Mevalonic acid, decarboxylative elimination

Elimination usually involves loss of a proton together with a nucleophilic group such as -OH, -NH3+, phosphate, or pyrophosphate. However, as in Eq. 13-18, step c, electrophilic groups such as -COO-can replace the proton. Another example is the conversion of mevalonic acid-5-pyrophosphate to isopentenyl pyrophosphate (Eq. 13-19) This is a key reaction in the biosynthesis of isoprenoid compounds such as cholesterol and vitamin A (Chapter 22). The phosphate ester formed in step a is a probable intermediate and the reaction probably involves a carbo-cationic intermediate generated by the loss of phosphate prior to the decarboxylation. 

Formation of the biological isoprene unit from mevalonic acid has been shown to proceed by stepwise phosphorylation of both alcohol groups, then elimination and decarboxylation to yield 3-methyl-3-butenyl pyrophosphate, 9 (often called A3-isopentenyl pyrophosphate) ... 

Figure 3.6 illustrates how, through phosphorylation, elimination and decarboxylation, mevalonic acid is converted to isopentenyl pyrophosphate, which can be isomerised enzymically to pentenyl pyrophosphate. 

Mevalonic acid is the precursor of the terpenes. Write its structure. After phosphorylation, it undergoes a decarboxylative elimination to yield 3-isopentenyl pyrophosphate. Outline the mechanism of this reaction. 

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... ... 

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. 

Scheme 11.41. The enzyme-catalyzed phosphorylation (ATP -y ADP) and decarboxylation (with elimination of inorganic phosphate) of (i )-mevalonate [(i )-3,5-dihydroxy-3-methylpentanoic acid] to isopentenyl diphosphate (diphosphoric acid mono-[3-methylbut-3-enyl] ester) and the isomerization of the latter to dimethylallyl diphosphate (EC 5.3.3.2). It is important to note that the isomerization involves the specific removal of the pro-R hydrogen of C2 of the former. EC numbers and some graphic materials provided in this scheme have been taken with permission from appropriate links in a URL starting with http // www.chem.qmul.ac.uk/iubmb/enzyme/.

---