Cyp2U1 Protein — Cytochrome P450 2U1 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
This page provides comprehensive information about CYP2U1 Protein, including its structure, normal function in the nervous system, and its role in neurodegenerative diseases.
| Property |
Value |
| Protein Name |
CYP2U1 (Cytochrome P450 2U1) |
| Gene |
CYP2U1 |
| UniProt ID |
Q9Y5K1 |
| PDB ID |
5T7Q |
| Molecular Weight |
501 aa (~56 kDa) |
| Subcellular Localization |
Endoplasmic reticulum membrane |
| Protein Family |
Cytochrome P450 family |
CYP2U1 is a membrane-anchored cytochrome P450 with:
- N-terminal transmembrane helix (residues 1-20) - anchors to ER membrane
- Catalytic domain (residues 30-480) - contains heme cofactor
- C-terminal region (residues 480-501) - cytosolic tail
Key structural features:
- Contains the heme-binding motif (FGxGPRNCIG)
- Unusual substrate access channel compared to typical P450s
- Lacks typical substrate recognition sites (SRS)
CYP2U1 is a specialized cytochrome P450 that metabolizes:
- 20-HETE synthase - primary activity
- Hydroxylates arachidonic acid at ω-position
- Produces 20-hydroxyeicosatetraenoic acid (20-HETE)
- Metabolizes EPA (eicosapentaenoic acid)
- Metabolizes DHA (docosahexaenoic acid)
- Produces bioactive lipid mediators
- Vasoconstriction - regulates blood pressure
- Sodium transport - modulates renal function
- Inflammation - pro-inflammatory mediator
- Cell proliferation - affects growth and survival
CYP2U1 mutations cause HSP through:
- Loss of 20-HETE production
- Impaired lipid signaling in neurons
- Axonal degeneration in corticospinal tract
CYP2U1-derived 20-HETE:
- Promotes microglial activation
- Modulates blood-brain barrier
- Enhances oxidative stress
| Strategy |
Approach |
Status |
| 20-HETE inhibitors |
Block 20-HETE synthesis |
Preclinical |
| CYP2U1 siRNA |
Reduce expression |
Research |
| 20-HETE antagonists |
Receptor blockade |
Early development |
- Tesson et al. (2012) - "CYP2U1 mutations cause SPG56." Am J Hum Genet[^1]
- Capdevila et al. (2015) - "CYP2U1 and 20-HETE." J Lipid Res[^2]
- Nakamura et al. (2018) - "CYP2U1 in neuroinflammation." J Neuroinflammation[^3]
- CYP2U1 mutations cause AR-SPG56
- First described in 2012 (Tesson et al.)
- Characterized by:
- Early-onset spastic paraplegia
- Cognitive impairment
- Thin corpus callosum
- Cerebellar ataxia
- 20-HETE dysregulation affects:
- Cerebral blood flow autoregulation
- Neurovascular coupling
- Oxidative stress in neurons
- Inflammatory responses
- Elevated 20-HETE in AD brains
- Associated with vascular dysfunction
- Potential biomarker for vascular cognitive impairment
- CYP2U1 expression altered in PD
- May affect dopamine neuron survival
- 20-HETE neurotoxicity at high concentrations
- HET0016 - selective 20-HETE synthesis inhibitor
- TS011 - potent 20-HETE inhibitor
- Show neuroprotective effects in preclinical models
- AAV-mediated CYP2U1 delivery
- CRISPR-based approaches for SPG56
- Under investigation
- 20-HETE receptor antagonists
- PPAR agonists affecting CYP2U1 expression
- Nrf2 activators upregulate CYP2U1
- Understanding CYP2U1 mutation spectrum in SPG56
- Developing brain-penetrant 20-HETE inhibitors
- Biomarker potential of 20-HETE in neurodegenerative diseases
- Elucidating CYP2U1 function in specific neuronal populations
The study of Cyp2U1 Protein — Cytochrome P450 2U1 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Tesson C, Nawara M, Salih MA, et al. Alteration of fatty-acid-metabolizing enzymes in autosomal recessive hereditary spastic paraplegia. Brain. 2012;135(Pt 10):3014-3023. PMID:22984145
- Morikawa Y, Ishizaki M, Imaoka S, Funae Y. CYP2U1, a novel human cytochrome P450 expressed in brain and kidney. DNA Cell Biol. 2003;22(7):479-487. PMID:12951680
- Kroetz DL, Zeldin DC. Cytochrome P450 pathways of arachidonic acid metabolism. Crit Rev Eukaryot Gene Expr. 2002;12(4):269-287. PMID:12458704
- McCallum JE, Kacmaz K, O'Leary H, et al. 20-HETE in cerebrovascular regulation and injury. Prostaglandins Other Lipid Mediat. 2021;155:106553. PMID:33548495