Isopentenyl-Diphosphate Isomerases in Human and Mouse: Evolutionary Analysis of a Mammalian Gene Duplication

Abstract

Isopentenyl diphosphate isomerase (IDI) activates isopentenyl diphosphate (IPP) for polymerization by converting it to its highly nucleophilic isomer dimethylallyl diphosphate (DMAPP). In plants, this central reaction of isoprenoid biosynthesis is catalyzed by various highly conserved isozymes that differ in expression pattern and subcellular localization. Here we report the identification of an IDI duplication in mammals. In contrast to the situation in plants, only one of the two isoforms (IDI1) is highly conserved, ubiquitously expressed and most likely responsible for housekeeping isomerase activity. The second isoform (IDI2) is much more divergent. We demonstrate that after the initial duplication IDI2 underwent a short phase of apparently random change, during which its active center became modified. Afterwards, IDI2 was exapted for a novel function and since then has been under strong purifying selection for at least 70 million years. Molecular modeling shows that the modified IDI2 is still likely to catalyze the isomerization of IPP to DMAPP. In humans, IDI2 is expressed at high levels only in skeletal muscle, where it may be involved in the specialized production of isoprenyl diphosphates for the posttranslational modification of proteins. The significant positive fitness effect of IDI2, revealed by the pattern of sequence conservation, as well as its specific expression pattern underscores the importance of the IDI gene duplication in mammals.

IDI2, a Second Isopentenyl Diphosphate Isomerase in Mammals

“…A model for catalytic activity in IDI2 was presented previously (10 (25). While further studies are required to identify the IDI2 specific active site residues, our data show that IDI2 is capable of catalyzing the isomerization of IPP to DMAPP by a novel mechanism.…”

“…IDI2 shares a high degree of sequence homology to its isozyme IDI1 at both the amino acid and nucleotide level (10). The predicted protein product shows 81% similarity and 65% identity to human IDI1.…”

“…Our previous work suggested that IDI2 may be a factor in muscle-specific pathologies, such as rhabdomyolysis stemming from treatment with statins (simvastatin), a class of cholesterol-lowering drugs that act specifically as HMG-CoA reductase (HMGCR) inhibitors (10).…”

“…The enzyme isopentenyl diphosphate isomerase (IDI1; EC 5.3.3.2) transforms unreactive IPP into its reactive isomer DMAPP by the concerted addition and abstraction of protons at C-4. These two isomers are the building blocks for the successive head-to-tail condensation reactions that result in the synthesis of geranyl diphosphate (GPP, C 10 ) FPP (C 15 ) and ultimately, non-sterol products and cholesterol (3).…”

“…We previously reported a detailed phylogenetic and structural analysis of IDI2 (10). Molecular modeling suggested that IDI2 is likely to perform functionally as an isomerase despite a Ser to Cys change within the putative active site.…”