Abstract
Decaprenyl diphosphate synthase from Mycobacterium tuberculosis (MtDPPS, also known as Rv2361c) catalyzes the consecutive elongation of ω,E,Z-farnesyl diphosphate (EZ-FPP) by seven isoprene units by forming new cis double bonds. The protein folds into a butterfly-like homodimer like most other cis-type prenyltransferases. The starting allylic substrate EZ-FPP is bound to the S1 site and the homoallylic substrate to be incorporated, isopentenyl diphosphate, is bound to the S2 site. Here, a 1.55 Å resolution structure of MtDPPS in complex with the substrate analogues geranyl S-thiodiphosphate (GSPP) and isopentenyl S-thiodiphosphate bound to their respective sites in one subunit clearly shows the active-site configuration and the magnesium-coordinated geometry for catalysis. The ligand-binding mode of GSPP in the other subunit indicates a possible pathway of product translocation from the S2 site to the S1 site, as required for the next step of the reaction. The preferred binding of negatively charged effectors to the S1 site also suggests a promising direction for inhibitor design.
Highlights
Tuberculosis (TB), which is one of the top ten causes of death worldwide, is a long co-existing human ‘crowd’ disease that is caused by a group of genetically related mycobacteria, namely the Mycobacterium tuberculosis complex (MTBC)
Rv1086 produces !,E,Zfarnesyl diphosphate (EZ-FPP; C15) from geranyl diphosphate (GPP; C10) and isopentenyl diphosphate (IPP; C5), which is used by Rv2361c for further elongation to form decaprenyl diphosphate (DPP; C50; Kaur et al, 2004)
MtDPPS does not release its product, which is to become the allylic substrate in the cycle of catalysis, until a final chain length of C50 is reached
Summary
Tuberculosis (TB), which is one of the top ten causes of death worldwide, is a long co-existing human ‘crowd’ disease that is caused by a group of genetically related mycobacteria, namely the Mycobacterium tuberculosis complex (MTBC). The emergence of multidrug-resistant TB (MDR-TB) is a major threat to public health, and the goal of eliminating this disease in the near future is being challenged (World Health Organization, 2018). Rv1086 produces !,E,Zfarnesyl diphosphate (EZ-FPP; C15) from geranyl diphosphate (GPP; C10) and isopentenyl diphosphate (IPP; C5), which is used by Rv2361c for further elongation to form decaprenyl diphosphate (DPP; C50; Kaur et al, 2004). Rv3378c transfers the diterpene moiety of tuberculosinyl diphosphate (TPP; C20) to adenosine, turning out 1-tuberculosinyladenosine (1-TbAd; Layre et al, 2014) as an abundant MTBC marker
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More From: Acta crystallographica. Section F, Structural biology communications
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