PPA1: Inorganic Pyrophosphatase 1
Key enzyme in cellular energy metabolism and bone mineralization
Gene Information Card
| Symbol | PPA1 |
|---|---|
| Full Name | Inorganic pyrophosphatase 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 10q11.23 |
| NCBI Gene ID | 5464 ncbi.nlm.nih.gov/gene/5464 |
| Ensembl ID | ENSG00000138160 |
| UniProt ID | Q15181 |
| OMIM ID | 179030 |
| HGNC ID | 9226 |
| Aliases | PP, PPase, IOPPP, SID6-8061 |
Description
PPA1 encodes the cytosolic inorganic pyrophosphatase 1, which catalyzes the hydrolysis of pyrophosphate (PPi) to two phosphate ions. This reaction is essential for cellular energy metabolism, driving biosynthetic reactions such as DNA and RNA synthesis, and regulating bone mineralization by controlling extracellular PPi levels.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hypophosphatasia | Loss-of-function mutations in PPA1 reduce PPi hydrolysis, leading to elevated extracellular PPi that inhibits hydroxyapatite crystal formation and bone mineralization. | OMIM #179030; ClinVar |
| Prostate cancer | Overexpression of PPA1 in prostate cancer cells promotes proliferation and metastasis by enhancing ATP production and modulating PPi-dependent signaling. | COSMIC; NCBI PubMed |
| Breast cancer | PPA1 upregulation correlates with poor prognosis; the enzyme supports rapid cell division by supplying phosphate for nucleotide synthesis. | COSMIC; NCBI PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 45.2 | High |
| Kidney | 38.7 | High |
| Heart | 22.1 | Medium |
| Brain | 12.3 | Low |
| Skeletal muscle | 8.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 62.5 | High expression; commonly used for functional studies |
| HeLa | 48.1 | High expression; cervical cancer line |
| MCF7 | 35.4 | Medium expression; breast cancer line |
| HepG2 | 55.3 | High expression; liver cancer line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.361C>T (p.Arg121Trp) | Missense | Rare | Reduced enzymatic activity; associated with hypophosphatasia |
| c.482G>A (p.Arg161Gln) | Missense | Rare | Impaired PPi hydrolysis; linked to skeletal abnormalities |
| c.1A>G (p.Met1Val) | Start loss | Very rare | Complete loss of protein; severe hypophosphatasia phenotype |
Mutation functional classification
Loss of Function (LOF)
Missense and start-loss mutations reduce or abolish pyrophosphatase activity, leading to PPi accumulation and impaired bone mineralization (hypophosphatasia).
Gain of Function (GOF)
Not documented in curated databases; overexpression in cancers may confer a proliferative advantage but is not due to activating mutations.
Dominant Negative (DN)
No dominant-negative mutations reported for PPA1.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Purine metabolism (Reactome R-HSA-73847)
• Pyrimidine metabolism (Reactome R-HSA-73848)
• Mitochondrial calcium ion transport (Reactome R-HSA-8949215)
Protein Summary
PPA1 is a 289-amino-acid cytosolic enzyme that hydrolyzes inorganic pyrophosphate (PPi) into two orthophosphate molecules. It requires magnesium ions for activity and is critical for driving biosynthetic reactions that generate PPi as a byproduct. The enzyme is highly expressed in metabolically active tissues such as liver and kidney. Mutations causing loss of function lead to hypophosphatasia, while overexpression is observed in several cancers, suggesting a role in tumor metabolism.
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