| Category | Key details | Key sources with year, DOI/URL |
|---|---|---|
| Identity/aliases | Human **ENPP7** encodes **ectonucleotide pyrophosphatase/phosphodiesterase 7**, also called **alkaline sphingomyelinase (Alk-SMase)** and **NPP7**. It is an ENPP family member with the conserved phosphodiesterase catalytic core; ENPP4–7 retain this PDE domain, and ENPP7 is a **single-pass type I membrane protein** adapted as a phospholipase rather than a nucleotide-hydrolyzing ENPP. UniProt target identity in the cited sources matches the requested human ENPP7/Q6UWV6 annotation. (pqac-00000004, pqac-00000003, pqac-00000001) | **Borza et al., 2022**, *J Biol Chem*, DOI: 10.1016/j.jbc.2021.101526, https://doi.org/10.1016/j.jbc.2021.101526; **Imam et al., 2024**, *Metabolites*, DOI: 10.3390/metabo14120659, https://doi.org/10.3390/metabo14120659 |
| Enzymatic reactions & substrates | Best-supported native activity is **hydrolysis of sphingomyelin (SM)**. ENPP7 also shows **lyso-phospholipase C (lyso-PLC)** activity toward **lysophosphatidylcholine (LPC/lyso-PC)** and **platelet-activating factor (PAF)**, and hydrolyzes the artificial substrate **p-nitrophenylphosphorylcholine (pNPPC)**. The datasheet additionally notes phospholipase C activity toward palmitoyl lyso-phosphocholine. (pqac-00000003, pqac-00000002) | **Borza et al., 2022**, https://doi.org/10.1016/j.jbc.2021.101526; **ENPP7 datasheet** (compiled functional summary cited in evidence snippet) (pqac-00000002) |
| Products | For sphingomyelin, ENPP7 generates **ceramide + phosphocholine**. This is consistently described in the ENPP review and recent reviews of alkaline phosphatase/sphingomyelin metabolism; phosphocholine is highlighted as a precursor that can feed extracellular choline metabolism. (pqac-00000001, pqac-00000003, pqac-00000005) | **Imam et al., 2024**, https://doi.org/10.3390/metabo14120659; **Borza et al., 2022**, https://doi.org/10.1016/j.jbc.2021.101526; **Wang et al., 2024**, DOI: 10.1016/j.heliyon.2024.e40810, https://doi.org/10.1016/j.heliyon.2024.e40810 |
| Mechanism/structural determinants | ENPP7 uses the ENPP/alkaline phosphatase superfamily catalytic architecture with **two Zn²⁺ ions** in the active site. Structural work/reviewed models indicate a **solvent-exposed catalytic site**, **absence of a nucleotide-binding slot**, and a **cation-π box** formed by **Tyr109, Tyr166, Tyr194** that stabilizes the positively charged **choline headgroup** of substrates; this explains preference for choline-containing phospholipids. A nearby **hydrophobic loop (342–351)** and surface cationic patches may support interaction with bile salt micelles. Structural reference noted as **PDB 5TCD**. (pqac-00000003, pqac-00000004, pqac-00000013) | **Borza et al., 2022**, https://doi.org/10.1016/j.jbc.2021.101526 |
| Localization/tissue | ENPP7 is described as **predominantly expressed in the intestinal tract/small intestine** and functioning during digestion. The datasheet localizes it to the **surface of the microvillar membrane (brush border) of small-intestinal enterocytes**, and also to **Golgi** and **endosome-like structures**; it is reported in **human bile** as well. As a type I membrane ectoenzyme, it acts at the extracellular/luminal side of intestinal epithelial membranes. (pqac-00000001, pqac-00000002, pqac-00000004, pqac-00000010) | **Imam et al., 2024**, https://doi.org/10.3390/metabo14120659; **Slieker et al., 2023**, *Nat Commun*, DOI: 10.1038/s41467-023-38148-7, https://doi.org/10.1038/s41467-023-38148-7; **ENPP7 datasheet** (pqac-00000002) |
| Pathways/physiology | ENPP7 participates in **dietary sphingomyelin digestion in intestinal mucosa**, producing **ceramide** and **phosphocholine**. Recent review evidence further places ENPP7 in **extracellular choline-associated lipid hydrolysis**, with likely downstream dephosphorylation of phosphocholine by **TNAP/alkaline phosphatase** to support **choline availability**. Wang et al. note that sphingomyelin is abundant in membranes (~**23% of total membrane lipids**) and that intestinal sphingomyelin hydrolysis links dietary lipids to ceramide/sphingolipid signaling and metabolic effects. ENPP7 deficiency is linked in review text to **defective sphingomyelin digestion**. (pqac-00000001, pqac-00000005) | **Imam et al., 2024**, https://doi.org/10.3390/metabo14120659; **Wang et al., 2024**, https://doi.org/10.1016/j.heliyon.2024.e40810 |
| Disease/biomarker links 2023-2024 | In a 2023 multi-cohort diabetes biomarker study, plasma **ENPP7** was among proteins associated with **faster glycaemic deterioration / time to insulin requirement**; ENPP7 was one of six top proteins with aptamer specificity supported by a **cis-pQTL**. Study scale: ~**1,195 proteins** measured in **1,188** individuals; discovery proteomics included **DCS n=600** and **GoDARTS n=600** (599 post-QC), with validation in **ANDIS n=1,992** and **ACCELERATE n=1,850**; the paper also states ENPP7 is strongly expressed in the small intestine and involved in sphingomyelin hydrolysis/absorption of ceramide and phosphocholine. Open Targets/GWAS-credible-set evidence links ENPP7 to **liver disease**, **intrahepatic cholestasis of pregnancy**, **cholestasis, intrahepatic, of pregnancy 3**, **hypocalcemia**, and **bipolar disorder**, citing PMIDs including **35977952, 36653562, 39024449, 40069456**. (pqac-00000007, pqac-00000010, pqac-00000011, pqac-00000006) | **Slieker et al., 2023**, https://doi.org/10.1038/s41467-023-38148-7; **Open Targets Platform query for ENPP7** (GWAS credible-set associations; PMIDs listed in evidence) (pqac-00000006) |
| Evidence/notes | Additional functional notes from the datasheet: ENPP7 activity is reported to be **inhibited dose-dependently by ATP, imidazole, orthovanadate, and zinc ions**. The strongest evidence base in the supplied snippets supports **intestinal digestive/luminal phospholipid metabolism**, especially sphingomyelin cleavage, plus broader choline-containing lysophospholipid hydrolysis. Quantitative enzyme kinetics were **not provided** in the available snippets, so substrate scope is supported qualitatively rather than by Km/kcat values here. (pqac-00000002, pqac-00000003) | **ENPP7 datasheet** (pqac-00000002); **Borza et al., 2022**, https://doi.org/10.1016/j.jbc.2021.101526 |


*Table: This table summarizes the supported functional annotation of human ENPP7/Q6UWV6, including catalytic activities, structural determinants, localization, physiology, and recent disease/biomarker links. It is restricted to claims backed by the provided evidence snippets and includes source URLs/DOIs for quick verification.*