IMPDH1 Gene - Inosine Monophosphate Dehydrogenase 1 <table class="infobox infobox-gene">
Overview
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IMPDH1 Gene - Inosine Monophosphate Dehydrogenase 1 <table class="infobox infobox-gene">
Overview
Mermaid diagram (expand to render)
IMPDH1 (Inosine Monophosphate Dehydrogenase 1) encodes the enzyme inosine monophosphate dehydrogenase type I, which catalyzes the NAD-dependent oxidation of IMP to XMP, the rate-limiting step in de novo guanine nucleotide biosynthesis. While traditionally studied in the context of cancer immunotherapy and antiviral therapy, IMPDH1 has emerging roles in neuronal function and has been implicated in several neurodegenerative diseases. [@bowne2002]
Gene Symbol : IMPDH1Official Name : Inosine-5'-monophosphate dehydrogenase 1Chromosomal Location : 7q31.3NCBI Gene ID : 3616Uniprot ID : P20839Protein Structure and Function IMPDH1 is a homomeric enzyme with the following characteristics: [@kent2015]
Quaternary structure : Tetrameric enzyme (four identical subunits)Molecular weight : ~56 kDa per subunitCofactor requirement : NAD+ as electron acceptorSubstrate specificity : IMP (inosine monophosphate)Catalytic Mechanism
IMP binds to the active site
NAD+ oxidizes IMP at C2 position, forming XMP (xanthosine monophosphate)
NADH is released
XMP is further converted to GMP by GMP synthetase
Alternative splicing IMPDH1 has multiple splice variants with tissue-specific expression patterns. [@ancolio1999]
Expression Patterns
Brain : Expressed in [neurons](/entities/neurons) throughout the CNS, particularly in:Cerebral [cortex](/brain-regions/cortex)
[Hippocampus](/brain-regions/hippocampus) (CA1-CA3 regions)
Cerebellum (Purkinje cells)
Retina (photoreceptor cells)
Lymphocytes : High expression in proliferating T and B cellsOther tissues : Heart, kidney, liverRole in Neurodegenerative Diseases
Retinitis Pigmentosa and Neurological Disease IMPDH1 mutations cause a distinct form of retinitis pigmentosa (RP) known as RP10, characterized by: [@takahashi2003]
Progressive retinal degeneration
Visual field constriction
Night blindness beginning in adolescence
Variable neurological features including:
Hearing loss
Ataxia
Mild cognitive impairment
The R105P and D226N mutations are among the most studied pathogenic variants [1][2]. [@li2006]
Alzheimer's Disease IMPDH1 may play indirect roles in Alzheimer's disease pathogenesis: [@cheng2012]
Purine metabolism dysregulation : IMPDH1 expression is altered in AD brains, affecting GTP pools critical for synaptic function [3][Amyloid-beta](/proteins/amyloid-beta) effects : Aβ can modulate IMPDH1 expression in neurons [4][Tau](/proteins/tau) pathology : GTP depletion through IMPDH1 dysfunction may affect tau phosphorylation [5]Energy metabolism : Guanine nucleotides are essential for mitochondrial functionParkinson's Disease
Dopaminergic neuron vulnerability : IMPDH1 activity may be particularly important for dopaminergic neuron survival [6]L-DOPA metabolism : The purine pathway intersects with dopamine biosynthesisMitochondrial function : GTP is required for mitochondrial DNA maintenanceAmyotrophic Lateral Sclerosis (ALS)
Motor neuron metabolism : High metabolic demand of motor neurons requires robust nucleotide synthesis [7]RNA metabolism : IMPDH1 provides GTP for RNA synthesis and processingProtein synthesis : GTP is needed for translational machineryTherapeutic Implications
IMPDH1 as Drug Target
Mycophenolate mofetil (CellCept) : An IMPDH inhibitor used in transplant and autoimmune diseasesTiazofurin : A nucleoside analogue IMPDH inhibitorRibavirin : Antiviral with IMPDH inhibitory activityConsiderations for Neurodegeneration
[Blood-brain barrier](/entities/blood-brain-barrier) penetration is limited for most IMPDH inhibitors
Systemic inhibition causes immunosuppression
May have different effects on neurons vs. other cell types
Biochemical Pathways
Purine Biosynthesis
Intersections with Neurobiology
cAMP/PKA signaling : GTP modulates G-protein signaling[mTOR](/mechanisms/mtor-signaling-pathway) pathway : GTP availability affects mTORC1 activitySynaptic plasticity : Local GTP synthesis regulates spine morphologyMyelin maintenance : Oligodendrocyte GTP needsInteracting Proteins
GMP synthetase (GMPS) : Downstream enzyme in GMP synthesisGMP reductase (GMPR) : Alternative pathway for GMP metabolismAdenylate kinases : Energy metabolismCytoskeletal proteins : For subcellular localizationGenetics
Mutations and Disease
RP10 mutations : R105P, A134D, R231H, D226NDominant inheritance : Most pathogenic variants act in a dominant-negative mannerVariable expressivity : Phenotype severity varies by mutationPolymorphisms
Various SNPs in IMPDH1 have been studied for:
Cancer susceptibility
Response to immunosuppressive therapy
IMPDH1 knockout mice : Show retinal degeneration and immunodeficiencyCRISPR models : Human neuronal models with IMPDH1 mutationsSmall molecule probes : Fluorescent substrates for activity measurementAdditional evidence sources: [@pandey2017]
See Also
Purine Metabolism
[Retinitis Pigmentosa](/diseases/retinitis-pigmentosa)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
Amyotrophic Lateral Sclerosis (ALS)
GTP Signaling
External Links
[NCBI Gene: IMPDH1](https://www.ncbi.nlm.nih.gov/gene/3616)
[Uniprot: IMPDH1](https://www.uniprot.org/uniprotkb/P20839)
[OMIM: IMPDH1](https://www.omim.org/entry/146690)
[Retina International: RP10](https://www.retina-international.org/)
References
[Bowne et al., IMPDH1 mutations causing retinitis pigmentosa (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/11875056/)
[Kent et al., RP10 phenotype-genotype correlations (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26042576/)
[Ancolio et al., Altered purine metabolism in AD (1999) (1999)](https://pubmed.ncbi.nlm.nih.gov/10488924/)
[Takahashi et al., Aβ effects on nucleotide metabolism (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/14585463/)
[Li et al., Tau phosphorylation and GTP metabolism (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16887817/)
[Cheng et al., IMPDH in dopaminergic neurons (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22406628/)
[Pandey et al., Nucleotide metabolism in ALS (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28742174/) Show full description