Abnormal protein folding and glutathione depletion

[Guest guest]

>

> > Glutathione(GSH) is essential to protein synthesis and the

> maintaining of heat shock protein tertiary structure(eg, R. Van

> Konynenburg 2004 AACFS Poster)

> >

Hi, and the group.

I think you're correct in connecting these new abnormal protein

folding research results with glutathione depletion, .

To summarize, as many of you know, a paper was published recently by

Jim Baraniuk, Dan Clauw et al that involved analyzing spinal fluid

for proteins in people with CFS, Gulf War illnesses, and

fibromyalgia. One of the main conclusions of the paper was that

there appears to be a problem with protein folding in these

disorders.

Protein folding involves the formation of disulfide bonds between

cysteine residues within the amino acid sequence that makes up the

protein. In order for protein folding to occur properly, it is

necessary to be able to control and to change the oxidation-

reduction (redox) status of the sulfur atoms in the cysteine

residues of the protein within the endoplasmic reticulum, the place

where proteins are synthesized inside cells. Because glutathione is

responsible for redox control in cells, it is intimately involved in

this process. If glutathione becomes depleted, I think it should be

expected that protein folding would not proceed normally.

I continue to be encouraged as new research results come out, since

they continue to be consistent with the glutathione depletion

hypothesis for CFS. Incidentally, some of you may remember that I

made the case for glutathione depletion in Gulf War Illnesses to the

Research Advisory Committee for Gulf War Veterans' Illnesses some

time ago, and I think that the presence of glutathione depletion in

all these disorders is what produces the protein folding problem in

all of them.

I'm beginning to think that the results of even more research

studies that haven't yet been done could be predicted by

scrupulously " following the glutathione. " Anything that glutathione

is supposed to do is likely not being done in people with these

disorders, and this approach should therefore predict the results of

a variety of studies in CFS.

Below is an abstract that discusses the role of glutathione (via

ascorbate or vitamin C) in controlling protein folding.

Rich

" Biofactors. 2003;17(1-4):37-46.

Role of ascorbate in oxidative protein folding.

Banhegyi G, Csala M, Szarka A, Varsanyi M, Benedetti A, Mandl J.

Department of Medical Chemistry, Molecular Biology and

Pathobiochemistry, Semmelweis University, Budapest, Hungary.

Both in prokaryotic and eukaryotic cells, disulfide bond formation

(oxidation and isomerization steps) are catalyzed exclusively in

extracytoplasmic compartments. In eukaryotes, protein folding and

disulfide bond formation are coupled processes that occur both co-

and posttranslationally in the endoplasmic reticulum (ER), which is

the main site of the synthesis and posttranslational modification of

secretory and membrane proteins. The formation of a disulfide bond

from the thiol groups of two cysteine residues requires the removal

of two electrons, consequently, these bonds cannot form

spontaneously; an oxidant is needed to accept the electrons. In

aerobic conditions the ultimate electron acceptor is usually oxygen;

however, oxygen itself is not effective in protein thiol oxidation.

Therefore, a small molecular weight membrane permeable compound

should be supposed for the transfer of electrons from the ER lumen.

The aim of the present study was the investigation of the role of

ascorbate/dehydroascorbate redox couple in oxidative folding of

proteins. We demonstrated that ascorbate addition or its in situ

synthesis from gulonolactone results in protein thiol (and/or

glutathione; GSH) oxidation in rat liver microsomes. Since

microsomal membrane is hardly permeable to ascorbate, the existence

of a transport metabolon was hypothesized. Three components of the

system have been described and partially characterized: (i) A

microsomal metalloenzyme is responsible for ascorbate oxidation on

the outer surface of the ER. Ascorbate oxidation results in

ascorbate free radical and dehydroascorbate production. (ii)

Facilitated diffusion of dehydroascorbate is present in microsomal

vesicles. The transport is presumably mediated by a GLUT-type

transporter. On the contrary, the previously hypothesized

glutathione disulfide (GSSG) transport is practically absent, while

GSH is transported with a moderate velocity. (iii) Protein disulfide

isomerase catalyzes the reduction of dehydroascorbate in the ER

lumen. Both GSH and protein thiols can be electron donors in the

process. Intraluminal dehydroascorbate reduction and the consequent

ascorbate accumulation strictly correlate with protein disulfide

isomerase activity and protein thiol concentration. The concerted

action of the three components of the system results in the

intraluminal accumulation of ascorbate, protein disulfide and GSSG.

In fact, intraluminal ascorbate and GSSG accumulation could be

observed upon dehydroascorbate and GSH uptake. In conclusion,

ascorbate is able to promote protein disulfide formation in an in

vitro system. Further work is needed to justify its role in intact

cellular and in vivo systems, as well as to explore the

participation of other antioxidants (e.g. tocopherol, ubiquinone,

and vitamin K) in the electron transfer chain responsible for

oxidative protein folding in the ER.

PMID: 12897427 [PubMed - indexed for MEDLINE]