Discovery of a metabolic alternative to the classical mevalonate pathway

Dellas, Nikki; Thomas, Suzanne T.; Manning, Gerard; Noel, Joseph P.

doi:10.7554/elife.00672

Cited by 89 publications

(96 citation statements)

References 46 publications

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“…Ta0461 and Ta0893, are distinguishable from standard DMDs. In a recent paper announcing the first discovery of PMD, Dellas et al (9) reported the difference in the amino acid sequences between DMDs and the orthologs of PMD. The difference presumably endows PMD with a preference to MVA-5-P over MVA-5-PP.…”

Section: Discussionmentioning

confidence: 99%

(R)-Mevalonate 3-Phosphate Is an Intermediate of the Mevalonate Pathway in Thermoplasma acidophilum

Azami

Hattori

Nishimura

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

(R)-Mevalonate 3-Phosphate Is an Intermediate of the Mevalonate Pathway in Thermoplasma acidophilum

Azami

Hattori

Nishimura

et al. 2014

Journal of Biological Chemistry

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“…A. thaliana IPK was previously identified and kinetically characterized in vitro using IP as a substrate (10). Because thermophilic archaeal IPKs are promiscuous with regard to substrate use (18), we analyzed whether AtIPK can also use DMAP and geranyl phosphate (GP) as substrates.…”

Section: Ipk Is Coexpressed With the Mva Pathway And Downstream Terpementioning

confidence: 99%

“…Given their strong substrate preference for MVAPP, it seems unlikely that in Arabidopsis IPK is part of an alternative MVA pathway. Rather, in response to metabolic demands, IPK is likely to function in reactivating a pool of IP generated by endogenous plant phosphatases and as part of a homeostatic mechanism to balance the levels of IPP (10,(13)(14)(15).…”

Section: Ipk Is Coexpressed With the Mva Pathway And Downstream Terpementioning

confidence: 99%

“…Unexpectedly, functional IPK homologs were found in every sequenced plant genome (10), despite the fact that plants contain a complete classic MVA pathway. The ubiquitous presence of an IPP-generating kinase in the green plant lineage suggests that the presence of IP, and its phosphorylation to IPP, may play a critical role in terpenoid metabolism and homeostasis.…”

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confidence: 99%

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Orthologs of the archaeal isopentenyl phosphate kinase regulate terpenoid production in plants

Henry

Gutensohn

Thomas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Terpenoids, compounds found in all domains of life, represent the largest class of natural products with essential roles in their hosts. All terpenoids originate from the five-carbon building blocks, isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), which can be derived from the mevalonic acid (MVA) and methylerythritol phosphate (MEP) pathways. The absence of two components of the MVA pathway from archaeal genomes led to the discovery of an alternative MVA pathway with isopentenyl phosphate kinase (IPK) catalyzing the final step, the formation of IPP. Despite the fact that plants contain the complete classical MVA pathway, IPK homologs were identified in every sequenced green plant genome. Here, we show that IPK is indeed a member of the plant terpenoid metabolic network. It is localized in the cytosol and is coexpressed with MVA pathway and downstream terpenoid network genes. In planta, IPK acts in parallel with the MVA pathway and plays an important role in regulating the formation of both MVA and MEP pathway-derived terpenoid compounds by controlling the ratio of IP/DMAP to IPP/DMAPP. IP and DMAP can also competitively inhibit farnesyl diphosphate synthase. Moreover, we discovered a metabolically available carbon source for terpenoid formation in plants that is accessible via IPK overexpression. This metabolite reactivation approach offers new strategies for metabolic engineering of terpenoid production.A ll living organisms produce terpenoids, directing a considerable amount of their available carbon to the biosynthesis of one of the most structurally and functionally diverse classes of primary and secondary metabolites in nature (1). These molecules play essential and specialized roles in their hosts in photosynthesis and respiration (the phytyl side-chain of chlorophyll, quinones), modulating membrane fluidity (sterols), regulating growth and development (hormones), photoprotection and energy transfer (carotenoids), and communication, environmental adaptation, and chemical defense (mono-, sesqui-, and diterpenes) (2, 3). Some compounds, like quinones, chlorophylls, and certain proteins, which require targeting to membranes for their functions, are anchored by terpenoid structures. In addition to their vital biological roles, terpenoids are also widely used by humans as nutritional supplements, flavors, fragrances, biofuels, and pharmaceuticals (4-6). Multiple metabolic pathways operate in parallel, often intersect, and routinely exchange intermediates, leading to one of the most chemically complex groups of natural products in the biosphere. Therefore, achieving a complete understanding at both genetic and biochemical levels of the underlying regulatory networks that coordinate and homeostatically govern these biosynthetic systems is of paramount importance to fully capitalize on the utility of terpenoids to natural ecosystems and humans.All terpenoids originate from C5 building blocks, isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), which are ...

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“…Although plants use both pathways (synthesizing mevalonate in the cytosol and DXP in the plastid) most other organisms utilize only one of them, with the DXP route dominant in bacteria and the mevalonate route in eukaryotes and archaea (Lange et al, 2000; Kirby and Keasling, 2009; Boucher and Doolittle, 2000). Some archaea also use a modified version of the mevalonate pathway (Dellas et al, 2013). Both pathways produce a mixture of the C5 compounds isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), the building blocks for isoprenoid biosynthesis, in seven steps starting from central metabolism.…”

Section: Introductionmentioning

confidence: 99%

Engineering a functional 1-deoxy-D-xylulose 5-phosphate (DXP) pathway in Saccharomyces cerevisiae

Kirby

Dietzel

Wichmann

et al. 2016

Metabolic Engineering

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Isoprenoids are used in many commercial applications and much work has gone into engineering microbial hosts for their production. Isoprenoids are produced either from acetyl-CoA via the mevalonate pathway or from pyruvate and glyceraldehyde 3-phosphate via the 1-deoxy-D-xylulose 5-phosphate (DXP) pathway. Saccharomyces cerevisiae exclusively utilizes the mevalonate pathway to synthesize native isoprenoids and in fact the alternative DXP pathway has never been found or successfully reconstructed in the eukaryotic cytosol. There are, however, several advantages to isoprenoid synthesis via the DXP pathway, such as a higher theoretical yield, and it has long been a goal to transplant the pathway into yeast. In this work, we investigate and address barriers to DXP pathway functionality in S. cerevisiae using a combination of synthetic biology, biochemistry and metabolomics. We report, for the first time, functional expression of the DXP pathway in S. cerevisiae. Under low aeration conditions, an engineered strain relying solely on the DXP pathway for isoprenoid biosynthesis achieved an endpoint biomass 80% of that of the same strain using the mevalonate pathway.

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Discovery of a metabolic alternative to the classical mevalonate pathway

Cited by 89 publications

References 46 publications

(R)-Mevalonate 3-Phosphate Is an Intermediate of the Mevalonate Pathway in Thermoplasma acidophilum

(R)-Mevalonate 3-Phosphate Is an Intermediate of the Mevalonate Pathway in Thermoplasma acidophilum

Orthologs of the archaeal isopentenyl phosphate kinase regulate terpenoid production in plants

Engineering a functional 1-deoxy-D-xylulose 5-phosphate (DXP) pathway in Saccharomyces cerevisiae

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