Changes

''IDH1'' is most highly expressed in the mammalian liver, with moderate expression in other tissues [1]. A C-terminal peroxisome targeting signal 1 sequence allows for its peroxisomal localization [2]. The IDH1 protein is comprised of a large domain (residues 1-103 and 286-414, NM_005896.2/NP_005887.2), a small domain (residues 104-136 and 186-285, NM_005896.2/NP_005887.2) and a clasp domain (residues 137-185, NM_005896.2/NP_005887.2) [3]. The clasp domain holds together two IDH1 subunits and the enzyme active site is formed in a cleft created by the large and small domains of each subunit. Each active site can bind NADP+ and a metal ion in addition to the isocitrate substrate.

''IDH1'' is most highly expressed in the mammalian liver, with moderate expression in other tissues [1]. A C-terminal peroxisome targeting signal 1 sequence allows for its peroxisomal localization [2]. The IDH1 protein is comprised of a large domain (residues 1-103 and 286-414, NM_005896.2/NP_005887.2), a small domain (residues 104-136 and 186-285, NM_005896.2/NP_005887.2) and a clasp domain (residues 137-185, NM_005896.2/NP_005887.2) [3]. The clasp domain holds together two IDH1 subunits and the enzyme active site is formed in a cleft created by the large and small domains of each subunit. Each active site can bind NADP+ and a metal ion in addition to the isocitrate substrate.

With no bound substrate, the Asp279 residue (NM_005896.2/NP_005887.2) occupies the active site where isocitrate would ordinarily form a hydrogen bond with the Ser94 residue (NM_005896.2/NP_005887.2). This steric hindrance prohibits substrate binding until Asp279 (NM_005896.2/NP_005887.2) moves away, contacting Arg132 (NM_005896.2/NP_005887.2) in the process[3]. Once the isocitrate substrate is bound, it forms three hydrogen bonds with Arg132 (NM_005896.2/NP_005887.2) [4]. Arg132 (NM_005896.2/NP_005887.2) therefore plays a critical role in the conformational changes of the IDH enzyme that allow the enzyme to function normally.

With no bound substrate, the Asp279 residue (NM_005896.2/NP_005887.2) occupies the active site where isocitrate would ordinarily form a hydrogen bond with the Ser94 residue (NM_005896.2/NP_005887.2). This steric hindrance prohibits substrate binding until Asp279 (NM_005896.2/NP_005887.2) moves away, contacting Arg132 (NM_005896.2/NP_005887.2) in the process [3]. Once the isocitrate substrate is bound, it forms three hydrogen bonds with Arg132 (NM_005896.2/NP_005887.2) [4]. Arg132 (NM_005896.2/NP_005887.2) therefore plays a critical role in the conformational changes of the IDH enzyme that allow the enzyme to function normally.

The conversion of isocitrate to αKG for use in the TCA cycle is primarily carried out by IDH3 in mitochondria. Although the expression profile of genes involved in metabolism is altered in IDH1-mutated cells [5], IDH1 likely evolved primarily for the purpose of NADPH production and is the main producer of NADPH in the brain[6]. NADPH generated by IDH1 contributes to the cellular defence against reactive oxygen species (ROS), and IDH1 activity increases in response to oxidative insults [7,8]. IDH1 can also modulate the availability of αKG, which itself can function as a potent antioxidant [8].

The conversion of isocitrate to αKG for use in the TCA cycle is primarily carried out by IDH3 in mitochondria. Although the expression profile of genes involved in metabolism is altered in IDH1-mutated cells [5], IDH1 likely evolved primarily for the purpose of NADPH production and is the main producer of NADPH in the brain[6]. NADPH generated by IDH1 contributes to the cellular defence against reactive oxygen species (ROS), and IDH1 activity increases in response to oxidative insults [7,8]. IDH1 can also modulate the availability of αKG, which itself can function as a potent antioxidant [8].