The Inhibition of Mevalonic Kinase by Geranyl and Farnesyl Pyrophosphates

Dorsey, Jill; Porter, John W.

doi:10.1016/s0021-9258(18)93170-4

Cited by 82 publications

(14 citation statements)

References 28 publications

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“…However, other studies have shown that MKs are subject to feedback inhibition by lycopene biosynthesis intermediates, such as geranyldiphosphate (GPP), farnesyldiphosphate (FPP), and geranylgeranyldiphosphate (GGPP). 8 Dorsey and Porter 12 first suggested that MK activity in porcine liver was subject to feedback inhibition by low GPP and FPP concentrations. Similar results were witnessed in rat and plant MK studies.…”

Section: Introductionmentioning

confidence: 99%

Directed evolution of mevalonate kinase inEscherichia coliby random mutagenesis for improved lycopene

Chen

Liu

et al. 2018

RSC Adv.

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a Lycopene is a terpenoid pigment that has diverse applications in the fields of food and medicine. Metabolic engineering in microbial hosts has shown that mevalonate kinase (MK, EC2.7.1.366) is one of the ratelimiting enzymes in the lycopene synthetic pathway. In this study, a directed evolution strategy in Escherichia coli was used to optimize the activity of Saccharomyces cerevisiae MK. Using three rounds of error-prone PCR; screening the development of a lycopene-dependent color reaction; and combinatorial site-specific saturation mutagenesis, three activity-enhancing mutations were identified: V13D, S148I, and V301E. V13D was near the MK catalytic center, in the b-sheet that forms a salt-bridge with nearby Arg-248. S148I was located in the a-helix lid and improved the stability of the a-helix. V301E may increase MK folding by influencing its secondary structure. The K m (RS)-mevalonate of purified mutant MK decreased by 74% compared with the K m (RS)-mevalonate of the wild-type MK, and the K cat (RS)-mevalonate was improved by 26% compared with wild type. Fermentation experiments revealed that lycopene production of the mutant MK increased 2.4-fold compared with wild-type MK.

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Section: Introductionmentioning

confidence: 99%

Directed evolution of mevalonate kinase inEscherichia coliby random mutagenesis for improved lycopene

Chen

Liu

et al. 2018

RSC Adv.

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“…Farnesyl and geranyl pyrophosphates exert an inhibitory influence on the enzyme, while isopentenyl and dimethylallyl pyrophosphates do not. 66 Step 5 also involves phosphorylation. The ERG8 gene encodes Figure 3.…”

Section: Sterol Biosynthesis: Acetate To Farnesyl Pyrophosphatementioning

confidence: 99%

Biochemistry, cell biology and molecular biology of lipids ofSaccharomyces cerevisiae

Daum

Lees

Bard

et al. 1998

Yeast

580

380

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The yeast Saccharomyces cerevisiae is a powerful experimental system to study biochemical, cell biological and molecular biological aspects of lipid synthesis. Most but not all genes encoding enzymes involved in fatty acid, phospholipid, sterol or sphingolipid biosynthesis of this unicellular eukaryote have been cloned, and many gene products have been functionally characterized. Less information is available about genes and gene products governing the transport of lipids between organelles and within membranes, turnover and degradation of complex lipids, regulation of lipid biosynthesis, and linkage of lipid metabolism to other cellular processes. Here we summarize current knowledge about lipid biosynthetic pathways in S. cerevisiae and describe the characteristic features of the gene products involved. We focus on recent discoveries in these fields and address questions on the regulation of lipid synthesis, subcellular localization of lipid biosynthetic steps, cross‐talk between organelles during lipid synthesis and subcellular distribution of lipids. Finally, we discuss distinct functions of certain key lipids and their possible roles in cellular processes. © 1998 John Wiley & Sons, Ltd.

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“…57,[59][60][61][62] In most organisms, downstream diphosphate intermediates such as IPP, DMAPP, GPP, FPP and GGPP inhibit M5K by binding competitively to the ATPbinding site of M5K. 60,[63][64][65] Streptococcus pneumoniae M5K is inhibited by MVAPP, 66 but Staphylococcus aureus M5K is not. 60 S. aureus and S. cerevisiae M5K are also inhibited by substrate at millimolar MVA concentrations.…”

Section: The Mva Pathwaymentioning

confidence: 99%

“…As discussed above, the phosphorylation of MVA by M5K in the classical MVA pathway is one of the most heavily regulated enzymatic steps in the pathway. 63 Consequently, an alternative pathway that by-passes this enzyme is of potential interest for terpenoid production. M3P accumulates in T. acidophilum and could be used to increase terpenoid production by heterologous expression of this alternative MVA pathway in E. coli .…”

Section: Alternative Precursor Pathwaysmentioning

confidence: 99%

Alternative metabolic pathways and strategies to high-titre terpenoid production inEscherichia coli

2022

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The Inhibition of Mevalonic Kinase by Geranyl and Farnesyl Pyrophosphates

Cited by 82 publications

References 28 publications

Directed evolution of mevalonate kinase inEscherichia coliby random mutagenesis for improved lycopene

Directed evolution of mevalonate kinase inEscherichia coliby random mutagenesis for improved lycopene

Biochemistry, cell biology and molecular biology of lipids ofSaccharomyces cerevisiae

Alternative metabolic pathways and strategies to high-titre terpenoid production inEscherichia coli

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