Serendipity and drug discovery

Frequently scientists talk about the serendipitous finding that leads to important discoveries. In psychiatry serendipitous drug discoveries, however, may not advance understanding of psychiatric illnesses very much. Dopamine antagonists are useful in the treatment of schizophrenia but there has been no revolution in the understanding of schizophrenia resulting from the discovery that dopamine antagonists can partially treat schizophrenia. Lithium has uses but lithium has not revolutionized the understanding of bipolar disorder.

A lot of research seems directed at finding the hidden fact that will be the key to unraveling a disease. Researchers seem to be in search of serendipity which is not how serendipity works. Psychiatric research would better off if there was more emphasis on basic research with translational research then sticking closely to basic research. Succeeding at translational research may require that all the various factors that complicate a hypothesis be considered. The devil is the details. Possessing a sliver of truth is surer route to scientific discovery than searching for serendipity.

The basic idea that the transsulfuration pathway is dysregulated in schizophrenia is a simple idea but treatment is complicated by the fact that downstream pathways from the transsulfuration pathway have to be addressed. Treatment would be so much simpler if only lowering homocysteine levels worked or only increasing l-cysteine levels worked but neither do. There can be effective treatments for schizophrenia that address the fundamental biology of schizophrenia but there can be no simple effective treatments for schizophrenia that address the fundamental biology of schizophrenia.

Autism and the transsulfuration pathway

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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.

Huntington’s disease and pathways downstream from the transsulfuration pathway

Huntington’s disease is associated with dysregulation of the transsulfuration pathway. Research points to cystathionine gamma-lyase, the second enzyme in the transsulfuration pathway, as being profoundly depleted in Huntington’s disease. L-cysteine is synthesized via the transsulfuration pathway.

Huntington’s disease develops in later decades. By the time Huntington disease manifests dysregulations of the transsulfuration pathway could have resulted in epigenetic changes. See Treatment-resistant schizophrenia: focus on the transsulfuration pathway and A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway as to how dysregulation of the transsulfuration pathway could result in epigenetic changes. Pathways downstream of the transsulfuration pathway, for example, iron-sulfur cluster formation where sulfur for iron-sulfur cluster formation is derived from cysteine, seleonprotein synthesis where the transsulfuration pathway is required to metabolize selenomethionine which is the food form selenium, glutathione synthesis where cysteine is the rate limiting amino acid in glutathione synthesis and taurine synthesis where taurine is synthesized from L-cysteine could all be dysregulated due to the transsulfuration pathway being dysregulated.

Since mutation in genes that confer Huntington’s disease are present from birth but Huntington’s disease only develops in later decades manifestations of Huntington’s disease must be due to accumulated changes where such accumulated changes could be epigenetic changes attendant on dysregulations of cystathionine gamma-lyase. Supplementation of sulfur containing free form amino acids, except L-taurine, would not be of assistance in the treatment of Huntington’s disease both due to the toxicities of such supplements and due to pathways downstream of the transsulfuration pathway being dysregulated due to epigenetic changes attendant on dysregulations of the transsulfuration pathway.

Bone mineral density and negative symptoms of schizophrenia

A meta-analysis points to bone mineral density being significantly decreased in individuals with schizophrenia compared to healthy controls. Bone mineral density in schizophrenia could be decreased in individuals with schizophrenia due to dysregulation of the transsulfuration pathway. Taurine is synthesized from L-cysteine which is synthesized via the transsulfuration pathway.

Taurine is required for intracellular calcium homeostasis. Bile acids are required for absorption of fat soluble vitamins. Vitamin D and vitamin K are fat soluble vitamins involved in bone formation. Various bile acids are synthesized from taurine. With deficiencies of taurine calcium homeostasis can be upset and there can also be deficiencies of vitamin D and vitamin K which could lead to low bone mineral density in schizophrenia.

Low bone mineral density in schizophrenia point to there being hidden osteomalicias in schizophrenia. With taurine deficiencies intracellular calcium homeostasis can be upset, though extracellular calcium levels could be normal, leading to a hidden osteomalicias.

Dysregulation of the transsulfuration pathway can result in epigenetic changes whereby there could be localized osteomalacias. Given osteomalacias due to taurine deficiencies develop in the back of the head negative symptoms of schizophrenia could develop due to compressions of cerebellums. There are a wide range of symptoms in schizophrenia so individuals with schizophrenia do not present as only having back of the head pains which makes correct diagnoses difficult though x-ray studies of backs of skulls in individuals with symptoms of schizophrenia could go a long ways in making correct diagnoses straightforward.

Negative symptoms of schizophrenia could be treated by supplementation with taurine, Vitamin K2 MK-7, which a kind of vitamin K that is highly absorbed, and vitamin D3. As negative symptoms of schizophrenia are due to hidden osteomalicias taurine, vitamin K2 MK-7 could take a long while to be completely effective. To treat the range of symptoms seen is schizophrenia due to dysregulations of the transsulfuration pathway supplements, beyond supplements that treat hidden osteomalicias, are required.

Friedreich’s ataxia and tight iron utilization

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Friedreich’s ataxia is a genetic disease, where there are expansions of GAA trinucleotide repeats in intron 1 of both frataxin alleles. Gait and limb ataxia, dysarthria and loss of lower limb reflexes are clinical features Friedrich’s ataxia.

Mice models of Friedreich’s ataxia have been developed in which the gene for frataxin in is mutated, where the mice exhibit a progressive Friedreich’s ataxia-like pathology. Frataxin binds iron which assists in iron-sulfur cluster biogenesis.

Giving mice, with ataxia due to mutations in genes for frataxin, iron from iron carbonyl by gavage three times a day could be a treatment for such an ataxia as iron carbonyl given by gavage three times a day could tightly regulate iron utilization, making iron constantly available thereby making the frataxin protein less required or even redundant. As the iron chelator, desferal decreases expressiot of frataxin, carbonyl iron given by gavage three times a day to mice could also increase expression of the gene for frataxin.

As deferiprone, an iron chelator, can worsen ataxia in patients with Friedreich’s ataxia iron carbonyl given three times a day to humans could be part of a treatment for Friedreich’s ataxia. Prior to any clinical trials in humans, carbonyl iron, given by gavage three times a day from birth to mice with mutated frataxin genes, would have to stop a Friedreich’s ataxia-like pathology from developing and/or treat in mice, a Friedreich’s ataxia-like pathology after mice with mutated frataxin genes develope a Friedreich’s ataxia-like pathology.

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.

Measuring selenium in prostate cancer

There are conflcting reports about selenium levels in prostate cancer. Rearch indicates that there are reduced levels of selenoprotein P in prostate cancer. High levels of selenoprotein P are also associcated with low risk of high grade prostate cancer. Other research indicates that circulating selenium levels are high in advanced prostate cancer.

I have been arguing that in many illnesses that the transsulfuration pathway is dysregulated. Besides synthesizing L-cysteine from homocysteine the transsulfuration pathway also metabolizes L-selenomethionine which is the food form of selenium. L-selenomethionine is stored in the body via replacing methionine in proteins. If selenium never makes it out of selenomethionine there could be both high selenium levels and low selenoprotein levels. High levels of circulating selenium in advanced prostate cancer could paradoxcially indicate that there are selenoprotein deficiencies in prostate cancer which appears to be the case both for selenoprotein P and glutathione peroxidase. Glutathione peroxidase, another selenoprotein, is also reduced in prostate cancer.

Se-methylselenocysteine is a form of selenium that is not metabolized via the transsulfuration pathway so formation of selenoproteins from Se-methylselenocysteine would not be impeded by dysregulation of the transsulfuration pathyway. While supplemental selenomethionine apparently does not reduce the risk of prostate cancer supplemental Se-methylselenocysteine could reduce the risk of prostate cancer. The advantage of Se-methylselenocysteine as a cancer preventive could be exactly due to metabolism of Se-methylselenocysteine not depending on the transsulfuration pathway.