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I found a case report in which the authors say that Terbinafine might have possibly affected the methylation cycle in a patient, necessitating the prescription of 5-methylfolate to correct the imbalance. I tried googling to find some description that would include the interaction of ergosterol synthesis and methylation cycle, and found nothing.

Maybe I was not googling the right words.

I can't seem to find how exactly we can affect the methylation cycle by affecting squalene epoxidase (the target of terbinafine, the drug used by the patient in the case report).

The article quoted is titled Antifolates and MTHFR (Trachtman and Pagano, 2015)

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  • $\begingroup$ This might be a better fit in Biology. $\endgroup$ – Carey Gregory Feb 7 at 21:43
  • $\begingroup$ @CareyGregory - feel free to move the question to Biology, I wouldn't mind )) $\endgroup$ – CopperKettle Feb 8 at 6:15
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Preamble

I have tried to follow the logic of the rationalization of the clinical case described in the report of Trachtman and Pagano, but have failed. I suspect from the quality of their biochemical illustration (arrows leading from compounds to enzymes, and talk about ends of cycles) that they do not have a clear idea themselves. However, having done the literature search, let me set out the picture as I see it, in the hope that this may enable someone else to see a connection I may have missed.

Anti-fungals inhibit the erosterol biosynthesis pathway in fungi

As the poster states, anti-fungals such as terbinafine do act by inhibiting the synthesis of ergosterol, which is a cell-membrane steroid, unique to yeast. Of relevance to this analysis, there is a methylation reaction in this pathway, that lies after the target of terbinafine, squalene epoxidase:

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Methylation step in ergosterol synthesis (from Uniprot)

Inhibition of ergosterol synthesis can affect S-adenosyl methionine in yeast

The only experiments that I can find linking ergosterol synthesis with the methylation cycle in yeast do not involve anti-fungals. Rather, they involve yeast with mutations in the genes encoding enzymes of ergosterol synthesis. In a study performed by Shobayashi et al. (2006), mutants of the gene, Erg6, encoding the methyltransferase, resulted in the accumulation of S-adenosyl methionione (SAM). Clearly there are other methylation reactions in the cell which utilize SAM, but this suggests that the ergosterol synthesis pathway is so active in yeast that its disruption affects the concentrations of intermediates of the methylation cycle.

What is the relevance of this to methylation in humans?

Although the situation described above confirms a connection between the methylation cycle and ergosterol intermediates in yeast, as mentioned in the original clinical report, it is difficult to see how it relates to human metabolism. This is because, although squalene epoxidase does exist in man, the ergosterol synthesis pathway and the methylation step catalysed by the methyltransferase (the erg6 gene product) do not. In any case, inhibition of a methylation step would result in an increase in SAM, whereas just the opposite appears to be the case in the patient.

Final observations

The clinical report is of one patient with a mutation (MTHFR) in the methylene tetrahydrofolate reductase gene, which would reduce his ability to regenerate the methionine and S-adenosyl methionine needed for methylation. L-methylfolate greatly reduced his symptoms. Nevertheless, this report is for a single patient, whereas “The gene mutation known as the MTHFR affects approximately 45% of the US population”. If MTHFR were the only factor involved in this case one would expect other reports of adverse reaction to terbinafine. In the apparent absence of such reports one suspects that in this patient the affect of terbinafine — whatever it may be — involves some other, yet undiscovered metabolic interaction.

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