Decarboxylation pyrophosphate esters

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... ... 

In keeping with its biogenetic origin m three molecules of acetic acid mevalonic acid has six carbon atoms The conversion of mevalonate to isopentenyl pyrophosphate involves loss of the extra carbon as carbon dioxide First the alcohol hydroxyl groups of mevalonate are converted to phosphate ester functions—they are enzymatically phosphorylated with introduction of a simple phosphate at the tertiary site and a pyrophosphate at the primary site Decarboxylation m concert with loss of the terti ary phosphate introduces a carbon-carbon double bond and gives isopentenyl pyrophos phate the fundamental building block for formation of isoprenoid natural products... 

The only known substrate for enzymic decarboxylation is uridine 5 -(a-D-glucopyranosyluronic acid pyrophosphate). A simple reaction of this type, ieading to the a-D-xylopyranosyl ester, has been ob-... 

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. 

This biosynthetic path consists of the Claisen-type condensation of two acetyl CoA units to form the four-carbon substance acetoacetyl CoA a third equivalent of acetyl CoA is then added in an aldol-type reaction giving, after hydrolysis of one of the thiol esters, hydroxymethylglutaryl CoA (HMG-CoA). HMG-CoA is then reduced by a net four electrons to mevalonic acid and is subsequently phosphorylated to mevalonic acid 5-pyrophosphate (MVA-5PP). This substrate is finally phosphorylated and decarboxylated with concomitant loss of inorganic phosphate to give the five-carbon isoprenoid isopentenyl pyrophosphate (IPP). IPP is then isomerized to DMAPP by an isomerase. 

The three branched chain amino acids are normally metabolized as shown in Figure 6.2. Each amino acid is converted to the corresponding Of-keto acid by a transaminase specific for that amino acid. A solitary case of valinaemia is known, caused by lack of valine transaminase [76] the patient is mentally retarded. The three a-keto acids are decarboxylated by two (or possibly three) enzyme systems, one specific for a-keto-isovaleric acid, the other acting on a-keto-isocaproic and Q -keto-j3-methylvaleric acids [77, 78]. The reaction is complex, proceeding in three distinct steps [78] and requiring coenzyme A, thiamine pyrophosphate, lipoic acid and NAD. The end products are the co-enzyme A thio-esters of the branched chain fatty acids. 

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