Mevalonic Acid Pyrophosphate and Isopentenylpyrophosphate

Bloch, Konrad; Chaykin, Sterling; Phillips, Alvah H.; Waard, A. de

doi:10.1016/s0021-9258(18)69744-3

Cited by 207 publications

(29 citation statements)

References 20 publications

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“…Negative elasticity would reflect possible inhibition. The sign of elasticity, among the calculated, complied with well-known feedback inhibition of farnesyl pyrophosphate (FPP) on mevalonate kinase (MK), 24 and inhibition of ATP on phosphomevalonate kinase (PMK); 25 thus, it further demonstrated the approximation capability of the model. Moreover, maximum connectivity was assumed when a priori knowledge was unavailable.…”

Section: ■ Results and Discussionsupporting

confidence: 65%

In Vitro Metabolic Engineering of Amorpha-4,11-diene Biosynthesis at Enhanced Rate and Specific Yield of Production

et al. 2017

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In vitro metabolic engineering is an alternative approach to cell-based biosynthesis. It offers unprecedented flexibility for the study of biochemical pathways, thus providing useful information for the rational design and assembly of reaction modules. Herein, we took the advantage of in vitro metabolic engineering to initially gain insight into the regulatory network of a reconstituted amorpha-4,11-diene (AD) synthetic pathway. Guided by lin-log approximation, we rapidly identified the hitherto unrecognized inhibition of adenosine triphosphate (ATP) on both farnesyl pyrophosphate synthase (FPPS) and amorpha-4,11-diene synthase (ADS). Furthermore, the byproduct, pyrophosphate (PPi), potently inhibits ADS, but not FPPS. To lower the inhibition, an ATP recycling system and pyrophosphatase were used and resulted in a significant (∼3-fold) enhancement in the rate of AD production (∼5.7 μmol L min). A coimmobilized multienzyme reaction system was then developed to recycle the enzymes. When inhibitory metabolites concentrations were reduced, the specific enzymatic yield of AD was further enhanced (>6-fold). This study demonstrated that mitigating the accumulation of inhibitory metabolites can result in higher yields of AD production by in vitro multienzymatic reactions.

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Section: ■ Results and Discussionsupporting

confidence: 65%

In Vitro Metabolic Engineering of Amorpha-4,11-diene Biosynthesis at Enhanced Rate and Specific Yield of Production

et al. 2017

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“…This changed with Ruzicka’s formulation of the isoprene rule . Between the 1940s and 1960s, the structure elucidations of cholesterol and other natural products led to the identification and characterization of their basic isoprenoid building blocks, namely, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). ,− Experiments with isotopically labeled acetate showed that these fundamental units are derived from acetyl-CoA, and several research groups subsequently identified and characterized a corresponding biosynthetic reaction sequence . This was termed the mevalonate pathway, after its key intermediate (3 R )-3,5-dihydroxy-3-methylpentanoic acid (mevalonic acid, MVA) (Figure ).…”

Section: Introductionmentioning

confidence: 99%

“…PMK completes the formation of the pyrophosphate moiety by transferring a second terminal phosphate, now acid-labile, from ATP. This reaction was shown to be easily reversible upon addition of ADP. , To obtain the final isoprenoid product of the MVA pathway, dehydration and decarboxylation reactions are required. Both were suggested to occur through a concerted and, at the time of discovery, unprecedented mechanism catalyzed by mevalonate diphosphate decarboxylase (MDD).…”

Section: Introductionmentioning

confidence: 99%

The Methylerythritol Phosphate Pathway to Isoprenoids

2016

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Isoprenoids constitute one of the most diverse classes of natural products. As a compound class, they are essential to basic metabolic processes including cell-wall biosynthesis, post-translational protein modifications, and signaling. In addition, isoprenoid secondary metabolites are highly valuable natural products with a wide range of biotechnological applications. The biosynthesis of their two universal building blocks, isopentenyl diphosphate and dimethylallyl diphosphate, was thought to proceed exclusively by way of mevalonate as a key intermediate until a novel pathway involving methylerithritol phosphate (MEP) was discovered in the early 1990s. In this review, we describe the seven enzymes of the MEP pathway, along with their discoveries, three-dimensional structures, and mechanisms. The latter include examples of remarkable enzyme catalysis including an unusual cytidilation reaction and the use of iron-sulfur cluster cofactors in reductive ring opening and hydroxy-group elimination. Furthermore, isoprenoid biosynthesis shows a characteristic species distribution. A brief overview highlights the MEP pathway's potential as a selective drug target, which is absent in humans but essential to the survival of many important bacterial and apicomplexan pathogens.

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“…These isomeric precursors are coupled in a head-to-tail manner by prenyl transferases that result in the mono-TPS substrate geranyl diphosphate (GPP) and sesqui-TPS substrate farnesyl diphosphate (FPP). FPP can be isomerised in a rate-limiting reaction to form the nerolidol diphosphate (NPP) substrate [ 8 , 9 , 10 , 11 ]. The array of terpenes produced by a single TPS varies greatly, from a single product to an excess of 40 terpenes [ 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Seeing the Forest through the (Phylogenetic) Trees: Functional Characterisation of Grapevine Terpene Synthase (VviTPS) Paralogues and Orthologues

Smit

Vivier

Young

2021

Plants

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Gene families involved in specialised metabolism play a key role in a myriad of ecophysiological and biochemical functions. The Vitis vinifera sesquiterpene synthases represent the largest subfamily of grapevine terpene synthase (VviTPS) genes and are important volatile metabolites for wine flavour and aroma, as well as ecophysiological interactions. The functional characterisation of VviTPS genes is complicated by a reliance on a single reference genome that greatly underrepresents this large gene family, exacerbated by extensive duplications and paralogy. The recent release of multiple phased diploid grapevine genomes, as well as extensive whole-genome resequencing efforts, provide a wealth of new sequence information that can be utilised to overcome the limitations of the reference genome. A large cluster of sesquiterpene synthases, localised to chromosome 18, was explored by means of comparative sequence analyses using the publicly available grapevine reference genome, three PacBio phased diploid genomes and whole-genome resequencing data from multiple genotypes. Two genes, VviTPS04 and -10, were identified as putative paralogues and/or allelic variants. Subsequent gene isolation from multiple grapevine genotypes and characterisation by means of a heterologous in planta expression and volatile analysis resulted in the identification of genotype-specific structural variations and polymorphisms that impact the gene function. These results present novel insight into how grapevine domestication likely shaped the VviTPS landscape to result in genotype-specific functions.

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Mevalonic Acid Pyrophosphate and Isopentenylpyrophosphate

Cited by 207 publications

References 20 publications

In Vitro Metabolic Engineering of Amorpha-4,11-diene Biosynthesis at Enhanced Rate and Specific Yield of Production

In Vitro Metabolic Engineering of Amorpha-4,11-diene Biosynthesis at Enhanced Rate and Specific Yield of Production

The Methylerythritol Phosphate Pathway to Isoprenoids

Seeing the Forest through the (Phylogenetic) Trees: Functional Characterisation of Grapevine Terpene Synthase (VviTPS) Paralogues and Orthologues

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