Human farnesyl pyrophosphate synthase is allosterically inhibited by its own product

Abstract

Farnesyl pyrophosphate synthase (FPPS) is an enzyme of the mevalonate pathway and a well-established therapeutic target. Recent research has focused around a newly identified druggable pocket near the enzyme's active site. Pharmacological exploitation of this pocket is deemed promising; however, its natural biological function, if any, is yet unknown. Here we report that the product of FPPS, farnesyl pyrophosphate (FPP), can bind to this pocket and lock the enzyme in an inactive state. The Kd for this binding is 5–6 μM, within a catalytically relevant range. These results indicate that FPPS activity is sensitive to the product concentration. Kinetic analysis shows that the enzyme is inhibited through FPP accumulation. Having a specific physiological effector, FPPS is a bona fide allosteric enzyme. This allostery offers an exquisite mechanism for controlling prenyl pyrophosphate levels in vivo and thus contributes an additional layer of regulation to the mevalonate pathway.

Crystallographic and thermodynamic characterization of phenylaminopyridine bisphosphonates binding to human farnesyl pyrophosphate synthase

“…The binding is entropically driven, with a positive, unfavorable enthalpy change ( T Δ S >Δ H , Table 3 ). This is in sharp contrast to that seen with the substrates DMAPP and GPP, the binding of which at the same site is exothermic and enthalpically driven [ 23 ]. The differences in the enthalpy of binding between the individual bisphosphonates well explain the protein-ligand interactions confirmed crystallographically.…”

High manganese exposure decreased the risk of high triglycerides in male workers: a cross-sectional study

“…Furthermore, another mechanism by which Mn may be involved in lipids metabolism was the process involved in lipids synthesis [12][13][14][15]. In summary, previous studies may suggest that Mn plays an important role in the mechanism of lipids.…”

QSAR Models for Nitrogen Containing Monophosphonate and Bisphosphonate Derivatives as Human Farnesyl Pyrophosphate Synthase Inhibitors Based on Monte Carlo Method

“…The result of table 6S (supplementary information) clearly shows that the bisphosphonates developed as hFPPS inhibitors are more potent inhibitors than monophosphonates. It has been reported in literature [1,3,[7][8][9][10][11][12] that the interactions of the bisphosphonates in the active site of the HFFPS are highly conditioned by the protonation state of the functional groups but the method used in this work does not consider this aspect. It is a limitation of this work.…”

“…Recently, J. Park et al [12] discovered the biological importance of the allosteric pocket, near the IPP substrate binding site of the hFPPS active site, and exhibited that FPP product can bind to this allosteric pocket. This binding sealed the enzyme in an inactive conformation and therefore, suppling a feedback mechanism for regulating the intra-cellular levels of isoprenoid biosynthesis in vivo.…”