Recombinant Bovine 3-ketodihydrosphingosine reductase (KDSR)
Description
Role in Bovine Spinal Muscular Atrophy (SMA)
A naturally occurring A175T mutation in bovine FVT1 (KDSR) causes SMA, a neurodegenerative disorder. This mutation abolishes enzymatic activity in vitro but allows partial function in vivo, explaining postnatal disease onset .
Key Findings from SMA Studies
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In Vitro Activity:
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In Vivo Complementation:
| Assay | Wild-Type KDSR | A175T Mutant | Outcome |
|---|---|---|---|
| In Vitro | Active | Inactive | Complete loss of 3KDS reduction |
| In Vivo (Yeast) | Fully functional | Partial function | Viability retained in yeast model |
Enzymatic Activity and Mutation Impact
The A175T mutation disrupts the enzyme’s catalytic efficiency by altering the local conformation near the active site. Thr-175’s bulkier side chain may interfere with substrate binding or NADPH interaction .
Mechanism of Toxicity in SMA
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3KDS Accumulation: Inactive KDSR leads to elevated 3KDS levels, which disrupt endoplasmic reticulum (ER) function and proteostasis .
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ER Stress and Unfolded Protein Response: 3KDS accumulation triggers upregulation of ER chaperones (e.g., HSPA5) and ubiquitin-dependent degradation pathways, causing neuronal toxicity .
Recombinant Production and Applications
While direct data on bovine KDSR recombinant production is limited, yeast-based systems have been used to study its function. For example, bovine FVT1 was expressed in Saccharomyces cerevisiae to assess mutant complementation .
Research Findings and Clinical Implications
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Bovine SMA as a Model: The A175T mutation provides an animal model to study SMA pathogenesis, highlighting the sensitivity of motor neurons to metabolic disruptions .
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Therapeutic Potential: Targeting 3KDS detoxification or sphingolipid biosynthesis may offer strategies for SMA treatment, though translation to humans requires further validation .
Product Specs
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Target Background
- A G-to-A missense mutation in the FVT1 gene, encoding 3-ketodihydrosphingosine reductase, is strongly implicated in bovine spinal muscular atrophy. PMID: 17420465
