IDI2, a Second Isopentenyl Diphosphate Isomerase in Mammals

Abstract

We recently described the identification of a novel isopentenyl diphosphate isomerase, IDI2 in humans and mice. Our current data indicate that, in humans, IDI2 is expressed only in skeletal muscle. Isoprenoids and isoprenoid-derived compounds play an essential role in all living systems. They provide a necessary function in the organization of many biological systems including membrane structure, signal transduction, and redox chemistry. Several of the important end products of the isoprenoid biosynthetic pathway include: prenylated proteins, dolichols, vitamins A, D, E, and K, steroid hormones, carotenoids, bile acids, and cholesterol (1). In addition, this complex pathway also produces farnesyl diphosphate (FPP) 2 and geranyl-geranyl diphosphate (GGPP), compounds required for the isoprenylation of various G proteins (2).All isoprenoids are derived from the 5-carbon isoprene defined by isopentenyl diphosphate (IPP) and its highly electrophilic isomer dimethylallyl diphosphate (DMAPP). 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).IDI1 first identified in Saccharomyces cerevisiae (4) has since been characterized in numerous organisms including humans. Most recently, IDI1 has been identified in hamster and rat where it was shown to localize to the peroxisome by a Pex-5p-dependent PTS1 mechanism (5).Analysis of IDI1 in S. cerevisiae revealed two catalytically active amino acids, Cys 139 and Glu 207 . Mutagenesis analysis in the yeast enzyme demonstrated that a C139S mutation resulted in a significant reduction in isomerase activity whereas a Cys to Val or Ala change at this site abolished activity completely (6).Several examples of multiple IDI isozymes have been reported in plants and algae. In Nicotiana tobacum, the two IDI isozymes are regulated at the transcriptional level under a variety of environmental conditions (7). Similar duplications exist in Cinchona robusta and the green alga Hematococcus pluvialis. Additionally, multiple isozymes of IDI have been identified in higher eukaryotes Sus domesticus and Gallus gallus. In all cases the isozymes maintain specialized functions by different expression patterns, subcellular localization, and susceptibility to inhibitors (8, 9).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. In the current study we present the biochemical and functional characterization of IDI2 in mammals. Our data illustrate that IDI2 has a distinct tissue expression pattern, has functional isomerase activity in vivo, a unique kinetic profile, and is...

A comprehensive machine-readable view of the mammalian cholesterol biosynthesis pathway

“…Both enzymes act via a proton addition/elimination mechanism [44]. IDI2 requires the presence of a reduced flavin mononucleotide cofactor [43] and both enzymes are localized to the peroxisome [45].…”

Modeling cholesterol metabolism by gene expression profiling in the hippocampus

“…However, since Idi2 controls a forward and backward reaction the net result is more modest, as expected with a freely reversible reaction. 48 …”

“…The equilibrium of Idi2 favors dimethylpyrophosphate (M10 in Table S1, ESI†), but the reversibility of the isomerase reaction demonstrated direct formation of the reactant, isopentyl-pyrophosphate (M9 in Table S1, ESI†). 48 Therefore, we set k f = k b .…”

Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers

“…Among the most significantly altered genes in biceps, IDI2 (isopentenyl-diphosphate delta isomerase 2) encodes a skeletal muscle-specific isozyme of isopentenyl diphosphate isomerase located in peroxisomes and involved in the mevalonate pathway, which is essential for cholesterol biosynthesis (35,36). Its expression is reduced in affected biceps by 1.6-fold (P = 0.000001), whereas its expression was not significantly altered in deltoid.…”