Structures of M. tuberculosis Rv2173 isoprenyl diphosphate synthase in substrate-bound forms
James A. Titterington, Ngoc Anh Thu Ho, Charles P.H. Beasley, Francis Mann, Edward N. Baker, Timothy M. Allison, Jodie M. Johnston [1]
Molecular Tour
Rv2173 is an Isoprenyl diphosphate synthase (prenyltransferase) from the human pathogen Mycobacterium tuberculosis. Prenyltransferases are important enzymes whose products act as components in the synthesis of a wide variety of natural products such as steroids, chlorophyll, carotenoids, and vitamin K2 (menaquinone). These enzymes act to produce long terpene polymers by sequentially adding IPP (isoprenyl diphosphate) monomers to an allylic substrate such as DMAP (dimethylallyldiphosphate). The family of proteins Rv2173 belongs to are known as the all-E-prenyltransferase due to the stereochemistry of their product. This family produce a diverse array of products with the unique size and shape of each member enzymes active site pocket influencing the size (carbon length) of product they can make. Understanding the size of the product they produce helps to more clearly define their function within a cell. The cellular function of Rv2173 is a bit unclear, though recent work has suggested it may make shorter chain products (C10-C15 in length) and be involved in isoprenoid production for the synthesis of glycosyl carrier lipids. Analysis of the structures of Rv2173 managed to confirm it was a homodimer with a fold consistent with other all-E-prenyltransferases and gave important insights into the size of the active site pocket that controls product length. This analysis supports the suggestion that Rv2173 produces short chain products as the pocket size is limited by a range of bulky amino acid residues. Structures in the absence and presence of substrate were able to be compared revealing more open and closed forms of the enzyme. This gave insight into how the enzyme may close or open its active site by structural movements in order to protect its substrates during reaction and release product.
References
- ↑ Titterington JA, Ho NAT, Beasley CPH, Mann F, Baker EN, Allison TM, Johnston JM. Structures of Mycobacterium tuberculosis isoprenyl diphosphate synthase Rv2173 in substrate-bound forms. Acta Crystallogr F Struct Biol Commun. 2025 May 1;81(Pt 5):193-200. PMID:40166974 doi:10.1107/S2053230X25002298
