> > by

> > > its unique localization in a small rim of hepatocytes around

the

> > > central vein (Häussinger et al. 1984; Moorman et al. 1988,

> 1990). "

> > >

> > > " In order to fulfill this scavenger function, GS needs large

> > amounts

> > > of glutamate. In the pericentral zone, two compartments were

> > > distinguished (Geerts et al. 1997): a two-cell-thick rim of

> > > pericentral cells adjacent to the central vein (GS positive

> > subzone

> > > that contains the highest glutamate concentrations and a

larger

> > > layer of pericentral hepatocytes around the GS-positive

subzone

> > that

> > > contains less glutamate (Fig. 3). GDH is expressed in the

entire

> > > pericentral zone. It is hypothesized that pericentral GDH is

> > highly

> > > active in the direction of glutamate production. The

relatively

> > low

> > > affinity of pericentral GDH for glutamate (Jonker et al. 1996)

> and

> > > the presence of GS, a glutamate-consuming system, in this zone

> are

> > > in good agreement with this concept. The relatively high

> cellular

> > > glutamate concentration in the GS-positive subzone shows that

> > > glutamate availability is not limiting GS activity under

normal

> > > conditions.

> > >

> > > In this way, NH4+ is neutralized efficiently and recirculated

as

> > > glutamine via the blood stream. However, the situation can be

> > > different under more extreme conditions (i.e., 60% protein

diet)

> > > when GS has to detoxify large amounts of NH4+. Under these

> > > conditions, both GDH and GS mRNA levels were increased. In

> > addition

> > > to this, we observed that OAT expression was strongly

> upregulated

> > in

> > > pericentral zones and may, therefore, serve as a glutamate

> source

> > > for GS at the cost of ornithine (Fig. 3). Due to the unique

> > > localization of OAT as compared with other transaminases that

> are

> > > localized in periportal zones, ornithine is not degraded in

the

> > > periportal ornithine cycle. As a consequence, ornithine is the

> > only

> > > amino acid that is degraded pericentrally. Due to this

> > > compartmentalization, ornithine is not degraded where it is

> > > essential for its catalytic function in the ornithine cycle

> > > (periportally), whereas it can be converted to glutamate as

> > > substrate for GS in the ornithine cycle-negative zone.

> > >

> > > The present study shows that the complex regulation of

ornithine

> > > degradation and NH4+ detoxification by the liver in the

> different

> > > zones of the lobulus, as summarized in Fig. 3, ensures, on the

> one

> > > hand, availability of free NH4+ in the liver for the

production

> of

> > > non-essential amino acids, purines, pyrimidines, and other

> > nitrogen-

> > > containing compounds, and, on the other hand, it guarantees

> > > detoxification of free NH4+, even under extreme conditions,

> before

> > > it can enter the circulation. "

> > >

> >

>