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Farnesyl pyrophosphate synthase Farnesyl pyrophosphate synthase Geranylgeranyl pyrophosphate synthase HMG-CoA reductase Mevalonate kinase Phosphomevalonate kinase Squalene synthase Diphosphomevalonate decarboxylase Hydroxymethylglutaryl- CoA synthase, cytoplasmic Acetyl-CoA acetyltransferase, mitochondrial Pamidronate Pamidronate Pamidronate Pamidronate Pamidronate 3-Hydroxy-3-methylglutaryl-CoA NADPH H+ NADP CoA Mevalonate ATP Mevalonate-5P ADP ATP Mevalonate-5PP ADP Isopentenyl-PP Dimethylallylpyrophosphate PPi Geranyl-PP Isopentenyl pyrophosphate Farnesyl pyrophosphate PPi H+ NADPH PPi NADP Squalene Cholesterol ATP ADP Pi CO2 Isopentenyl pyrophosphate Geranylgeranyl-PP PPi Acetyl-CoA H2O Acetoacetyl-CoA CoA CoA Magnesium Magnesium Magnesium Magnesium Osteoclast Cytosol Pamidronate enters the cell through endocytosis. The endocytic vesicles are acidified and the pamidronate is released into the cytosol. Pamidronate inhibit farnesyl pyrophosphate synthase and geranylgeranyl pyrophosphate synthaseby binding in it's active site. Reduced production of farnesyl-PP, geranylgernayl-PP and other sterols which are essential for anchoring cell surface protein via prenylation, and are necessary for osteoclast function and survival. Low concentrations of these lipids prevents osteoclast attachment to the bone, thereby inducing apoptosis of the osteoclast, reducing osteoclast activity and bone resorption. Mevalonate Pathway Bone Loss Pamidronate is administered intravenously and travels to the bone Pamidronate acts to counteract osteoclast activity and reduce bone degradation
FDPS FDPS GGPS1 HMGCLL1 MVK PMVK FDFT1 MVD HMGCS1 ACAT1 Pamidronate Pamidronate Pamidronate Pamidronate Pamidronate 3-Hydroxy-3- methylglutaryl- CoA NADPH Hydrogen Ion NADP Coenzyme A Mevalonate Adenosine triphosphate Mevalonate-5P Adenosine diphosphate Adenosine triphosphate Mevalonate-5PP Adenosine diphosphate Isopentenyl-PP Dimethylallylpyrophosphate Pyrophosphate Geranyl-PP Isopentenyl pyrophosphate Farnesyl pyrophosphate Pyrophosphate Hydrogen Ion NADPH Pyrophosphate NADP Squalene Cholesterol Adenosine triphosphate Adenosine diphosphate Phosphate Carbon dioxide Isopentenyl pyrophosphate Geranylgeranyl- PP Pyrophosphate Acetyl-CoA Water Acetoacetyl-CoA Coenzyme A Coenzyme A
FDPS FDPS GGPS1 HMGCLL1 MVK PMVK FDFT1 MVD HMGCS1 ACAT1 Pamd Pamd Pamd Pamd Pamd HMG-CoA NADPH H+ NADP CoA Meval ATP Meva-5P ADP ATP Mev-5PP ADP Isop-PP Ipe PPi Gryl-PP IsopPyr FarPP PPi H+ NADPH PPi NADP Squalen Lanol ATP ADP Pi CO2 IsopPyr GGDP PPi Ac-CoA H2O ActaCoA CoA CoA Mg2+ Mg2+ Mg2+ Mg2+ Osteoclast Cytosol Pamidronate enters the cell through endocytosis. The endocytic vesicles are acidified and the pamidronate is released into the cytosol. Pamidronate inhibit farnesyl pyrophosphate synthase and geranylgeranyl pyrophosphate synthaseby binding in it's active site. Reduced production of farnesyl-PP, geranylgernayl-PP and other sterols which are essential for anchoring cell surface protein via prenylation, and are necessary for osteoclast function and survival. Low concentrations of these lipids prevents osteoclast attachment to the bone, thereby inducing apoptosis of the osteoclast, reducing osteoclast activity and bone resorption. Mevalonate Pathway Bone Loss Pamidronate is administered intravenously and travels to the bone Pamidronate acts to counteract osteoclast activity and reduce bone degradation
FDPS FDPS GGPS1 HMGCLL1 MVK PMVK FDFT1 MVD HMGCS1 ACAT1 Pamd Pamd Pamd Pamd Pamd HMG-CoA NADPH H+ NADP CoA Meval ATP Meva-5P ADP ATP Mev-5PP ADP Isop-PP Ipe Ppi Gryl-PP IsopPyr FarPP Ppi H+ NADPH Ppi NADP Squalen Lanol ATP ADP Pi CO2 IsopPyr GGDP Ppi Ac-CoA H2O ActaCoA CoA CoA