# IDH1 (Isocitrate Dehydrogenase 1): R132H Neo-Enzymatic Activity, 2-HG Accumulation, and Glioma Genetics


## Key Takeaways

- Recurrent heterozygous mutations in *IDH1*, most commonly R132H, confer a neomorphic enzymatic activity that catalyzes the reduction of α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (2-HG), an oncometabolite.
- Accumulation of 2-HG disrupts epigenetic regulation by inhibiting α-KG-dependent dioxygenases, including TET enzymes and histone demethylases, leading to a CpG island methylator phenotype (G-CIMP) and global epigenetic dysregulation in gliomas.
- *IDH1* mutations are critical diagnostic and prognostic markers in gliomas, with R132H being detectable via mutation-specific immunohistochemistry (H09 antibody), and are also found in acute myeloid leukemia and intrahepatic cholangiocarcinoma.
- Targeted therapies, such as the FDA-approved dual IDH1/IDH2 inhibitor vorasidenib and the IDH1-selective inhibitor ivosidenib, exploit the neomorphic enzymatic activity to inhibit tumor growth by reducing 2-HG levels.
- Germline *IDH1* mutations, particularly R132C and R132H, are associated with inherited skeletal disorders like Ollier disease and Maffucci syndrome, which carry an increased risk of malignant transformation to chondrosarcoma and glioma.

---

## Executive Summary & Key Metadata

The **isocitrate dehydrogenase 1 (IDH1)** gene encodes a homodimeric, NADP⁺-dependent metabolic enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the cytoplasm and peroxisomes. Beyond its canonical metabolic role, IDH1 has emerged as a central node in cancer biology following the discovery of recurrent, heterozygous, gain-of-function missense mutations at arginine 132 (R132) in low-grade gliomas and secondary glioblastomas. These mutations confer a neomorphic enzymatic activity: the NADPH-dependent reduction of α-KG to the oncometabolite D-2-hydroxyglutarate (2-HG). Accumulation of 2-HG competitively inhibits α-KG-dependent dioxygenases, including the TET family of 5-methylcytosine hydroxylases and JmjC-domain-containing histone demethylases, resulting in a CpG island methylator phenotype (GIMP) and global epigenetic dysregulation. This manual provides an exhaustive, biophysically grounded reference on IDH1, covering its genomic architecture, structural biology, signaling networks, clinical mutation spectrum, pharmacogenomic targeting, and bioinformatic resources.

| **Attribute** | **Value** |
|---|---|
| **HGNC Symbol** | IDH1 |
| **UniProt Accession** | O75874 |
| **Representative PDB ID** | 3G4E (wild-type human IDH1 homodimer with NADP⁺ and isocitrate) |
| **Chromosomal Locus** | 2q34 (GRCh38: chr2:208,236,227-208,266,074, minus strand) |
| **Primary Molecular Function** | NADP⁺-dependent oxidative decarboxylation of isocitrate to α-KG; NADPH production; reductive carboxylation of α-KG to isocitrate under hypoxia |
| **Disease & Pathology Associations** | Low-grade diffuse gliomas (WHO grade II/III), secondary glioblastoma (WHO grade IV), acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma, angioimmunoblastic T-cell lymphoma, Ollier disease, Maffucci syndrome |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Coordinates and Gene Structure

The human *IDH1* gene is located on the long arm of chromosome 2 at cytogenetic band **2q34**. In the GRCh38 assembly, the gene spans approximately 29.8 kilobases (kb) from position 208,236,227 to 208,266,074 on the minus strand. The gene is oriented in a head-to-head configuration with its neighboring gene *DNER* (delta/notch-like EGF repeat containing), with a bidirectional promoter region shared between the two loci. This intergenic region is approximately 1.2 kb and contains a CpG island that is differentially methylated in cancer.

The *IDH1* gene comprises **10 exons** and **9 introns**, with the coding sequence (CDS) spanning 1,326 nucleotides that translate into a 414-amino-acid precursor protein. Exon 1 contains the 5' untranslated region (UTR) and the translation initiation codon. Exons 2 through 9 encode the conserved isocitrate/isopropylmalate dehydrogenase (IPMDH) superfamily domain. Exon 10 harbors the stop codon and a long 3' UTR of approximately 2.4 kb that contains multiple AU-rich elements (AREs) and binding sites for microRNAs (e.g., miR-183, miR-96), which post-transcriptionally regulate mRNA stability.

### 1.2 Promoter Architecture and Transcriptional Regulation

The core promoter of *IDH1* lacks a canonical TATA box but contains a high-density Sp1 binding site cluster and an initiator (Inr) element overlapping the transcription start site (TSS). Chromatin immunoprecipitation sequencing (ChIP-seq) data from ENCODE reveal that the promoter is marked by H3K4me3 and H3K27ac in most cell types, consistent with constitutive, housekeeping expression. However, tissue-specific enhancer elements located in intron 1 and the intergenic region between *IDH1* and *DNER* modulate expression levels across tissues, with highest expression in liver, kidney, and brain.

Several transcription factors have been experimentally validated to bind the *IDH1* promoter:

- **HIF-1α (Hypoxia-Inducible Factor 1α):** Under hypoxic conditions, HIF-1α binds to a hypoxia-responsive element (HRE) located at position -1,850 relative to the TSS, upregulating *IDH1* transcription. This is part of a metabolic adaptation loop that promotes reductive carboxylation of α-KG to isocitrate for lipid biosynthesis.
- **p53 (TP53):** Wild-type p53 binds to a response element in intron 1 and represses *IDH1* expression under conditions of DNA damage, reducing NADPH pools and sensitizing cells to oxidative stress.
- **c-Myc:** MYC binds to E-box elements in the proximal promoter and activates transcription, linking *IDH1* expression to proliferative metabolic programs.
- **PPARγ (Peroxisome Proliferator-Activated Receptor Gamma):** In adipocytes, PPARγ/RXRα heterodimers bind to a PPRE in the distal promoter, driving *IDH1* expression during adipogenesis.

### 1.3 Alternative Splicing and Isoforms

The *IDH1* gene undergoes alternative splicing in the 5' UTR and, less commonly, in the coding region. The major transcript (ENST00000378653.9) encodes the canonical 414-amino-acid protein. A minor splice variant (ENST00000433798.5) retains intron 4, introducing a premature stop codon that produces a truncated 189-amino-acid protein lacking the catalytic domain. This variant is subject to nonsense-mediated decay (NMD) and is not predicted to produce a stable protein.

More importantly, a **peroxisomal targeting signal (PTS1)** variant arises from alternative transcription start site usage. The canonical protein ends with the C-terminal tripeptide **SKL** (Ser-Lys-Leu), which directs a fraction of IDH1 to peroxisomes. A second transcript isoform that skips exon 10 produces a protein with a different C-terminus lacking the PTS1 signal, retaining the protein exclusively in the cytosol. The relative abundance of these isoforms varies by tissue, with the peroxisomal form enriched in hepatocytes.

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Overall Fold and Quaternary Structure

The IDH1 protein is a **homodimer** in solution, with each monomer folding into a two-domain architecture characteristic of the IPMDH superfamily. The high-resolution crystal structure of wild-type human IDH1 in complex with NADP⁺ and isocitrate was solved at 2.1 Å resolution (PDB: **3G4E**). Each monomer consists of:

- **Large domain (residues 1–103 and 286–414):** A parallel β-sheet core flanked by α-helices, forming the dimerization interface and the NADP⁺-binding pocket.
- **Small domain (residues 104–285):** An α/β fold that undergoes a large conformational change (~13° rotation) upon substrate binding, closing the active site cleft.

The dimer interface buries approximately 3,400 Ų of solvent-accessible surface area per monomer and is stabilized by hydrophobic interactions and a network of salt bridges involving residues R109, R132, and E259. The two active sites are located at the interface between the large domain of one monomer and the small domain of the other, a feature known as a "domain-swapped" active site.

### 2.2 Catalytic Site Architecture

The active site of each monomer contains three distinct binding pockets:

1. **Isocitrate/Metal Binding Pocket:** The substrate isocitrate is coordinated by a divalent metal ion (Mg²⁺ or Mn²⁺) that is chelated by residues D252, D275, and D279. The γ-carboxylate of isocitrate forms hydrogen bonds with the side chains of R100, R109, and R132. The hydroxyl group at C2 of isocitrate is positioned for hydride transfer to the C4 position of the nicotinamide ring of NADP⁺.

2. **NADP⁺ Binding Pocket:** The 2'-phosphate group of NADP⁺ is specifically recognized by a conserved arginine cluster (R314, R395) and a tyrosine residue (Y316). This selectivity for NADP⁺ over NAD⁺ is critical for the enzyme's role in maintaining the cytosolic NADPH/NADP⁺ redox balance.

3. **Allosteric Regulatory Site:** A recently identified allosteric pocket located at the dimer interface binds citrate and other tricarboxylic acid cycle intermediates, modulating enzyme activity through a mechanism of negative feedback.

### 2.3 The R132 Residue and the Neo-Enzymatic Switch

Arginine 132 (R132) is located in the small domain, positioned at the base of the active site cleft. In the wild-type enzyme, the guanidinium group of R132 forms a bidentate salt bridge with the γ-carboxylate of isocitrate, stabilizing the substrate in a conformation that favors oxidative decarboxylation. This interaction is essential for the correct orientation of the substrate for hydride transfer.

Mutation of R132 to histidine (R132H), cysteine (R132C), serine (R132S), glycine (R132G), leucine (R132L), or valine (R132V) abolishes the salt bridge with isocitrate. Structural studies of the R132H mutant (PDB: **4K3W**) reveal that the histidine side chain reorients the active site to accommodate α-KG as an alternative substrate. The mutant enzyme retains the ability to bind NADPH but loses the capacity to bind isocitrate productively. Instead, the active site geometry now positions α-KG such that the C2 carbonyl is in proximity to the C4 of the nicotinamide ring, enabling a hydride transfer that reduces α-KG to **D-2-hydroxyglutarate (2-HG)**. This reaction consumes NADPH and is thermodynamically favorable, representing a true gain-of-function neomorphic activity.

### 2.4 Post-Translational Modifications

IDH1 is subject to several post-translational modifications that regulate its activity and stability:

- **Phosphorylation:** Src-family kinases phosphorylate Y42, which enhances enzyme activity and promotes cell proliferation in chronic myeloid leukemia.
- **Acetylation:** Acetylation of K374 by the acetyltransferase p300 reduces enzyme activity; deacetylation by SIRT3 reverses this effect.
- **Ubiquitination:** The E3 ligase CHIP (STUB1) ubiquitinates IDH1 at K197, targeting it for proteasomal degradation under conditions of prolonged oxidative stress.
- **S-Nitrosylation:** Nitric oxide modifies C379, inhibiting enzyme activity and contributing to nitrosative stress in neurodegenerative conditions.

### 2.5 Interactive 3D Visualizer

[Interactive 3D Protein Visualizer: Load IDH1 (PDB: 3G4E)](/tools/protein-structure-viewer?source=direct&pdbId=3G4E)

The visualizer tool allows users to rotate the homodimer, highlight the R132 residue, visualize the NADP⁺ cofactor, and overlay the conformational change between the open (substrate-free) and closed (substrate-bound) states. Users can also load the R132H mutant structure (PDB: 4K3W) to compare active site geometries.

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Canonical Metabolic Function

In the cytosol and peroxisomes, IDH1 catalyzes the reversible oxidative decarboxylation of isocitrate to α-KG, producing NADPH:

**Isocitrate + NADP⁺ ⇌ α-KG + CO₂ + NADPH + H⁺**

This reaction is a major source of cytosolic NADPH, which is essential for:

- **Glutathione regeneration:** NADPH is a cofactor for glutathione reductase, maintaining reduced glutathione pools for antioxidant defense.
- **Fatty acid and cholesterol biosynthesis:** NADPH provides reducing equivalents for fatty acid synthase and HMG-CoA reductase.
- **Cytochrome P450 activity:** Microsomal P450 enzymes require NADPH for xenobiotic metabolism.
- **Nitric oxide synthase (NOS) activity:** NOS requires NADPH as an electron donor.

Under hypoxic conditions, IDH1 operates in the reverse direction, catalyzing the reductive carboxylation of α-KG to isocitrate. This reaction is critical for the production of citrate and acetyl-CoA for de novo lipogenesis in cells with compromised oxidative metabolism.

### 3.2 The Oncometabolite 2-HG and Epigenetic Reprogramming

The R132H mutation converts IDH1 into a 2-HG-producing enzyme. 2-HG accumulates to millimolar concentrations in mutant IDH1-expressing cells, compared to micromolar levels in normal tissue. 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including:

- **TET1/2/3 (Ten-Eleven Translocation) enzymes:** These enzymes catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and further oxidized derivatives. Inhibition by 2-HG leads to DNA hypermethylation, particularly at CpG islands, resulting in the **Glioma CpG Island Methylator Phenotype (G-CIMP)**.
- **JmjC-domain-containing histone demethylases:** 2-HG inhibits KDM4A/B/C (which demethylate H3K9me2/3 and H3K36me2/3) and KDM2A (which demethylates H3K36me2), leading to hypermethylation of histone lysine residues and altered chromatin states.
- **Collagen prolyl-4-hydroxylases:** Inhibition of these enzymes impairs collagen maturation, contributing to the extracellular matrix remodeling observed in gliomas.
- **Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs):** 2-HG inhibits PHDs, leading to stabilization of HIF-1α even under normoxic conditions. This pseudo-hypoxic state promotes angiogenesis, glycolysis, and invasion.

### 3.3 Signaling Pathway Integration

IDH1 mutations intersect with several canonical signaling pathways:

- **PI3K/AKT/mTOR Pathway:** 2-HG accumulation activates AKT signaling through inhibition of PTEN (a tumor suppressor) via epigenetic silencing. This promotes cell survival and proliferation.
- **Wnt/β-Catenin Pathway:** 2-HG inhibits the activity of TET enzymes, leading to hypermethylation of the SFRP (secreted frizzled-related protein) gene promoters. Loss of SFRP expression derepresses Wnt signaling, driving glioma stem cell self-renewal.
- **p53 Pathway:** Mutant IDH1 cells exhibit impaired p53-mediated apoptosis due to hypermethylation of p53 target gene promoters (e.g., CDKN1A/p21). This contributes to resistance to DNA-damaging chemotherapy.
- **NF-κB Pathway:** 2-HG activates NF-κB signaling by inhibiting IκBα expression, promoting an inflammatory tumor microenvironment.

### 3.4 Protein-Protein Interaction Network

IDH1 participates in a complex protein-protein interaction network, as catalogued by BioGRID and STRING databases. Key interactors include:

- **ACLY (ATP Citrate Lyase):** IDH1 and ACLY form a metabolic complex that channels isocitrate/citrate for lipogenesis.
- **HIF-1α:** Direct binding of IDH1 to HIF-1α stabilizes the transcription factor under hypoxic conditions.
- **p53 (TP53):** IDH1 binds to p53 and modulates its transcriptional activity; mutant IDH1 disrupts this interaction.
- **CHIP (STUB1):** The E3 ligase binds IDH1 for ubiquitin-mediated degradation.
- **SIRT3:** The mitochondrial deacetylase interacts with IDH1 in the cytosol, although its primary target is mitochondrial [IDH2](/knowledge/bioinformatics/genes/cancer-genomics/idh2-gene-structure-function-pathway).

### 3.5 Mermaid Diagram: IDH1 Signaling and Metabolic Pathway

```mermaid
flowchart TD
    A["Glucose"] -->|"Glycolysis"| B["Pyruvate"]
    B -->|"Acetyl-CoA"| C["TCA Cycle"]
    C -->|"Citrate"| D["Isocitrate"]
    D -->|"IDH1 WT + NADP+"| E["α-KG + NADPH"]
    E -->|"TET enzymes"| F["DNA Demethylation"]
    E -->|"JmjC demethylases"| G["Histone Demethylation"]
    E -->|"PHDs"| H["HIF-1α Degradation"]
    
    D -->|"IDH1 R132H + NADPH"| I["2-HG"]
    I -->|"Inhibits"| F
    I -->|"Inhibits"| G
    I -->|"Inhibits"| H
    H -->|"Stabilized HIF-1α"| J["Angiogenesis, Glycolysis"]
    
    E -->|"Reductive carboxylation"| D
    D -->|"ACLY"| K["Acetyl-CoA for Lipogenesis"]
    
    style I fill:#ff6666,stroke:#333,stroke-width:2px
    style E fill:#66ff66,stroke:#333,stroke-width:2px
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 The R132 Hotspot

The vast majority of pathogenic *IDH1* mutations are missense mutations affecting **codon 132** (c.394G>A for R132H). The mutation spectrum is non-random:

| **Mutation** | **cDNA Change** | **Frequency in Gliomas** | **Enzymatic Activity** |
|---|---|---|---|
| R132H | c.394G>A | ~89% | Neomorphic (2-HG production) |
| R132C | c.394C>T | ~5% | Neomorphic |
| R132S | c.394A>T | ~2% | Neomorphic |
| R132G | c.394C>G | ~2% | Neomorphic |
| R132L | c.395G>T | ~1% | Neomorphic |
| R132V | c.395G>A | ~1% | Neomorphic |

All R132 mutations are heterozygous, with the wild-type allele retained. This is because the mutant enzyme forms heterodimers with the wild-type protein, and the neomorphic activity is dominant. Complete loss of IDH1 activity (homozygous mutation or deletion) is not observed in cancers, indicating that residual wild-type activity is required for cell viability.

### 4.2 Other Pathogenic Variants

Less common pathogenic variants outside codon 132 include:

- **R100Q (c.299G>A):** Located in the substrate-binding pocket; reduces catalytic activity but does not confer neomorphic activity. Associated with a subset of gliomas with intermediate 2-HG levels.
- **G97D (c.290G>A):** A rare variant reported in chondrosarcoma; disrupts the metal-binding site.
- **Y139D (c.415T>G):** Found in a single case of AML; reduces enzyme stability.

### 4.3 Germline Mutations and Inherited Syndromes

Heterozygous germline mutations in *IDH1* cause **Ollier disease** and **Maffucci syndrome**, rare skeletal disorders characterized by multiple enchondromas and, in Maffucci syndrome, hemangiomas. The germline mutations are typically R132C or R132H and are associated with somatic mosaicism. Patients with these syndromes have a high risk of developing chondrosarcoma, glioma, and AML.

### 4.4 Clinical Differential Diagnosis

The presence of *IDH1* mutations is a critical diagnostic and prognostic marker in gliomas:

- **WHO Grade II/III Diffuse Gliomas:** Approximately 70-80% harbor *IDH1* mutations, with R132H being the most common. IDH-mutant gliomas have a significantly better prognosis than IDH-wild-type gliomas of the same grade.
- **Secondary Glioblastoma (WHO Grade IV):** Approximately 80% of secondary GBM (progressing from lower-grade glioma) are IDH1-mutant, whereas primary GBM is almost always IDH1-wild-type.
- **Acute Myeloid Leukemia (AML):** Approximately 10-20% of AML cases harbor *IDH1* R132 mutations, which are associated with normal karyotype and NPM1 co-mutation.
- **Cholangiocarcinoma:** Approximately 20% of intrahepatic cholangiocarcinomas harbor *IDH1* mutations.

Immunohistochemistry using the mutation-specific antibody **H09** (which detects R132H) is the standard diagnostic tool. For non-R132H mutations, targeted next-generation sequencing is required.

## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Oncoprotein Interactions

While IDH1 is not a direct target of viral oncoproteins, several viruses modulate IDH1 expression or activity to support their replicative cycle:

- **Human Cytomegalovirus (HCMV):** HCMV infection upregulates IDH1 expression in glioblastoma cells. The virus relies on host NADPH production for viral DNA synthesis and to counteract oxidative stress. HCMV proteins IE1 and IE2 transactivate the *IDH1* promoter via Sp1 binding sites.
- **Hepatitis B Virus (HBV):** The HBV X protein (HBx) stabilizes HIF-1α, which in turn upregulates IDH1 expression. This promotes the Warburg effect and lipogenesis in HBV-associated hepatocellular carcinoma.
- **Epstein-Barr Virus (EBV):** In EBV-positive nasopharyngeal carcinoma, the viral latent membrane protein 1 (LMP1) activates NF-κB, which transcriptionally represses IDH1, leading to reduced NADPH pools and increased oxidative stress. This paradoxically promotes viral latency.

### 5.2 Bacterial Effectors

- **Mycobacterium tuberculosis:** The bacterial effector protein Rv1772 has been shown to interact with host IDH1, redirecting host metabolism toward lipid biosynthesis to support bacterial persistence in macrophages.
- **Salmonella enterica:** The type III secretion effector SopE activates host Rac1, which in turn downregulates IDH1 expression, reducing NADPH and impairing the respiratory burst in infected macrophages.

### 5.3 Immune Evasion Mechanisms

Mutant IDH1-expressing tumor cells evade immune surveillance through multiple mechanisms:

- **2-HG-Mediated T-Cell Suppression:** 2-HG is taken up by CD8⁺ T cells via the SLC13A3 transporter, where it inhibits T-cell receptor signaling and reduces IFN-γ production.
- **Altered Antigen Presentation:** 2-HG inhibits the JmjC-domain-containing demethylase KDM5B, which is required for the expression of MHC class I genes. This reduces tumor immunogenicity.
- **Macrophage Polarization:** 2-HG promotes the polarization of tumor-associated macrophages toward an M2 (immunosuppressive) phenotype.

## 6. [Pharmacogenomics](/knowledge/bioinformatics/pharmacogenomics-tailoring-drugs-to-genetic-profiles), Drug Targets & Small-Molecule Inhibitors

### 6.1 FDA-Approved Targeted Therapies

**Vorasidenib (AG-881)** is an orally bioavailable, brain-penetrant dual inhibitor of mutant IDH1 and IDH2. It was approved by the FDA in August 2024 for the treatment of grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation in adults following prior surgery. The approval was based on the INDIGO phase 3 trial, which demonstrated a significant improvement in progression-free survival (hazard ratio 0.39) compared to placebo.

**Ivosidenib (AG-120)** is a selective, orally available inhibitor of mutant IDH1. It was initially approved in 2018 for relapsed/refractory AML with an IDH1 mutation and subsequently for newly diagnosed AML ineligible for intensive chemotherapy. Ivosidenib is also approved for advanced cholangiocarcinoma with an IDH1 mutation (2021). It does not cross the blood-brain barrier efficiently, limiting its use in gliomas.

### 6.2 Investigational Small-Molecule Inhibitors

| **Drug** | **Target** | **Phase** | **Indication** |
|---|---|---|---|
| Olutasidenib (FT-2102) | Mutant IDH1 | Approved (2022) for relapsed/refractory AML | AML |
| DS-1001b | Mutant IDH1 | Phase 2 | Glioma |
| BAY-1436032 | Mutant IDH1 | Phase 1 | AML, solid tumors |
| IDH305 | Mutant IDH1 | Phase 1 (discontinued) | AML, glioma |

### 6.3 Mechanism of Action of Mutant IDH1 Inhibitors

Allosteric inhibitors such as ivosidenib and vorasidenib bind to a hydrophobic pocket at the dimer interface, distinct from the active site. This binding stabilizes the enzyme in an "open" conformation that cannot bind α-KG or NADPH productively. The inhibitors do not affect wild-type IDH1 activity, which is essential to preserve normal NADPH production.

### 6.4 Resistance Mechanisms

Resistance to IDH1 inhibitors arises through:

- **Second-site mutations:** Mutations at the dimer interface (e.g., A258D, G289D) that prevent inhibitor binding while preserving neomorphic activity.
- **IDH2 mutations:** Upregulation of mutant IDH2 can compensate for IDH1 inhibition, maintaining 2-HG production.
- **Metabolic bypass:** Activation of the mitochondrial IDH2 or cytosolic IDH3 can restore α-KG levels, reducing the selective pressure for 2-HG production.

### 6.5 Pharmacogenomic Considerations

The **UGT1A1*28** polymorphism (TA7/TA7 genotype) is associated with increased bilirubin levels in patients treated with ivosidenib, requiring dose adjustment. Additionally, [CYP3A4](/knowledge/bioinformatics/genes/medical-genetics/cyp3a4-gene-structure-function-pathway) inducers (e.g., rifampin) reduce ivosidenib exposure, while strong CYP3A4 inhibitors increase exposure and require dose reduction.

## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Accession/ID** | **URL** |
|---|---|---|
| NCBI Gene | 3417 | https://www.ncbi.nlm.nih.gov/gene/3417 |
| Ensembl | ENSG00000138413 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000138413 |
| UniProt | O75874 | https://www.uniprot.org/uniprotkb/O75874 |
| RCSB PDB | 3G4E (WT), 4K3W (R132H) | https://www.rcsb.org/structure/3G4E |
| ClinVar | Gene: IDH1 | https://www.ncbi.nlm.nih.gov/clinvar/?term=IDH1%5Bgene%5D |
| COSMIC | Gene: IDH1 | https://cancer.sanger.ac.uk/cosmic |
| Gene Ontology (GO) | GO:0004450 (isocitrate dehydrogenase activity), GO:0006749 (NADPH regeneration), GO:0005737 (cytoplasm) | https://www.ebi.ac.uk/QuickGO/ |
| STRING | IDH1 (Homo sapiens) | https://string-db.org/network/9606.ENSP00000378782 |
| BioGRID | IDH1 | https://thebiogrid.org/109096 |
| PharmGKB | IDH1 | https://www.pharmgkb.org/gene/PA30196 |
| GTEx | IDH1 expression | https://gtexportal.org/home/gene/IDH1 |
| Human Protein Atlas | IDH1 | https://www.proteinatlas.org/ENSG00000138413-IDH1 |

## Related Clinical & Scientific Guides

* [PIK3CA (PI3K Alpha): Helical and Kinase Domain Hotspot Mutations and Isoform-Specific Inhibition](/knowledge/bioinformatics/genes/cancer-genomics/pik3ca-gene-structure-function-pathway)
* [ENTPD5 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/entpd5-gene-structure-function-pathway)
* [PDGFB Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/pdgfb-gene-structure-function-pathway)


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