Phosphomevalonic acid

Tada, M., and Lynen, F. (1961). On the biosynthesis of terpenes. XIV. On the determination of phosphomevalonic acid kinase and pyrophosphomevalonic acid decarboxylase in cell extracts. J Biochem 49 758-764. 

Bloch, K. J. Biol. Chem., 1959,234,2595. With the characterization of phosphomevalonic acid and the two pyrophosphate esters described in this paper. .. the active isoprenoid capable of condensing. .. (is described). The transformation of mevalonic acid to the isoprenoid-condensing units involves, apart from the decarboxylation, the elimination of two hydroxyl groups. It is a reasonable assumption that esterification with. .. phosphate serves to facilitate eliminations... ... 

Cell-free extracts and acetone powder preparations from Agave amerkana have been shown to phosphorylate mevalonic acid to give phosphomevalonic acid and thence pyrophosphomevalonic acid at an optimum pH of 7.0. Glutathione and mercaptoethanol enhance the activity of these preparations. Tracer studies with tissue cultures derived from Tanacetum vulgare have revealed the formation of phosphomevalonic acid, pyrophosphomevalonic acid, isopentenyl pyrophosphate, dimethylallyl pyrophosphate, and the incorporation of mevalonic acid into monoterpenes. However, the mono-terpene components of the tissue culture differed from those of the whole plant, sabinene being formed rather than isothujone. 

There have been synthesized in this laboratory over the past several years a variety of phosphonic acids which are nominally isosteric with natural monophosphate esters. Of this collection of compounds three are of particular interest for the present work. These are (S)-3,4-dihydroxybutyl-1-phosphonic acid (A)(1), an isosteric analogue of sn-glycerol-3-phosphate 4-hydroxy-3-oxobutyl-l-phosphonic acid (B)( ), an isosteric analogue of dihydroxyacetone phosphate and 5-carboxy-4-hydroxy-4-methylpentyl-l-phosphonic acid (C)(3), an isosteric analogue of 5-phosphomevalonate. 

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... 

The conversion of mevalonate (1) to isopentenyl pyrophosphate (IPP) (4) involves two consecutive phosphorylations at position 5 by successive action of mevalonate kinase (EC 2.7.4.2) and a decarboxylation and dehydration of the tertiary alcohol group by mevalonate 5-pyrophosphate decarboxylase (EC 4.1.1.33) (Fig. 18.4) (Crotean Johnson, 1985 Gershenzon and Croteau, 1990). One mole of ATP is required for each phosphorylation reaction. Mevalonate kinase converts mevalonic acid to (5/ )-phosphomevalonate (5). The second phosphorylation is catalyzed by phospho-mevalonate kinase. The subsequent decarboxylation and dehydration is mediated by the enzyme mevalonate diphosphate decarboxylase (di- or pyrophosphomevalonate decarboxylase EC 4,1.1.3.3) this enzyme requires Mg " or Mn + and ATP for activity (Beale and MacMillan, 1988 Harrison, 1988). All three of these enzymes are found in a number of plants. 

When mevalonate, written below as the anion of (iJ)-mevalonic add (Chapter 6, Section C, I and Chapter 11), is acted upon by the enzyme mevalonate-5-phosphotransferase, a phosphate unit is transferred from adenosine triphosphate (ATP) to the primary alcohol of mevalonate. Adenosine diphosphate (ADP) and phosphomevalonate are produced. Although enzyme mediated, this process may be viewed as the reaction of an activated derivative of phosphoric acid (an anhydride ) reacting with an alcohol to produce an ester of phosphoric acid [H3PO4 or 0=P(0H)3]. 

Then (Scheme 11.41) mevalonate [(l )-3,5-dihydroxy-3-methylpentanoic acid] is phosphorylated by the enzyme mevalonate kinase (EC 2.7.1.36) at the primary hydroxyl. The phosphate that is added is obtained (an addition-elimination reaction or a displacement reaction) from the terminal phosphate group of ATP forming ADP in turn. Another phosphorylation, again using ATP yields mevalonate diphosphate, this time by the enzyme phosphomevalonate kinase (EC 2.7.4.2) and then, after one more phosphorylation, this time on the tertiary hydroxyl, decarboxylation and dehydration co-occur, catalyzed by the enzyme mevalonate diphosphate decarboxylase (EC 4.1.1.43). The products are inorganic phosphate, carbon dioxide, and isopentenyl diphosphate (diphosphoric acid mono[3-methylbut-3-enyl] ester). Isopentenyl diphosphate isomerase (EC S.3.3.2) catalyzes the isomerization, via loss of the C2 pro-R hydrogen, between isopentenyl diphosphate and dimethylallyl diphosphate. 

Henning, V., E. M. Moslein, and F. Lynen Biosynthesis of terpenes V. Formation of 5-pyrophosphomevalonic acid by phosphomevalonic kinase. Arch. Biochem. 83, 259(1959). 

As soon as mevalonate acid has formed, a series of enzymes are involved in order to transform MVA to IPP. Mevalonate kinase [EC 2.7.1.36] phosphorylates the primary alcohol to mevalonate 5-phosphate, whereas phosphomevalonate kinase [EC 2.7.4.2] produces 5-pyrophosphomevalonate... 

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