{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Type II isopentenyl diphosphate isomerase (IDI‐2) is an enzyme that catalyzes the reversible isomerization of isopentenyl diphosphate (IPP) to dimethylallyl diphosphate (DMAPP), a reaction that provides the essential five‐carbon building blocks for isoprenoid biosynthesis. In mammals, gene duplication produced two isoforms of IDI; the highly conserved, ubiquitously expressed IDI‐1 and a more divergent IDI‐2 that is expressed in a tissue‐specific manner. In humans, IDI‐2 is predominantly expressed in skeletal muscle and has been shown to functionally complement IPP isomerase deficiency in yeast, suggesting that it furnishes specialized pools of isoprenyl diphosphates for posttranslational modification and other anabolic processes ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its canonical catalytic role, alterations in the genomic region that harbors the IDI genes have been linked to human disease. For example, immunohistochemical studies in neurodegenerative disorders indicate that IDI‐2—as well as IDI‐1—might contribute to the generation of cholesterol metabolites that promote α‐synuclein aggregation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "], while copy‐number gains in the IDI1/IDI2 gene region have been implicated in the pathogenesis of sporadic amyotrophic lateral sclerosis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In plants, members of the IPP isomerase gene family, including IDI‐2, have been associated with the regulation of secondary isoprenoid biosynthetic pathways. For instance, in Pogostemon cablin, expression of an isopentenyl pyrophosphate isomerase 2 gene correlates with the biosynthesis of important terpenoids such as patchoulol and pogostone, underscoring the enzyme’s role in directing metabolic flux toward specialized natural products ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "].\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n At the mechanistic level, studies in various bacterial and archaeal systems have elucidated that type II IDI enzymes employ a reduced flavin mononucleotide cofactor in an unusual acid/base catalytic mechanism to mediate protonation–deprotonation steps without a net redox change. These investigations have provided detailed insights into the chemical mechanism and cofactor utilization that appear to be conserved across divergent IDI‐2 homologues, although the functional diversification in eukaryotes (e.g., tissue‐specific expression and regulation) adds additional layers of biological nuance ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "].\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Thus, IDI‐2 fulfills a dual role: it is essential for the proper balance of IPP and DMAPP in isoprenoid biosynthesis, and its regulated, tissue‐specific expression—as well as genomic dosage—may have significant implications for metabolic specialization and disease.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daun B Clizbe, Michelle L Owens, Kimberly R Masuda, et al. 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