Glutathione depletion and disruption of the sleep-wake cycle in ME/CFS

August 9, 2011

Posts

1,314

Default Glutathione depletion and disruption of the sleep-wake cycle in ME/CFS

Hi, all.

As many of you know, I am the proponent of the Glutathione

Depletion--Methylation Cycle Block hypothesis for the pathogenesis and

pathophysiology of ME/CFS.

If glutathione depletion coupled with a partial block in the methylation

cycle is indeed the core mechanism in the pathophysiology of ME/CFS, then the

various abnormalities in ME/CFS must stem from it. In the past, I have been able

to find biochemical connections between this basic mechanism and many of the

abnormalities in ME/CFS.

One feature of ME/CFS that I have not yet connected to this mechanism is the

disruption in the sleep-wake cycle that many PWMEs experience.

Recently I came upon a paper that I think will enable me to make this

connection. The abstract is below, and the full paper is available from PubMed.

This paper discusses the presence of a disulfide bridge in the serotonin

N-acetyltransferase enzyme molecule. This enzyme catalyzes one of the steps in

the conversion of serotonin to melatonin, and this conversion is important in

controlling the sleep-wake cycle. Under reducing conditions, the disulfide

bridge does not form, and the enzyme can catalyze its reaction. Under oxidizing

conditions, when the disulfide bridge forms, the reaction is not catalyzed.

I suggest that if glutathione becomes depleted in the pineal gland, the

resulting oxidizing conditions will cause formation of this disulfide bond,

shutting off the conversion of serotonin to melatonin, and disrupting the

sleep-wake cycle.

If this is true, I think we can expect that if glutathione is brought back

up by lifting the partial methylation cycle block using one of the methylation

treatment protocols, the sleep-wake cycle abnormalities in ME/CFS should be

corrected. I note that some people who have tried this type of treatment have

indeed reported improvements in sleep.

Best regards,

Rich

J Biol Chem. 2002 Nov 15;277(46):44229-35. Epub 2002 Sep 4.

An intramolecular disulfide bridge as a catalytic switch for serotonin

N-acetyltransferase.

Tsuboi S, Kotani Y, Ogawa K, Hatanaka T, Yatsushiro S, Otsuka M, Moriyama Y.

Source

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama

University, Japan.

Abstract

Serotonin N-acetyltransferase (EC. 2.3.1.87) (AA-NAT) is a melatonin

rhythm-generating enzyme in pineal glands. To establish a melatonin rhythm,

AA-NAT activity is precisely regulated through several signaling pathways. Here

we show novel regulation of AA-NAT activity, in which an intramolecular

disulfide bond may function as a switch for the catalysis. Recombinant AA-NAT

activity was irreversibly inhibited by N-ethylmaleimide (NEM) in an

acetyl-CoA-protected manner. Oxidized glutathione or dissolved oxygen reversibly

inhibited AA-NAT in an acetyl-CoA-protected manner. To identify the cysteine

residues responsible for the inhibition, AA-NAT was first oxidized with

dissolved oxygen, treated with NEM, reduced with dithiothreitol, and then

labeled with [(14)C]NEM. Cys(61) and Cys(177) were specifically labeled in an

acetyl-CoA-protected manner. The AA-NAT with the Cys(61) to Ala and Cys(177) to

Ala double substitutions (C61A/C177A-AA-NAT) was fully active but did not

exhibit sensitivity to either oxidation or NEM, whereas the AA-NATs with only

the single substitutions retained about 40% of these sensitivities. An

intramolecular disulfide bond between Cys(61) and Cys(177) formed upon oxidation

and cleaved upon reduction was identified. Furthermore, C61A/C177A-AA-NAT

expressed in COS7 cells was relatively insensitive to H(2)O(2)-evoked oxidative

stress, whereas wild-type AA-NAT was strongly inhibited under the same

conditions. These results indicate that the formation and cleavage of the

disulfide bond between Cys(61) and Cys(177) produce the active and inactive

states of AA-NAT. It is possible that intracellular redox conditions regulate

AA-NAT activity through switching via an intramolecular disulfide bridge.

PMID:

12215431

August 10, 2011

Thanks Rich, for all your do for us!!!

God Bless,

Sara

>

> Posts

> 1,314

>

> Default Glutathione depletion and disruption of the sleep-wake cycle in ME/CFS

>

> Hi, all.

>

> As many of you know, I am the proponent of the Glutathione

Depletion--Methylation Cycle Block hypothesis for the pathogenesis and

pathophysiology of ME/CFS.

>

> If glutathione depletion coupled with a partial block in the methylation

cycle is indeed the core mechanism in the pathophysiology of ME/CFS, then the

various abnormalities in ME/CFS must stem from it. In the past, I have been able

to find biochemical connections between this basic mechanism and many of the

abnormalities in ME/CFS.

>

> One feature of ME/CFS that I have not yet connected to this mechanism is

the disruption in the sleep-wake cycle that many PWMEs experience.

>

> Recently I came upon a paper that I think will enable me to make this

connection. The abstract is below, and the full paper is available from PubMed.

>

> This paper discusses the presence of a disulfide bridge in the serotonin

N-acetyltransferase enzyme molecule. This enzyme catalyzes one of the steps in

the conversion of serotonin to melatonin, and this conversion is important in

controlling the sleep-wake cycle. Under reducing conditions, the disulfide

bridge does not form, and the enzyme can catalyze its reaction. Under oxidizing

conditions, when the disulfide bridge forms, the reaction is not catalyzed.

>

> I suggest that if glutathione becomes depleted in the pineal gland, the

resulting oxidizing conditions will cause formation of this disulfide bond,

shutting off the conversion of serotonin to melatonin, and disrupting the

sleep-wake cycle.

>

> If this is true, I think we can expect that if glutathione is brought back

up by lifting the partial methylation cycle block using one of the methylation

treatment protocols, the sleep-wake cycle abnormalities in ME/CFS should be

corrected. I note that some people who have tried this type of treatment have

indeed reported improvements in sleep.

>

> Best regards,

>

> Rich

>

> J Biol Chem. 2002 Nov 15;277(46):44229-35. Epub 2002 Sep 4.

>

> An intramolecular disulfide bridge as a catalytic switch for serotonin

N-acetyltransferase.

>

> Tsuboi S, Kotani Y, Ogawa K, Hatanaka T, Yatsushiro S, Otsuka M, Moriyama

Y.

> Source

>

> Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama

University, Japan.

> Abstract

>

> Serotonin N-acetyltransferase (EC. 2.3.1.87) (AA-NAT) is a melatonin