Fatty acid synthesis and metabolism and negative symptoms

In previous posts I held that biotin and pantothenic are helpful in the treatment of negative symptoms of schizophrenia and the two supplements are. I have not, however, stressed the role biotin and coenzyme A, which is synthesized from pantothenic acid, play in the synthesis and metabolism of non-essential fatty acids. Fatty acid synthesis and fatty acid metabolism require coenzyme A and biotin. Acetyl-CoA carboxylase catalyzes the rate limiting step in the synthesis of fatty acids. Acetyl-CoA carboxylase requires CoA and biotin.

Biotin and pantothenic acid work a lot better for negative symptom of schizophrenia if intake of animal fats is increased concurrently. Low levels of biotin would adversely affect the synthesis and metabolism of non-essential fatty acids. Fatty acids derived from essential fatty acids would not be affected by low levels of biotin.

In terms of what non-essential fatty acids to supplement with animal fatty acids are basically the only route to go. Non-essential fatty acids from plants will have high levels of polyphenols and the mix of non-essential fatty acids from meat is a better non-essential fatty acid mix than can be obtained from various plants.

I have heavily stressed adverse affects of polyphenols. I have focused on decreases in iron absorption that can result from polyphenols. Polyphenols, however, can also increase beta-oxidation. Increasing beta-oxidation results in huge difficulties if there are difficulties in fatty acid synthesis and metabolism. Individuals who have difficulties synthesizing and metabolizing non-essential fatty acids will be adversely affected by high intakes of polyphenols.

Intakes of animal fatty acids must be increased for full effectiveness of biotin and pantothenic acid in the treatment of the negative symptoms of schizophrenia. See the Treatment page on what more would be required.

Recommendations against saturated fats by the American Heart Association could have had disastrous effects on the mental and neurological health of tens of millions of individuals. There is the likelihood that Warren Buffett would be a poor unhappy man now if he had followed the dietary recommendations of the American Heart Association.

Coenzyme A as a supplement

Coenzyme A could be a very useful supplement. Pantothenic acid is supplemented to increase coenzyme A levels. Supplementing with coenzyme A would directly increase coenzyme A levels. There are supplements labeled as coenzyme A that do not contain any coenzyme A.  For example  Coenyzme-A Technologies has a supplement labeled as Pure Coenzyme A that contains no coenzyme A where the actual ingredients of the product are ingredients that should not be supplemented.   Apparently there are no supplements on the market that contain coenzyme A.  There may be a reason why coenzyme A is not sold as a supplement but I have seen medical journal articles where coenzyme A was prescribed for patients. Coenzyme A should not be confused with coenzyme Q10 or with vitamin A.

Sulbutiamine  and biotin would still have to be supplemented even given coenzyme A were supplemented.

Pantothenic acid and acetylcholine in Alzheimer’s disease

Synthesis of acetylcholine requires acetyl-coenzyme A which donates an acetyl group to choline. With dysregulation of the transsulfuration pathway in Alzheimer’s disease, marked by high levels of homocysteine,  L-cysteine is not synthesized at sufficient levels. See my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway. With low levels of l-cysteine coenzyme A, which is synthesized from pantothenic acid and which requires l-cysteine for synthesis, is not synthesized at appropriate levels. With low levels of coenzyme A the E2 subunit of the pyruvate dehydrogenase complex is underactive. Acetyl-coenzyme A required for the synthesis of acetylcholine is derived from the pyruvate dehydrogenase complex. Dysregulation of the pyruvate dehydrogenase complex could lead to shortages of acetylcholine in Alzheimer’s disease. Shortages of acetylcholine are a hallmark of Alzheimer’s disease. Supplementation with pantothenic acid and sulbutiamine, a fat-soluble thiamine derivative, could improve symptoms of Alzheimer’s disease due to acetylcholine deficiencies such as poor  memory.  There is a lot askew in Alzheimer’s disease so supplementation with  pantothenic acid and sulbutiamine would only be partly effective in Alzheimer’s disease. As always various supplements must be avoided. See the Treatment page on what supplements to avoid.

Pantothenic acid and iron-sulfur cluster formation

Supplemental pantothenic acid increases levels of fatty acid synthase and the acyl carrier protein. Pantothenic acid donates a 4′-phosphopantetheine moiety to the acyl carrier protein. The mitochondrial acyl carrier protein (ACP) of fatty acid synthase is required for iron-sulfur cluster biogenesis.

Supplemental pantothenic acid is then of assistance both in increasing activity of the citric acid cycle and of assistance in increasing iron-sulfur cluster biogenesis.

Treating the negative symptoms of schizophrenia

The negative symptoms of schizophrenia are at least partly due to a shortage of coenzyme A which is used by the E2 unit of the 2-oxoglutarate dehydrogenase complex and the E2 unit of the pyruvate dehydrogenase complex in the citric acid cycle. What is needed is to increase levels of coenzyme A which can be done by supplemental pantothenic acid.

Why are coenzyme A levels low in schizophrenia? L-cysteine is required to synthesize coenzyme A. Due dysregulation of the transsulfuration pathway in schizophrenia, as explained in my paper Treatment-resistant schizophrenia: focus on the transsulfuration pathway, intracellular levels of L-cysteine can be low in schizophrenia which will decrease synthesis of coenzyme A.

Supplementation with L-carnitine from carnitine tartrate is needed as L-carnitine reverses the inhibition of pantothenic kinase by coenzyme A and acetyl-coenzyme A. Pantothenic kinase is the rate-limiting enzyme in coenzyme A synthesis. Supplementation with acetyl-l-carnitine is avoided as palmitonylcarnitine , which is what actually reverses the inhibition of pantothenic kinase, is synthesized from L-carnitine not acetyl-L-carnitine. For reasons I will not go into here the L-carnitine must be L-carnitine from L-carnitine tartrate. L-carnitine fumarate must be avoided.

Supplementation with sulbutiamine will also be helpful in the treatment of the negative symptoms of schizophrenia. Sulbutiamine is a fat-soluble form of thiamine which can greatly increase thiamine diphosphate levels . Thiamine diphoshpate is used by the E1 unit of the 2-oxogularate dehydrogenase complex and the E1 subunit of the pyruvate dehydrogenase complex.

Supplementation with sublingual biotin would be useful. The sodium-dependent multivitamin transporter (SMVT) transports pantothenic acid, biotin and lipoate. Biotinyalition of histones associated with with the sodium-dependent multivitamin transporter silences transcription of the sodium-dependent multivitamin transporter gene. High dosages of pantothenic acid could competitively biotin transport in the gut but this would be avoided with sublingual biotin. Very surprisingly coenzyme Q10 must be taken when biotin is supplemented. Biotin apparently can have a large effect on the TCA cycle. If the TCA cycle hangs up at the succinate dehydrogenase step supplemental biotin is not of assistance.

Acetyl-coenzyme A can be synthesized from fatty acids. EPA + DHA where EPA makes up 65 to 70% of the EPA + DHA combination will be helpful. A EPA + DHA combination has been extensively studied and has good safety profile.

Supplemental coenzyme Q10 is also required. Succinate dehydrogenase which is an iron-sulfur protein in the citric acid cycle, requires coenzyme Q10. Biotin is not useful without coenzyme Q10. If the citric acid cycle gets hung up at the succinate dehydrogenase step biotin is not helpful.

Activities of the E3 subunits of the pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex, which have NAD+ as substrates, unstimulated by supplements are  completely acceptable as is.

If niacin, niacin derivatives,  riboflavin and/or lipoic acid are supplemented pantothenic acid and thiamine will not work against the negative symptoms of schizophrenia.  A B-50 supplement is a terrible supplement. What not to supplement with is as important as what to supplement with.  Lipoic acid increases l-cysteine levels by reducing cystine to L-cysteine but cystine must be present to enter cells by way of the cystine/glutamate antiporter. Once in cells cystine is rapidly reduced to L-cysteine.  In any case lipoic acid is synthesized on lysine residues of proteins so supplemental lipoic acid would not boost activities of the  E2 subunit of the pyruvate dehydrogenase complex and E2 subunit of the 2-oxoglutarate complex. Do not supplement with pantethine. Pantethine depletes cystine.

The supplements must be taken with food. Taking the supplements with food makes a huge difference.

Can pantothenic acid, sulbutiamine, sublingual biotin, EPA + DHA, coenzyme Q10 and l-carnitine be effective against  the negative symptoms of schizophrenia when taken alone? I don’t know. Minimally, to be avoided supplements as listed on the Treatment page should be avoided.