Friday, August 15, 2008

Mindgames with SAM-analogs

I keep on wondering what different S-adenosylmethionine analogs would do to the cellular metabolism and if such molecules might prove useful for investigating experimental leishmaniasis. Obviously, these molecules are likely to be toxic to the host as well as the parasite, but perhaps there might be a way to limit their exposure to macrophages, targeting amstigotes, and thereby reducing the expected undersired side effects to a minimum.

Compared to S-adenosylmethionine:

The following molecule would not be expected to act as a substrate in methylation (of DNA, rRNA, mRNA caps, tRNA, proteins, and phospholipids) or the transfer of propylamine, but not interfere with putrescine synthesis directly as sinefungin might:

This one could be able to catalyse the formation of spermidine and spermine, but lead to ethylation instead of methylation:

Whilst this molecule, if accepted by the respective enzymes as a substrate, could only be used for the transfer of propylamine but not for methylation/ethylation:

On the other hand, the following molecule would only act as a substrate for methylation and not for polyamine synthesis:

Whilst tubericidin is a SAM-analog that has been shown to affect L. donovani promastigotes but treatment has also led to tubericidin-resistant strains emerging:

In addition, attention should be paid to the stereoisomeric form of S-adenosylmethionine (AdoMet), the (Sc, Ss) isomer being the biologically active form, the (Sc, Rs) isomer being a potent inhibitor. (See review by Ronald Bentley).

Another idea that crossed my mind was whether methyl donor supplementation during pregnancy might render C57BL/6 or CBA mice more susceptible to leishmaniasis (similar to the results obtained for agouti mice regarding coat colour [Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003 Aug;23(15):5293-300.]).

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