Current development in isoprenoid precursor biosynthesis and regulation

Abstract

Isoprenoids are one of the largest classes of natural products and all of them are constructed from two precursors, isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). For decades, the mevalonic acid (MVA) pathway was proposed to be the only IPP and DMAPP biosynthetic pathway. This review summarizes the newly discovered IPP and DMAPP production pathways since late 1990s, their distribution among different kingdoms, and their roles in secondary metabolite production. These new IPP and DMAPP production pathways include the methylerythritol phosphate (MEP) pathway, a modified MVA pathway, and the 5-methylthioadenosine shunt pathway. Relative to the studies on the MVA pathway, information on the MEP pathway regulation is limited and the mechanistic details of several of its novel transformations remain to be addressed. Current status on both MEP pathway regulation and mechanistic issues is also presented.

Figure 1

Pathways for the production of isoprenoid precursors: (A) The mevalonic acid (MVA) pathway. (B) A modified MVA pathway in Methanocaldococcus jannaschii. (C) The methylerythritol phosphate (MEP) pathway. (D) A newly discovered isoprenoid shunt pathway related to S-adenosylmethioneine metabolism. Two new activities found for IspF are shown in E.

Figure 2

The involvement of the MVA pathway in the biosynthesis of furanonaphthoquinone (a secondary isoprenoid metabolite) in Streptoyces cinnamonensis DSM 1042.

Figure 3

Working models accounting for the IspG-catalyzed reaction. (A) The epoxide model. According to this model, the epoxide (28) serves as a key intermediate. Once 28 is formed, two sequential single electron reduction steps lead to the formation of HMBPP (17). (B) Cation and organometallic models. In this case, the first step is the formation of a carbocation intermediate (31) by the C-O cleavage. Subsequent reductive dehydroxylation can proceed via either the radical cation intermediate (33) or the organometallic intermediate (34).

Figure 4

Working models accounting for the IspH-catalyzed reaction. (A) Birch reduction model. In this model, the iron-sulfur cluster has two functions: (1) mediating two sequential one-electron reduction, and (2) serving as the Lewis acid to facilitate C₄-dehydroxylation. (B) Organometallic model. This model has two unique features: (1) the HMBPP C₄-OH group rotates away from the [4Fe-4S] cluster to form an internal H-bond (40), and (2) an iron-sulfur cluster mediated two-electron reductive dehydroxylation step (40 → 41). (C) Substrate bound active site structure of wt and E126Q variant IspH.

Figure 4

Working models accounting for the IspH-catalyzed reaction. (A) Birch reduction model. In this model, the iron-sulfur cluster has two functions: (1) mediating two sequential one-electron reduction, and (2) serving as the Lewis acid to facilitate C₄-dehydroxylation. (B) Organometallic model. This model has two unique features: (1) the HMBPP C₄-OH group rotates away from the [4Fe-4S] cluster to form an internal H-bond (40), and (2) an iron-sulfur cluster mediated two-electron reductive dehydroxylation step (40 → 41). (C) Substrate bound active site structure of wt and E126Q variant IspH.