This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

Farnesyl diphosphate synthase

From Proteopedia

Revision as of 14:34, 16 July 2020 by Hannah Campbell (Talk | contribs)

(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)

Jump to: navigation, search

Introduction

Human farnesyl diphosphate synthase complex with lipophylic bisphosphonate inhibitor and Mg+2 ions (green) (PDB code 2opm)

Drag the structure with the mouse to rotate

Farnesyl pyrophospate synthase (FPPS), also named Farnesyl diphosphate synthase (FPS), is a chain elongation enzyme that catalyzes carbon-carbon formation in two consecutive condensation reactions that convert one equivalent of dimethylallyl diphosphate (DMAPP) and two equivalents of isopentyl diphosphates (IPP) into one equivalent of Farnesyl pyrophospate. (FPP) ^[1]

1 Function
2 Relevance
3 Structure
4 3D structures of farnesyl diphosphate synthase

Function

In the first step, IPP and its isomer DMAPP react to form a ten-carbon geranyl diphosphate (GPP), while in the second step, the product geranyl diphosphate from the first step and an additional IPP molecule react to make FPP (see diagram). It is an essential enzyme in the biosynthesis of mevalonate, isoprenoids, and sterols in a variety of organisms. FFPS has been studied in conjunction with different parasites. TcFPPS refers to FPPS in the Typanosoma cruzi parasite while LmFPPS refers to FPPS in the Leishmania major parasite. Bisphosphonates have been shown to inhibit FPPS and are currently being used as antiparasitic drugs as well as a treatment for various bone diseases.

Relevance

FPS bisphosphonate inhibitors (like zoledronic acid) are used as drugs for treatment of bone resorption diseases^[2]. FPS inhibitor Alendronate or Fosamax is used in treatment of osteoporosis^[3]. Bisphosphonates have been explored as antiparasitic drugs with FPPS because current treatments are expensive, have low efficacy, and have dangerous side effects. FPPS is important in the lengthening of hydrophobic chains and determination of their specificity.

Structure

FPPS exists as a homodimer, with each monomer having an active site. The monomers have the characteristic FPPS fold of a ten-helix bundle and four other helices that run perpendicular to the bundle. There are two substrate sites, one is allylic and the other is homoallylic. GPP and DMAPP bind to the allylic site, while IPP binds to the homoallylic site. These two sites are connected to the top of the bundle and exist as part of a cavity. ^[4], water molecules are shown as red spheres.

3D structures of farnesyl diphosphate synthase

Farnesyl diphosphate synthase 3D structures

Crystal structure of LmFPPS, a dimer, in complex with P2H, IPP and Ca2+. [PDB:4JZB]

Drag the structure with the mouse to rotate

References

↑ Schulbach MC, Mahapatra S, Macchia M, Barontini S, Papi C, Minutolo F, Bertini S, Brennan PJ, Crick DC. Purification, enzymatic characterization, and inhibition of the Z-farnesyl diphosphate synthase from Mycobacterium tuberculosis. J Biol Chem. 2001 Apr 13;276(15):11624-30. Epub 2001 Jan 4. PMID:11152452 doi:http://dx.doi.org/10.1074/jbc.M007168200
↑ Das S, Edwards PA, Crockett JC, Rogers MJ. Upregulation of endogenous farnesyl diphosphate synthase overcomes the inhibitory effect of bisphosphonate on protein prenylation in Hela cells. Biochim Biophys Acta. 2014 Apr 4;1841(4):569-73. doi:, 10.1016/j.bbalip.2013.12.010. Epub 2013 Dec 22. PMID:24369118 doi:http://dx.doi.org/10.1016/j.bbalip.2013.12.010
↑ Selby P. Alendronate treatment for osteoporosis: a review of the clinical evidence. Osteoporos Int. 1996;6(6):419-26. doi: 10.1007/bf01629572. PMID:9116385 doi:http://dx.doi.org/10.1007/bf01629572
↑ PMID:24598749<ref></ref> [1] Another characteristic feature of all FPPS enzymes are two highly conserved aspartate rich motifs. These motifs are called , and have sequences of DDXX(XX)D and DDXXD respectively. FARM and SARM are found on opposite sides on the active site cavity facing one another. [2] When FPPS interacts with bisphosphonates, the bisphosphonates bind in the homoallylic binding sites and are coordinated by three divalent cations (Ca 2+ or Mg 2+). FPS contains and binds ; see also , (PDB code 2opm)<ref>PMID:19309137</li></ol></ref>

Proteopedia Page Contributors and Editors (what is this?)

Hannah Campbell, Michal Harel, Tihitina Y Aytenfisu, Alexander Berchansky, Joel L. Sussman, Sandra B. Gabelli

Retrieved from "http://52.214.119.220/wiki/index.php/Farnesyl_diphosphate_synthase"

Farnesyl diphosphate synthase

From Proteopedia

Introduction

Contents

Function

Relevance

Structure

3D structures of farnesyl diphosphate synthase

References

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox