Formation of ATP Derivatives of Intermediates in Cholesterol Biosynthesis: Potential Relevance to Energy Metabolism in the Brain, etc.

This article [Sillero et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19414000)] discuss the capacity of some bisphosphonates to inhibit farnesyl pyrophosphate synthetase, thereby inhibiting cholesterol biosynthesis and also the posttranslational prenylation of GTPases and other proteins. The authors also found that a variety of ligase enzymes, such as DNA ligases, apparently, cleave ATP and, as part of their catalytic mechanisms, attach the AMP derived from that cleavage to the ligase enzyme or to a cosubstrate, X (it's not clear what the cosubstrates are, and I don't feel like looking them up). This forms an E-X-AMP or E-AMP complex of AMP with the enzyme. Some of the ligase enzymes can then transfer the AMP to isopentenyl pyrophosphate (Iso-pp) or to a bisphosphonate and form Iso-pppAdenosine or "ATP derivatives" of bisphosphonates that may contribute to the induction of apoptosis in osteoclasts or monocyte-macrophage lineage cells, including osteoclast progenitor cells. One mechanism by which these ATP derivatives are thought to cause apoptosis is through the inhibition of the mitochondrial adenine nucleotide translocase transporter. Faust et al. (1980) [Faust et al., 1980: (http://www.jbc.org/cgi/reprint/255/14/6546.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/7391033)] found that aminoacyl-tRNA synthetases could form delta2-isopentenyl-tRNA, and those tRNAs are similar to the ATP derivatives, discussed above, in the sense that the isopentenyl group is transfered to the N6 nitrogen atom of an adenosine that is part of the tRNA. Faust et al. (1980) claim that, when cholesterol levels are low in some cells, more mevalonate is diverted into cholesterol formation than into ubiquinone and isopentenyl derivatives (isopentenyladenosine is one commonly-discussed derivative, and I'm actually forgetting if that's the same thing as Iso-pppAdenosine or is different from that). I don't know that that's true, because supposedly the ubiquinone pathway, at least, is maintained very efficiently under almost all circumstances, as I recall. It's only when HMG-CoA reductase activity has become greatly decreased that ubiquinone formation decreases, as I remember. But Faust et al. (1980) nonetheless show that inhibiting HMG-CoA reductase can decrease mevalonate levels, as is well-known, and thereby reduce the formation of some of these endogenous isopentenyl-adenosine derivatives (either free Iso- derived species or tRNA-bound derivatives, etc.).

This could be relevant to the roles that decreases in the neuronal or astrocytic cholesterol contents may play in the etiologies of neurodegenerative or psychiatric conditions, in my view. If the cellular cholesterol concentration that is capable of influencing HMG-CoA reductase activity in a cell in the brain were to be too low to maintain low levels of these nucleotide derivatives of isoprenoids, it's conceivable that that could, in some way, influence energy metabolism. The isopentenyl adenosine derivatives might interfere with nucleotide transport or contribute to DNA damage, etc. I haven't thought about the details of this, but Sillero et al. (2009) discuss the very large capacity of the mevalonate-derived isoprenoids and other cholesterol-biosynthetic intermediates to sequester pyrophosphate, and that could compromise adenosine nucleotide salvage. Fructose, for example, can cause ATP depletion in the liver by sequestering phosphate in one of the fructose bisphosphates (I forget which one), etc. These are fairly crude suggestions, but it's an interesting area of research.