The Biosynthesis of Mevalonic Acid

Ferguson, James J.; Durr, I.F.; Rudney, Harry

doi:10.1073/pnas.45.4.499

Cited by 40 publications

(10 citation statements)

References 8 publications

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“…The MVA pathway, which is used by Staphylococcus aureus for IPP biosynthesis, starts with the acetylation of acetoacetyl-CoA to Hydroxy-3-methylglutaryl-CoA (HMG-CoA) catalyzed by the HMG-CoA synthase (MvaS) ( Ferguson et al, 1959 ). HMG-CoA is then reduced by the HMG-CoA reductase (MvaA) to MVA ( Durr and Rudney, 1960 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic Adaptation of a Mevalonate Pathway Deficient Mutant in Staphylococcus aureus

et al. 2018

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In this study we addressed the question how a mevalonate (MVA)-auxotrophic Staphylococcus aureusΔmvaS mutant can revert to prototrophy. This mutant couldn’t grow in the absence of MVA. However, after a long lag-phase of 4–6 days the mutant adapted from auxotrophic to prototrophic phenotype. During that time, it acquired two point mutations: One mutation in the coding region of the regulator gene spx, which resulted in an amino acid exchange that decreased Spx function. The other mutation in the upstream-element within the core-promoter of the mevalonolactone lactonase gene drp35. This mutation led to an increased expression of drp35. In repeated experiments the mutations always occurred in spx and drp35 and in the same order. The first detectable mutation appeared in spx and allowed slight growth; the second mutation, in drp35, increased growth further. Phenotypical characterizations of the mutant showed that small amounts of the lipid-carrier undecaprenol are synthesized, despite the lack of mvaS. The growth of the adapted clone, ΔmvaSad, indicates that the mutations reawake a rescue bypass. We think that this bypass enters the MVA pathway at the stage of MVA, because blocking the pathway downstream of MVA led to growth arrest of the mutant. In addition, the lactonase Drp35 is able to convert mevalonolactone to MVA. Summarized, we describe here a mutation-based two-step adaptation process that allows resuscitation of growth of the ΔmvaS mutant.

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Section: Introductionmentioning

confidence: 99%

Genetic Adaptation of a Mevalonate Pathway Deficient Mutant in Staphylococcus aureus

et al. 2018

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“…Isoprenoid synthesis first requires the formation of IPP by the mevalonate pathway (Ferguson et al, 1959), which, as already mentioned, takes place in the cytosol (see also Section II.1). Three molecules of IPP condense to form farnesyl diphosphate, which then reacts with a second molecule of farnesyl diphosphate to form squalene which is inserted into the ER membrane.…”

Section: (4) Lipid Biosynthesismentioning

confidence: 92%

“…The oligosaccharide donor dolichol pyrophosphate provides a lipid anchor which allows the proper positioning of the oligosaccharide at the ER membrane next to the OST complex. The biosynthesis of dolichol comes within the mevalonate pathway where isopentenyl diphosphate (IPP) molecules are produced (Ferguson, Durr & Rudney, 1959). An ER-resident isoprenyltransferase then catalyses a condensation reaction between varying numbers of IPPs with farnesyl diphosphate (FPP) to build polyprenyl diphosphate, which is further converted to dolichol in several reaction steps (Crick, Rush & Waechter, 1991;Schenk, Fernandez & Waechter, 2001a;Schenk et al, 2001b).…”

Section: (1) Protein Synthesis and The Secretory Pathwaymentioning

confidence: 99%

The enigmatic ATP supply of the endoplasmic reticulum

et al. 2018

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The endoplasmic reticulum (ER) is a functionally and morphologically complex cellular organelle largely responsible for a variety of crucial functions, including protein folding, maturation and degradation. Furthermore, the ER plays an essential role in lipid biosynthesis, dynamic Ca 2+ storage, and detoxification. Malfunctions in ER‐related processes are responsible for the genesis and progression of many diseases, such as heart failure, cancer, neurodegeneration and metabolic disorders. To fulfill many of its vital functions, the ER relies on a sufficient energy supply in the form of adenosine‐5′‐triphosphate (ATP), the main cellular energy source. Despite landmark discoveries and clarification of the functional principles of ER‐resident proteins and key ER‐related processes, the mechanism underlying ER ATP transport remains somewhat enigmatic. Here we summarize ER‐related ATP‐consuming processes and outline our knowledge about the nature and function of the ER energy supply.

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“…3-hydroxy-3methylglutaryl (HMG) Co-A is formed from one mole of acetyl Co-A and acetoacetyl Co-A in the presence of HMG Co-A synthase (HMGS). HMGCR converts HMG Co-A to mevalonic acid [109]. The rate-limiting enzyme of the pathway is HMGCR [110], one of the most highly regulated enzymes in nature [111].…”

Section: Pre-squalene Pathwaymentioning

confidence: 99%