Phosphonate inhibitors of human mevalonate kinase

Saman Salari
MSc Student
Department of Biochemistry

Date: March 6, 2023
Time: 1:00 p.m. to 2:00 p.m. 
Room: CSF 1302

The mevalonate (MVA) pathway is a fundamental metabolic pathway for isoprenoid synthesis in the cell. Mevalonate kinase (MK) is an enzyme within this pathway that converts mevalonic acid to mevalonate-5-phosphate, using ATP as a phosphoryl donor. A mutation in the gene encoding MK causes mevalonate kinase deficiency, affecting the immune system. In a previous study, farnesyl pyrophosphate (FPP), a downstream metabolite of MVA pathway, was shown to inhibit human MK (hMK). Crystallographic analysis indicated that FPP inhibits the enzyme by blocking its ATP binding site. Interestingly, FPP is also involved in the feedback inhibition of farnesyl pyrophosphate synthase (FPPS), the enzyme responsible for producing FPP. This provides evidence for multilayered regulation of the MVA pathway, where the single feedback inhibitor targets multiple enzymatic steps. In the current study, we aim to investigate the regulation of hMK further. Our hypothesis is that the phosphonate analogs of FPP that can inhibit FPPS will also inhibit hMK. To test this hypothesis, I have expressed and purified a recombinant form of hMK and established an in vitro assay protocol. Upon examining the effect of potential inhibitors on hMK activity, I have found a few compounds with nanomolar inhibitory potency. The details of the molecular interaction between hMK and these inhibitors will subsequently be investigated. These inhibitors may prove useful as a molecular tool for future research, for example, in assessing hMK as a new therapeutic target.