Enamelin is an enamel matrix protein (EMPs), that in humans is encoded by the ENAM gene.[5][6] It is part of the non-amelogenins, which comprise 10% of the total enamel matrix proteins.[7] It is one of the key proteins thought to be involved in amelogenesis (enamel development). The formation of enamel's intricate architecture is thought to be rigorously controlled in ameloblasts through interactions of various organic matrix protein molecules that include: enamelin, amelogenin, ameloblastin, tuftelin, dentine sialophosphoprotein, and a variety of enzymes. Enamelin is the largest protein (~168kDa) in the enamel matrix of developing teeth and is the least abundant (encompasses approximately 1-5%) of total enamel matrix proteins.[6] It is present predominantly at the growing enamel surface.

AliasesENAM, ADAI, AI1C, AIH2, enamelin
External IDsOMIM: 606585 MGI: 1333772 HomoloGene: 9698 GeneCards: ENAM
Gene location (Human)
Chromosome 4 (human)
Chr.Chromosome 4 (human)[1]
Chromosome 4 (human)
Genomic location for ENAM
Genomic location for ENAM
Band4q13.3Start70,628,744 bp[1]
End70,646,824 bp[1]
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 4: 70.63 – 70.65 MbChr 5: 88.49 – 88.51 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse


Enamelin is thought to be the oldest member of the enamel matrix protein (EMP) family, with animal studies showing remarkable conservation of the gene phylogenetically.[8] All other EMPs are derived from enamelin, such as amelogenin.[9] EMPs belong to a larger family of proteins termed 'secretory calcium-binding phosphoproteins' (SCPP).[10]

Similar to other enamel matrix proteins, enamelin undergoes extensive post-translational modifications (mainly phosphorylation), processing, and secretion by proteases. Enamelin has three putative phosphoserines (Ser54, Ser191, and Ser216 in humans) phosphorylated by a Golgi-associated secretory pathway kinase (FAM20C) based on their distinctive Ser-x-Glu (S-x-E) motifs.[11] The major secretory product of the ENAM gene has 1103 amino acids (post-secretion), and has an acidic isoelectric point ranging from 4.5–6.5 (depending on the fragment).[12]

At the secretory stage, the enzyme matrix metalloproteinase-20 (MMP20) proteolytically cleaves the secreted enamelin protein immediately upon release, into several smaller polypeptides; each having their own functions. However, the whole protein (~168 kDa) and its largest derivative fragment (~89 kDa) are undetectable in the secretory stage; these are existent only at the mineralisation front.[7] Smaller polypeptide fragments remain embedded in the enamel, throughout the secretory stage enamel matrix. These strongly bind to the mineral and retard seeded crystal growth.


The primary function of the proteins acts at the mineralisation front; growth sites where it is the interface between the ameloblast plasma membrane and lengthening extremity of crystals. The key activities of enamelin can be summarised:

  • Necessary for the adhesion of ameloblasts to the surface of the enamel in the secretory stage[13]
  • Binds to hydroxyapatite and promotes crystallite elongation
  • Act as a modulator for de novo mineral formation[7]

It is speculated that this protein could interact with amelogenin or other enamel matrix proteins and be important in determining growth of the length of enamel crystallites. The mechanism of this proposed co-interaction is synergistic ("Goldilocks effect"). With enamelin enhancing the rates of crystal nucleation via the creation of addition sites for EMPs, such as amelogenin, to template calcium phosphate nucleation.[14]

It is best thought to understand the overarching function of enamelin as the proteins responsible for correct enamel thickness formation.

Clinical significanceEdit

Mutations in the ENAM gene can cause certain subtypes of amelogenesis imperfecta (AI), a heterogenous group of heritable conditions in which enamel in malformed.[15] Point mutations can cause autosomal-dominant hypoplastic AI, and novel ENAM mutations can cause autosomal-recessive hypoplastic AI.[16][17] However, mutations in the ENAM gene mainly tend to lead to the autosomal-dominant AI.[13] The phenotype of the mutations are generalised thin enamel and no defined enamel layer.[7]

A moderately higher than usual ENAM expression leads to protrusive structures (often, horizontal grooves) on the surface of enamel, and with high transgene expression, the enamel layer is almost lost.[18]

See alsoEdit


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000132464 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029286 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Mårdh CK, Bäckman B, Holmgren G, Hu JC, Simmer JP, Forsman-Semb K (May 2002). "A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2)". Human Molecular Genetics. 11 (9): 1069–74. doi:10.1093/hmg/11.9.1069. PMID 11978766.
  6. ^ a b "Entrez Gene: ENAM enamelin".
  7. ^ a b c d Nanci A, Ten Cate AR (2012). Ten Cate's Oral Histology (8th ed.). Elsevier India. ISBN 978-8131233436. OCLC 1027350695.
  8. ^ Al-Hashimi N, Lafont AG, Delgado S, Kawasaki K, Sire JY (September 2010). "The enamelin genes in lizard, crocodile, and frog and the pseudogene in the chicken provide new insights on enamelin evolution in tetrapods". Molecular Biology and Evolution. 27 (9): 2078–94. doi:10.1093/molbev/msq098. PMID 20403965.
  9. ^ Sire JY, Davit-Béal T, Delgado S, Gu X (2007). "The origin and evolution of enamel mineralization genes". Cells Tissues Organs. 186 (1): 25–48. doi:10.1159/000102679. PMID 17627117.
  10. ^ Hu JC, Lertlam R, Richardson AS, Smith CE, McKee MD, Simmer JP (December 2011). "Cell proliferation and apoptosis in enamelin null mice". European Journal of Oral Sciences. 119 Suppl 1: 329–37. doi:10.1111/j.1600-0722.2011.00860.x. PMC 3292790. PMID 22243264.
  11. ^ Yan WJ, Ma P, Tian Y, Wang JY, Qin CL, Feng JQ, Wang XF (November 2017). "The importance of a potential phosphorylation site in enamelin on enamel formation". International Journal of Oral Science. 9 (11): e4. doi:10.1038/ijos.2017.41. PMC 5775333. PMID 29593332.
  12. ^ Hu JC, Yamakoshi Y (2003). "Enamelin and autosomal-dominant amelogenesis imperfecta". Critical Reviews in Oral Biology and Medicine. 14 (6): 387–98. doi:10.1177/154411130301400602. PMID 14656895.
  13. ^ a b Hand AR, Frank ME (2014-11-21). Fundamentals of oral histology and physiology. Ames, Iowa. ISBN 9781118938317. OCLC 891186059.
  14. ^ Tao J, Fijneman A, Wan J, Prajapati S, Mukherjee K, Fernandez-Martinez A, Moradian-Oldak J, De Yoreo JJ (2018-12-05). "Control of Calcium Phosphate Nucleation and Transformation through Interactions of Enamelin and Amelogenin Exhibits the "Goldilocks Effect"". Crystal Growth & Design. 18 (12): 7391–7400. doi:10.1021/acs.cgd.8b01066.
  15. ^ "ENAM enamelin [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2019-02-28.
  16. ^ Pavlic A, Petelin M, Battelino T (March 2007). "Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG". Archives of Oral Biology. 52 (3): 209–17. doi:10.1016/j.archoralbio.2006.10.010. PMID 17125728.
  17. ^ Hart TC, Hart PS, Gorry MC, Michalec MD, Ryu OH, Uygur C, et al. (December 2003). "Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects". Journal of Medical Genetics. 40 (12): 900–6. doi:10.1136/jmg.40.12.900. PMC 1735344. PMID 14684688.
  18. ^ Kim JW, Seymen F, Lin BP, Kiziltan B, Gencay K, Simmer JP, Hu JC (March 2005). "ENAM mutations in autosomal-dominant amelogenesis imperfecta". Journal of Dental Research. 84 (3): 278–82. doi:10.1177/154405910508400314. PMID 15723871.

Further readingEdit

External linksEdit