Autism and the transsulfuration pathway


Dysregulation of the transsulfuration pathway has been implicated in autism with research showing homocysteine and and oxidized glutathione levels were significantly higher in children diagnosed with autism spectrum disorders while cysteine levels, total glutathione and glutathione were remarkably lower in childiren with autism spectrum disorder compared to control subjects. Homocysteine levels levels correlated significantly with increasing Childhood Autism Rating Scale scores.

Taurine is synthesized from l-cysteine. Taurine is involved in calcium homeostasis. Taurine levels in autistic children were lower than than in controls. There may be low taurine levels only in a subset of indivduals with autism. Not all studies show taurine levels are low in autism.

Research points to intracellular calcium homeostasis being dysregulated in autism. Genes for various sub-units of proteins that act as calcium channels are associated with autism. In autism dysregulation of the transsulfuration pathway could dysregulate taurine synthesis which could dysregulate calcium homeostasis.

Whatever the answer is increasing levels of L-cysteine through supplementing with L-cysteine containing amino acids is not the answer. L-cysteine containing amino acids can be very toxic.

Bipolar disorder and bone mineral density

There are decreases in bone mineral density in drug naive individuals with bipolar disorder compared to age- and gender-matched healthy controls. Individuals with bipolar I disorder have have high homocysteine levels. High homocysteine levels in individuals with bipolar disorder point to the transsulfuration pathway being dysregulated. Via the transsulfuration pathway L-cysteine is synthesized from homocysteine. L-taurine is synthesized from L-cysteine.

Taurine is required for calcium homeostasis. Taurine, also, is conjugated to various bile acids. Bile acids are are required for absorption of fat-soluble vitamins. Vitamin D and vitamin K are fat-soluble vitamins. Individuals with bipolar disorder are 4.7 times more likely to be vitamin D deficient than individuals amongst the general population of the Netherlands, however, deficient levels of vitamin D are not specific to bipolar disorder but are also present in individuals with schizophrenia. The taurine transporter is present in osteoblasts. Osteoblasts synthesize bone.

With taurine metabolism dysregulated calcium homeostasis is dysregulated and absorption of vitamin D and vitamin K is decreased. Decreases in bone mineral density in bipolar disorder could be due to dysregulation of the transsulfuration pathway which dysregulates calcium homeostasis and vitamin D and vitamin K absorption resulting in low bone mineral density.

Homocystinuria due to cystathionine beta-synthase mutations

cystathionine beta-synthase

Mutations in cystathionine beta-sythase (CBS) can result in homocystinuria, which is very high levels of homocysteine. Severe illnesses can occur where there are mutations in CBS.

Lowering homocysteine levels is now the main focus of treatment where there are mutations in CBS with very high homocysteine levels. However, many of the difficulties associated with mutations in CBS could be due to dysregulations in pathways downstream from the transsulfuration pathway.

The treatment presented on the Treatmemt Page could be tested on rats with CBS mutations that result in very high levels of homocsyteine. Along with treatments to lower homocysteine levels treatments to address dysregulations in pathways downstream of the transsulfuration pathway could be of terrific assistance to individuals with mutations in CBS with very high homocysteine levels.

Se-methylselenocysteine and cancer

Selenium compounds as establishd by in vitro and in vivo experimental models show than that selenium is an effective anticancer agent. Clinical trials, however, have not shown that selenium supplementation in humans is an effective way to prevent cancer.

The transsulfuration pathway metabolizes L-selenomethionine which is the food form of selenium. L-selenomethionine is stored in the body through replacing L-methionine in proteins. Selenium not exiting L- selenomethionine can explain why selenium supplemenation, heretofore, has not been an effective way to prevent cancer in humans.

Tte transsulfuration pathway metabolizes homocysteine. High homocsyteine levels point to the transsulfurtation pathway being dsyregulated. High homocysteine levels are associated with cancer. High homocysteine levels in cancer would then point to the transsulfuration pathway being dysregulated in cancer. With the transsulfuration pathway dysregulated in cancer L-selenomethionine is not metabolized. As L-selenomethione is not metabolized selenium supplementation in the form of L-selenomethionine is not an effective way to prevent cancer in humans.

Se-methylselenocysteine is a very effective anti-cancer agent. Se-methylselenocysteine is a form of selenium that is not metabolized via the transsulfuration pathway but rather is metabolized by kynurenine aminotransferase, which is not an enzyme in the transsulfuration pathway, so formation of selenoproteins from Se-methylselenocysteine is not stopped by dysregulation of the transsulfuration pathway. Se-methylselenocysteine could be an effective anti-cancer agent in experimental models and also in humans.

Choosing an appropriate dosing scheduls is a key to effective selenium supplementation. Supranutrional selenium can increase activity of thioredoxin reductase. There is an end of dosarge effect with selenium apparently due to declines, during the day, in activity of thioredoxin reductase. For the prevention of cancer 100 micrograms of Se-methylselenocysteine taken twice a day would be a more effective selenium supplmentation schedule than 200 micrograms of of selenium from Se-methylselenocysteine taken once a day.

Regulation of iron metabolism by the transsulfuration pathway

top – ACO1; bottom – iron regulatory protein 1 bound to an mRNA

Iron metabolism is regulated by hepicidin, ferroportin and iron regulatory proteins. Aconitase 1 (ACO1) is a dual function protein that serves as an aconitase, which is an enzyme in the TCA cycle, when ACO1 has a 4Fe-4S iron sulfur cluster and as iron regulatory protein 1 when ACO1 looses a 4Fe-4S cluster. The sulfur for iron-sulfur clusters is derived from L-cysteine.

L-cysteine is synthesized from homocyteine via the transsulfuration pathway. Dysregulation of the transsufuration pathway by dysregulating L-cysteine synthesis could dysregulate iron-sulfur cluster formation thereby dyseregulating iron regulatory protein 1 and iron homestasis.

High homocysteine levels are present in a lot of illnesses, for example, schizophrenia, Parkinson’s disease, Alzheimer’s disease and bipolar disorder. A key part of the difficulties that arise from high homocysteine levels could be due to dysregulation of iron homeostasis.

The cerebellum and schizophrenia

The cerebellum sits at the bottom back of the brain. A meta-analysis indicates there are structural and functional abnormalties in the cerebellum in schizophrenia.

Intraellular calcium homeostasis is regulated by taurine. Taurine is synthesized from L-cysteine wihch is synthesized from homocsysteine via the transsulfuration pathway.

Hidden oosteomalacia due to dysregulation of intracellular calcium homeostasis arising from low levels of taurine stemming from dysregulation of the transsulfuration pathway .could be wide spread. In individuals with schizohpenia there could be hidden osteomalacia that do not show as back pain but could affect necks compressing cerebellums leading to severe psychological effects. Calcium blood levels could be low normal or slightly low.

Some x-ray studies of bones is the neck region are called for in schizophrenia. If cerebellums are being compressed by a hidden osteomalacia treatmens for a range of psychological symptoms in schizophrenia could be much, much different. Taurine, vitamin D, vitamin K and calcium carbonate could treat the hidden osteomalicia addressing structural and functional brain abnormalties in schizophrenia. Bone mineral densities are lower in older indivduals with schizophrenia compared to indivduals without schizophrenia. Early diagnosis would be a key.

With cerebellums compressed there could negative symptoms of schizohrenia. Negative symptoms are are deficit symptoms where such deficits could be due to deficits in the ability of the cerebellum to function due to being compressed from hidden osteomalacia.

Homocysteine and epigenetics

High levels of homocysteine are associated with increased risks for a number of illnesses. Hyperhomocysteinemia is a risk factor far osteoporosis, Alzheimer’s disease, Parkinson’s disease, stroke, cardiovascular disease, cancer, aortic aneurysm, hypothyroidism and end renal stage disease among other illnesses. I would add schizophrenia and bipolar disorder.

I have been arguing that high homocysteine levels point to the transsulfuration pathway being dysregulated. That there are so many illnesses associated with high homocysteine combined with the ineffectiveness of folic acid in reducing risk ratios for various illnesses point to high homocysteine levels being a proxy for other dysregulated biological processes. I have been arguing than high homocysteine levels are associated with increased risks for epigenetic dysregulations.

Folic acid supplementation, which reduces homocysteine levels, does not decrease risk ratios for the various illnesses that high homocysteine levels are associated with, for example, cardiovascular illnesses. Folic acid is ineffective as homocysteine must be metabolized through the transsulfuration pathway. Increasing remethylation of homocysteine to L-methionine does not fix the transsulfuration pathway leaving folic acid ineffective in decreasing risk ratios for various illnesses. Very unfortunately increasing levels of L-cysteine through supplementation with N-acetyl-L-cysteine, cysteine, cystine or lipoic acid also does not work where such supplementation can be very dangerous.

Polyphenols, homocysteine, Parkinson’s disease and Alzheimer’s disease

High homocysteine levels indicate the transsulfuration pathway (homocysteine to L-cysteine) is dysregulated. Taurine is synthesized from L-cysteine. Taurine is needed to form various bile acids. Bile acids are needed for fat absorption.

Polyphenols can increase beta-oxidation which can lead to serious difficulties if there are difficulties in fat absorption which are likely if there are high homocysteine levels.

Many illnesses for which polyphenols have been postulated to be treatments are associated with high levels of homocysteine, however, where there are high homocysteine levels there could be difficulties in fatty acid absorption. Increasing levels of polyphenols, which increase beta-oxidation, would be contradicted where there are difficulties in fatty acid absorption and metabolism.

Polyphenol supplements are frequently suggested as treatments for Alzheimer’s disease and Parkinson’s disease, however, both Alzheimer’s disease and Parkinson’s disease are associated with high homocyteine levels whereby there could be difficulties in fatty acid absoption. Polyphenol supplements could worsen Alzheimer’s disease and Parkinson’s disease. In the treatment of Alzheimer’s disease polyphenols have been full of promise but have failed to deliver effective treatments.

Caffeine pills have nowhere near the same effect as coffee. There must be more to the effects of coffee than caffeine and that something more is the polyphenol contents of coffee and the effect of those polyphenols on beta-oxidation.