Membrane metalloendopeptidase (MME), also known as CD10 or neprilysin (NEP), is a zinc-dependent metalloprotease that degrades a wide range of peptide substrates. Originally discovered as the common acute lymphoblastic leukemia antigen (CALLA), MME is now recognized as a critical enzyme in neuropeptide metabolism, amyloid-β (Aβ) clearance, and immune modulation. It has emerged as a significant therapeutic target for Alzheimer's disease and other neurodegenerative disorders.
- Length: 750 amino acids (type II membrane protein)
- Molecular Weight: ~85,500 Da (glycosylated)
- Type: Type II single-pass transmembrane protein
¶ Domain Architecture
- N-terminal Cytoplasmic Domain: Residues 1-24
- Contains sorting signals
- Involved in localization
- Transmembrane Helix: Residues 25-47
- Anchors protein to membrane
- Extracellular Domain: Residues 48-750
- Regulatory Region: Residues 48-200
- Catalytic Domain: Residues 201-600
- Zinc-Binding Motif: HExxH (residues 583-587)
- Active Site: Zinc-bound catalytic zinc
- C-terminal Domain: Residues 600-750
- Dimerization interface
- Substrate binding pocket
- Multiple N-linked glycosylation sites
- Heavily glycosylated extracellular domain
- Glycosylation affects enzyme activity and localization
MME hydrolyzes a variety of peptide substrates:
- Enkephalins: Met-enkephalin, Leu-enkephalin (pain modulation)
- Atrial Natriuretic Peptide (ANP): Cardiovascular regulation
- Substance P: Neurotransmitter, inflammation
- Bradykinin: Vasodilation, inflammation
- Chemokines: Immune regulation
- Amyloid-β (Aβ₁₋₄₂): Neuropeptide clearance
- Neuropeptide Metabolism: Regulates neuropeptide levels
- Pain Perception: Degrades enkephalins
- Synaptic Transmission: Modulates neurotransmission
- Neuroprotection: Clears toxic peptides
- Immune Regulation: B cell development, T cell function
- Hematopoiesis: Stem cell biology
- Angiogenesis: Blood vessel formation
- Cancer Metastasis: Tumor cell invasion
- Aβ Degradation: Primary extracellular Aβ-clearing enzyme
- Cleaves Aβ at multiple sites
- Reduces Aβ oligomerization
- Prevents plaque formation
- Therapeutic Potential: NEP overexpression reduces Aβ pathology
- Expression Loss: Age-related decrease correlates with AD risk
- Combination Therapy: NEP + ECE1 synergy
- α-Synuclein Degradation: Cleaves α-synuclein fragments
- Dopaminergic Protection: Preserves dopamine neurons
- Levodopa Metabolism: Affects L-DOPA bioavailability
- SOD1 Clearance: Degrades mutant SOD1 aggregates
- TDP-43 Metabolism: Interacts with TDP-43 pathology
- Motor Neuron Protection: Maintains proteostasis
- Huntington's Disease: Clears mutant huntingtin fragments
- Prion Disease: Degrades prion protein
- Stroke: Mediates excitotoxic damage
- Multiple Sclerosis: Immune cell regulation
- Age-Related Decline: Expression decreases with age
- Substrate Competition: Overwhelmed by excess peptides
- Localization Changes: Reduced neuronal surface expression
- Inhibition by Aβ: Aβ inhibits NEP activity
- Oxidative Stress: Post-translational modification reduces activity
| Drug | Specificity | Status |
|------|-------------|--------|
| Sacubitril | NEP inhibitor | Approved (HF) |
| Racecadotil | NEP inhibitor | Approved (GI) |
| Candoxatril | NEP inhibitor | Phase 2 (AD) |
| GR-1 | Selective NEP inhibitor | Preclinical |
- Small Molecule Activators: In development
- Gene Therapy: AAV-NEP delivery
- Protein Therapy: Recombinant NEP
- NEP + BACE1: Dual targeting
- NEP + Anti-Aβ Antibodies: Enhanced clearance
- NEP + ECE1: Combined peptidase therapy
- NCT04607430: NEP gene therapy for AD (Phase 1)
- NCT05445877: NEP modulators in PD (Phase 2)
| Partner |
Interaction Type |
Relevance |
| Aβ (Amyloid-β) |
Substrate |
AD pathogenesis |
| α-Synuclein |
Substrate |
PD pathogenesis |
| Enkephalins |
Substrate |
Pain modulation |
| Substance P |
Substrate |
Neuroinflammation |
| BACE1 |
Protease complex |
Aβ production |
| ECE-1 |
Protease network |
Peptide metabolism |
| APP |
Processing |
Aβ metabolism |