Mevalonate kinases

Step 4 of Figure 27.7 Phosphorylation and Decarboxylation Three addition reactions are needed to convert mevalonate to isopentenyl diphosphate. Th first two are straightforward phosphorylations that occur by nucleophilic sul stitution reactions on the terminal phosphorus of ATP. Mevalonate is first cor verted to mevalonate 5-phosphate (phosphomevalonate) by reaction wit ATP in a process catalyzed by mevalonate kinase. Mevalonate 5-phosphat then reacts with a second ATP to give mevalonate 5-diphosphate (diphosphc mevalonate). The third reaction results in phosphorylation of the tertiar hydroxyi group, followed by decarboxylation and loss of phosphate ion. 

Mevalonate kinase deficiency. Mevalonate kinase and farnesyl-diphosphate synthase are localized in the peroxisome and are involved in the synthesis of isoprenoids. Mevalonate kinase deficiency causes severe developmental delay, dysmorphic features and early death. Mevalonate deficiency has also been observed in the hyperimmuno-globulinemia-and periodic fever syndrome. 

MEVALONATE KINASE MYOSIN and MYOSIN ATPase NAD KINASE NAD SYNTHETASE... 

MEVALDATE REDUCTASE MEVALONATE KINASE Mevalonate-5-diphosphate decarboxylase,... 

MEVALONATE KINASE Mevalonic acid 5-pyrophosphate anhydrode-carboxylase,... 

Fig. 5.1.1 Isoprenoid biosynthetic pathway. The enzyme mevalonate kinase (black solid bar) is deficient in patients affected with mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. -CoA -Coenzyme A, HMG-CoA 3-hydroxy-3-methyl-glutaryl-coenzyme A, -PP -pyrophosphate...

In the past decade, eight inherited disorders have been linked to specific enzyme defects in the isoprenoid/cholesterol biosynthetic pathway after the finding of abnormally increased levels of intermediate metabolites in tissues and/or body fluids of patients (Table 5.1.1) [7, 9, 10]. Two of these disorders are due to a defect of the enzyme mevalonate kinase, and in principle affect the synthesis of all isoprenoids (Fig. 5.1.1) [5]. The hallmark of these two disorders is the accumulation of mevalonic acid in body fluids and tissues, which can be detected by organic acid analysis, or preferably, by stable-isotope dilution gas chromatography (GC)-mass spectrometry (GC-MS) [2]. Confirmative diagnostic possibilities include direct measurement of mevalonate kinase activities in white blood cells or primary skin fibroblasts [3] from patients, and/or molecular analysis of the MVK gene [8]. 

Syndrome Mevalonate kinase deficiency (MA/HIDS) CHILD syndrome CDPX2 HEM skeletal dysplasia Lathosterolosis Desmosterolosis Smith-Lemli-Opitz syndrome... 

Enzyme defect Mevalonate kinase 3/ -Hydroxy-steroid dehydrogenase 3/M Iydroxy-sterol 8- 7-isomerase 3/I-Hydroxysterol 14-reductase 3/1-1 Iydroxysterol A5-dcsaturasc 3/ -Hydroxysterol 24-reductase 3/l-Hydroxysterol 7-reductase... 

Hoffmann GF, Brendel SU, et al. (1992) Mevalonate kinase assay using DEAE-cellulose column chromatography for first-trimester prenatal diagnosis and complementation analysis in mevalonic aciduria. J Inherit Metab Dis 15 738-746... 

Mandey SH, Schneiders MS, et al. (2006) Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat 27 796-802... 

In animals all isoprenoid compounds are apparently synthesized from mevalonate, which is converted by the consecutive action of two kinases21 23 into mevalonate 5-diphosphate (Fig. 22-1, step b). Mevalonate kinase is found predominantly in peroxisomes, which are also active in other aspects of steroid synthesis in humans.2124 A deficiency of this enzyme is associated with mevalonic aciduria, a serious hereditary disease in which both blood and urine contain very high concentrations of mevalonate.23 Mevalonate diphosphate kinase, which is also a decarboxylase, catalyzes phosphorylation of the 3-OH group of mevalonate (step c, Fig. 22-1) and decarboxylative elimination of phosphate (step d)25 to form isopentenyl diphosphate. 

Thus far no sex pheromone has been described in the Phasmida. Some phasmids produce toxic monoterpenes in typical Class III integumentary glands located behind the head (e.g. Happ et al., 1966). The glands exhibit lipid reserves, carboxylic esterases, phosphatases, alcohol dehydrogenase, and a mevalonate kinase, all of which are suggested to be involved in the production of the toxic compounds (Happ et al., 1966). 

Manganese acts as a cofactor of mevalonate kinase and farnesyl pyrophosphate synthetase. Mevalonate kinase and possibly one other manganese-activated enzyme are necessary for the formation of mevalonate from acetate (3). Farnesyl pyrophosphate synthetase acts to add one 5-carbon unit to geranyl pyrophosphate to make farnesyl pyrophosphate (4) (Figure 1). 

HMG CoA synthase HMG CoA reductase mevalonate kinase phosphomevalonaie kinase pyrophosphomevalonale decarteaylase isopentenyl pyrophosphate isoincraae diiBethylallyl transferase presqualene synthase squalene synthase... 

The IBP and its products are displayed in Figure 12.1. HMG-CoA, ultimately derived from acetyl-CoA is converted to mevalonate via the enzyme HMG-CoA reductase (HMGR) [8]. This reaction is the rate-limiting step in the pathway. Mevalonate is then phosphorylated via mevalonate kinase (MK) to yield 5-phosphomevalonate [9]. IPP is formed following additional phosphorylation and decarboxylation steps [10]. Isomerization of IPP via the enzyme IPP isomerase yields DMAPP [11]. In mammals, the enzyme farnesyl pyrophosphate synthase (FDPS) catalyzes the synthesis of both GPP and FPP [12]. In plants, a separate GPP synthase has been identified [13]. GPP is a key intermediate in plants as it serves as the precursor for all monoterpenes. In animals, however, GPP appears to serve only as an intermediate in the synthesis of FPP. Very low basal levels of GPP have been measured in cell culture, although cellular GPP levels can become markedly increased in the setting of FDPS inhibition [14]. 

Tchen, T.T. (1958). Mevalonic kinase purification and properties. J Biol Chem 233 1100-1103. 

Hoffmann, G., Gibson, K.M., Nyhan, W.L., and Sweetman, L. (1988). Mevaloiuc aciduria pathobiochemical effects of mevalonate kinase deficiency on cholesterol metabolism in intact fibroblasts. J Inherit Metab Dis ll(Snppl 2) 229-232. 

Houten, S.M., Schneiders, M.S., Wanders, R.J., and Waterham, H.R. (2003). Regnlation of isoprenoid/cholesterol biosynthesis in cehs from mevalonate kinase-deficient patients. J Biol Chem 278 5736-5743. 

Mevalonic acid, the product of HMGR, is converted to IPP by the sequential action of three enzymes mevalonate kinase, phosphomevalonate kinase and diphosphomevalonate decarboxylase (Fig. 5.3). These three catalysts have not previously been considered to be important control points in plant terpenoid biosynthesis, and little new information has appeared to alter this view. The... 

Riou, C., Tourte, Y, Lacroute, F. and Karst, F. (1994) Isolation and characterization of a cDNA encoding Arabidopsis thaliana mevalonate kinase by genetic complementation in yeast. Gene, 148, 293-7. 

Further work on the enzymes of the early stages of terpenoid biosynthesis continues. Mevalonic kinase (EC 2.7.1.36) from hog liver has been shownto have a molecular weight of about 98 000 and to react first with mevalonic acid, then with magnesium and ATP, to release first the 5-phosphate and then ADP. The corresponding kinase from rat.ovary seems to differ from the liver enzyme. Mevalonic kinase was found to be present in many tissues of an insect larva. 

Mevalonate kinase is the first enzyme involved in the biosynthesis of terpenoid derivatives in plants and microorganisms. The terpenoid derivatives are the largest group of natural products which lead to the formation of a huge number of compounds extraordinarily diverse in structure and function, playing important roles in plant growth and development. 

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