GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type)

Note	Human GCNT3/C2GnT-M is located on chromosome 15 in the region of q21.3, oriented from centromere to telomere.
	Schematic representation of Human GCNT3/C2GnT-M gene and transcripts. There are three different sized transcripts. (TIS, Transcription Initiation Site designated as +1; E, Exon; I, Intron; UTR, Untranslated region; ATG, start codon; ORF, Open reading frame).
Description	Human GCNT3/C2GnT-M gene is approximatively 8.26 kb in size and located in chromosome 15q21.3 at the position of 57,691,415 - 57,699,501. Recently, the GCNT3/C2GnT-M promoter (-417/+187) containing two basal cis-regulatory region (-291/-182 and -62/-43) was identified. The Th2 cytokine and retinoic acid responsive cis-regulatory elements reside in -417/+187 region.
Transcription	Human GCNT3/C2GnT-M contains three different sized transcripts: 2.3-2.5, 3.6-3.8 and 6.8-7.0 kb. The transcript 1 (approximatively 2.3-2.5kb) is made of 3 exons, exon 1 (69-198 bp), exon 2 (333-401 bp), and exon 3 (1864 bp). Exon 3 contains 59 bp of 5' UTR, 1314 bp of ORF and 491 bp of 3'UTR. It does not contain any introns. Whereas, the intermediate sized transcript (3.6-3.8kb) contains 1.3kb of intron 2 and the large sized transcript (6.8-7.0 kb) contains 4.5kb of intron 1 in addition to all three exons. Exon 1 is heterogeneous in size, which ranges from 69 to 198 bp depending on tissues and cells. Exon 1 is present in all transcripts and has same 3' end but different 5' ends. A 333 bp Exon 2 is identified in most of the mucus secreting tissues and airway epithelial cells while a 401 bp of exon 2 is only detected in A549 cells.

Note	Human GCNT3/C2GnT-M (EC 2.4.1.102) has 438 amino acids and molecular weight of 50,863 Da.
	The predicted GCNT3/C2GnT-M structure shows a short N-terminal cytoplasmic tail (CT), a transmembrane domain (TM), a stem region and a long catalytic domain at the C-terminal region.
Description	GCNT3/C2GnT-M is a type II membrane protein located in the Golgi apparatus. It contains a nine-amino acid peptide tail at the N-terminus located in the cytoplasm, which is followed by a transmembrane domain consisted of 18 amino acids, a stem region, and a catalytic domain located in the Golgi lumen. The protein contains 13 cysteines, including 4 at the N-terminal region, which are conserved among GCNT3/C2GnT-M across species, and 9 at the C-terminal region, which are conserved among all mucin glycan b6GlcNAc branching enzymes. Structural information obtained from bovine GCNT3/C2GnT-M shows that among the 9 conserved cysteines, the second cysteine is unconjugated and the other 8 cysteines form 4 cystine bonds between first and ninth, third and seventh, fourth and fifth, and sixth and eighth. The disulfide bonds formed from the nine conserved cysteines are different between GCNT3/C2GnT-M and C2GnT-L. GCNT3/C2GnT-M contains two potential N-glycosyltaion sites at N-69 and N-289.
Expression	Human GCNT3/C2GnT-M gene is expressed in mucus-secretory tissues in the following decreasing order of expression: Colon; testis; stomach; small intestine; adrenal gland; kidney; trachea; thyroid gland; Uterus; Ovary; Pancreas; fetal liver; Prostate. Unlike bovine GCNT3/C2GnT-M gene, the type of transcript expressed by hC2GnT-M gene is not tissue specific among the mucus secretory tissues. Expression of GCNT3/C2GnT-M gene is down regulated in colon and colorectal tumors and various colorectal cancer cells. GCNT3/C2GnT-M expression is regulated by various external agent(s). It is inhibited by EGF and enhanced by Th2 cytokines, retinoic acids and sodium butyrate.
Localisation	Golgi membrane.
Function	GCNT3/C2GnT-M is responsible for the synthesis of all three branch structures, including core 2, core 4, and I antigen found in the glycans of secreted mucins. These three branch structures are generated by the transfer of GlcNAc from UDP-GlcNAc to core 1, core 3, and I antigen, respectively as shown below. 1. UDP-GlcNAc + Galbeta1-3GalNAca1-S/T gives Galbeta1-3(GlcNAcbeta1-6) GalNAca1-S/T + UDP 2. UDP-GlcNAc + GlcNAcbeta1-3GalNAc1a-S/T gives GlcNAcbeta1-3(GlcNAcbeta1-6) GalNAca1-S/T + UDP 3. UDP-GlcNAc + GlcNAcbeta1-3Galbeta1-R gives GlcNAcbeta1-3(GlcNAcbeta1-6)Galbeta1-R + UDP(R: sugars) The primary function of secreted mucins is to protect mucus secretory epithelium by retention of water and maintenance of the rheological properties of the mucus, and adherence to airborne and ingested pathogens to facilitate their removal from these tissues. The first two properties depend primarily on the carbohydrate content and this property depends on the heterogeneity of carbohydrate structure. Secreted mucins contain very high carbohydrate content, i.e. 70-90% by weight, and very heterogeneous carbohydrate structure, e.g. up to 100 different oligosaccharides in mucins isolated from a single donor. The three b6GlcNAc branch structures found in the secreted mucins are responsible for the increase of carbohydrate content and structural complexity. Decrease of GCNT3/C2GnT-M in the secretory epithelium can result in dehydration of the mucus and compromise of bacterial clearance.
Homology	Human GCNT3/C2GnT-M shows a very high level of similarity to other non-human GCNT3/C2GnT-M: bovine (83%), rat (78%) and mouse (77%). Further, it shows moderate level of (48% and 38%) similarity to human C2GnT-L and C2GnT-T, respectively.

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