Studies on Mevalonate Kinase, Phosphomevalonate Kinase and Pyrophosphomevalonate Decarboxylase in Developing Rat Brain

Abstract

Abstract— We have in the present study investigated the properties of mevalonate kinase, phosphomevalonate kinase and pyrophosphomevalonate decarboxylase in the 105,000 g supernatant fractions from rat brain, and determined whether the activities of these enzymes change during brain development. All three enzymes in brain showed a specific requirement for ATP for optimal activity. The presence of Mg2+ as divalent cation was also required for optimal activity of mevalonate kinase and phosphomevalonate kinase. Both Mg2+ and Mn2+ were equally effective divalent metal ions for pyrophosphomevalonate decarboxylase in brain. Mevalonate kinase as well as phosphomevalonate kinase were active in a broad pH range of 6.5–8 while the pH curve for pyrophosphomevalonate decarboxylase showed a peak activity at approx 6. No age‐dependent change occurred in the activities of mevalonate kinase and phosphomevalonate kinase in developing brain, whereas pyrophosphomevalonate decarboxylase activity in brain increased during the 1st week after birth, reached a peak value at about the 8th day of age and declined slowly thereafter. The Km for brain mevalonate kinase in 2, 13 and 52 day old rats were 312, 400 and 434 μM, respectively. The Vmax for the kinase in 2, 13 and 52 day old rats were in the range of 45–52 nmol/h/mg protein, respectively. This suggests that, like in liver (Ramachandran & Shah, 1976), pyrophosphomevalonate decarboxylase in brain may also be one regulatory step for cholesterol synthesis.

Brain Phosphorylation and Decarboxylation of Mevalonic Acid in the Neonatal Chick

“…Thus, pH values observed for optimal activity are higher than those reported for both kinases in mammal tissues [8,9]. How ever, the pH profile of MVAPP decarboxyl ase from chick brain is similar to that re ported from rat brain [14], On the basis of these results, the hypothe sis about a main role of the reactions of MVA phosphorylation and decarboxylation in the cholesterol biosynthesis may be corrobo rated.…”

“…Ramachandran and Shah [14] reported that the use of different buffering compo nents to obtain the necessary pH range did not influence the activities of any of the three enzymes in rat brain. Nevertheless, our re sults indicate the existence of differences in the amount of MVAP and MVAPP found when two different types of buffers were used.…”

“…On the other hand, it should be borne in mind that since the reaction catalyzed by MVAP kinase is reversible [8], the amount of MVAPP formed or accumulated is regulated by the equilibrium constant of the kinase reaction, particularly when the rate of decar boxylation is low [13], However, it is ac cepted that the specific activity of MVAPP decarboxylase was the lowest of the three mevalonate-metabolizing enzymes in the rat liver [3] and brain [14]. Our results in chick brain seem to corroborate these data.…”

“…Bhat and Ramasarma [2] have re ported a rhythmic activity in the utilization of mevalonate indicating that the step re sponsible is probably between mevalonate and isopentenyl pyrophosphate. Recently, Ramachandran and Shah [14] have also sug gested that decarboxylation is a key rate-lim iting step in cerebral sterol synthesis, ap pearing to be higher in immature brain than in adult brain.…”

Phytoalexins: Enzymology and Molecular Biology

“…Mevalonic acid 5-phosphate is further phosphorylated to yield MVA 5-pyrophosphate; the reaction is catalyzed by 5-phosphomevalonate kinase (EC 2.7.4.2). This reaction is freely reversible in animal systems (395,396,397). The product of the reaction has been demonstrated in a number of higher plants (377,380,(384)(385)(386); however, the specific kinase has only been detected in the latex of Heveu brasiliensis (398) and in leaves of Nepera cararia (399).…”