PHEX

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Phosphate-regulating endopeptidase homolog X-linked also known as phosphate-regulating gene with homologies to endopeptidases on the X chromosome or metalloendopeptidase homolog PEX is an enzyme that in humans is encoded by the PHEX gene.[1][2] This gene contains 18 exons and is located on the X chromosome.

## Function

The protein encoded by this gene is a transmembrane endopeptidase that belongs to the type II integral membrane zinc-dependent endopeptidase family. The protein is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption.[3] The bone and dentin protein osteopontin (OPN) which inhibits mineralization in the skeleton and in teeth is a substrate for PHEX.[4] In the absence of functional PHEX in the mouse model (Hyp) of X-linked hypophosphatemia (XLH), and in human XLH where PHEX activity is decreased or absent, increased circulating FGF23 hormone results in low serum phosphate (caused by renal phosphate wasting) such that there is an insufficient level of this mineral ion in the blood in transit to mineralized tissues compared to the normal amount that is required for proper bone and tooth mineralization; this leads to soft bones and teeth.

In addition to renal phosphate wasting, the mineralization-inhibiting phosphoprotein osteopontin and osteopontin fragments accumulate in the extracellular matrix of bones and teeth to contribute locally to the reduction in mineralization, which together with the systemic lower level of circulating serum phosphate, both lead to the decreased mineralization (hypomineralization) characteristic of the osteomalacia and odontomalacia typically seen in XLH/Hyp.[5][6][7][8][9] XLH patients have soft and deformed skeletons, and soft teeth that easily become infected. Osteopontin (OPN) is a substrate protein for the enzyme PHEX whose enzymatic activity degrades/removes the mineralization-inhibiting function of OPN in normal mineralized tissue physiology,[10]

In disease, when the PHEX gene is mutated causing reduced or absent PHEX enzymatic activity, OPN that would normally be degraded and cleared remains behind in the extracellular matrix of bones and teeth, accumulating locally in the tissue to contribute to the osteomalacia and odontomalacia.[11][12] A relationship describing local, physiologic double-negative (inhibiting inhibitors) regulation of mineralization involving OPN has been termed the Stenciling Principle of mineralization, whereby enzyme-substrate pairs imprint mineralization patterns into the extracellular matrix (most notably for bone) by degrading mineralization inhibitors (e.g. TNAP/TNSALP/ALPL enzyme degrading the pyrophosphate inhibition, and PHEX enzyme degrading the osteopontin inhibition).[13][14][15] The Stenciling Principle for mineralization is particularly relevant to the osteomalacia and odontomalacia observed in hypophosphatasia and X-linked hypophosphatemia.[16]

## Clinical significance

Mutation of PHEX leads to X-linked hypophosphatemia.[1]

## References

1. ↑ 1.0 1.1 "A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium". Nature Genetics 11 (2): 130–136. October 1995. doi:10.1038/ng1095-130. PMID 7550339.
2. ↑ "Expression and cloning of the human X-linked hypophosphatemia gene cDNA". Biochemical and Biophysical Research Communications 231 (3): 635–639. February 1997. doi:10.1006/bbrc.1997.6153. PMID 9070861.
3. ↑ "Entrez Gene: phosphate regulating endopeptidase homolog". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5251.
4. ↑ "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". Journal of Bone and Mineral Research 28 (3): 688–699. March 2013. doi:10.1002/jbmr.1766. PMID 22991293.
5. ↑ "Abnormal presence of the matrix extracellular phosphoglycoprotein-derived acidic serine- and aspartate-rich motif peptide in human hypophosphatemic dentin". The American Journal of Pathology 177 (2): 803–812. August 2010. doi:10.2353/ajpath.2010.091231. PMID 20581062.
6. ↑ "Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia". Bone 95: 151–161. February 2017. doi:10.1016/j.bone.2016.11.019. PMID 27884786.
7. ↑ "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". Journal of Bone and Mineral Research 28 (3): 688–699. March 2013. doi:10.1002/jbmr.1766. PMID 22991293.
8. ↑ "Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia". Periodontology 2000 63 (1): 102–122. October 2013. doi:10.1111/prd.12029. PMID 23931057.
9. ↑ "Abnormal osteopontin and matrix extracellular phosphoglycoprotein localization, and odontoblast differentiation, in X-linked hypophosphatemic teeth". Connective Tissue Research 55 (Suppl 1): 79–82. August 2014. doi:10.3109/03008207.2014.923864. PMID 25158186.
10. ↑ "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". Journal of Bone and Mineral Research 28 (3): 688–699. March 2013. doi:10.1002/jbmr.1766. PMID 22991293.
11. ↑ "Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia". Bone 95: 151–161. February 2017. doi:10.1016/j.bone.2016.11.019. PMID 27884786.
12. ↑ "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". Journal of Bone and Mineral Research 28 (3): 688–699. March 2013. doi:10.1002/jbmr.1766. PMID 22991293.
13. ↑ "Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization". Journal of Structural Biology 214 (1): 107823. December 2021. doi:10.1016/j.jsb.2021.107823. PMID 34915130.
14. ↑ "Crossfibrillar mineral tessellation in normal and Hyp mouse bone as revealed by 3D FIB-SEM microscopy". Journal of Structural Biology 212 (2): 107603. November 2020. doi:10.1016/j.jsb.2020.107603. PMID 32805412. https://escholarship.mcgill.ca/concern/articles/vq27zt432.
15. ↑ "Biological stenciling of mineralization in the skeleton: Local enzymatic removal of inhibitors in the extracellular matrix". Bone 138: 115447. September 2020. doi:10.1016/j.bone.2020.115447. PMID 32454257.
16. ↑ "Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization". Journal of Structural Biology 214 (1): 107823. December 2021. doi:10.1016/j.jsb.2021.107823. PMID 34915130.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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Proteases: metalloendopeptidases (EC 3.4.24)

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