Haptocorrin

Haptocorrin also known as transcobalamin-1 (TC-1) or cobalophilin is a transcobalamin protein that in humans is encoded by the TCN1 gene.[3] The essential function of haptocorrin is protection of the acid-sensitive vitamin B₁₂ while it moves through the stomach.

TCN1
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 4KKI, 4KKJ
Identifiers
Aliases	TCN1, HC, TC-1, TC1, TCI, transcobalamin 1
External IDs	OMIM: 189905 HomoloGene: 47985 GeneCards: TCN1
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q12.1 Start 59,852,800 bp[1] End 59,866,489 bp[1]
Gene ontology Molecular function • cobalamin binding Cellular component • extracellular region • extracellular • specific granule lumen • tertiary granule lumen Biological process • cobalamin metabolic process • cobalt ion transport • ion transport • cobalamin transport • neutrophil degranulation • transport Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6947	n/a
Ensembl	ENSG00000134827	n/a
UniProt	P20061	n/a
RefSeq (mRNA)	NM_001062	n/a
RefSeq (protein)	NP_001053	n/a
Location (UCSC)	Chr 11: 59.85 – 59.87 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

Function

Haptocorrin (HC), also commonly known as the R-protein, or the R-factor, or previously referred to as transcobalamin I, is a unique glycoprotein produced by the salivary glands of the oral cavity, in response to ingestion of food. This protein binds strongly to vitamin B₁₂ in what is an intricate and necessary mechanism to protect this vitamin from the acidic environment of the stomach.[4]^:44 Vitamin B₁₂ is an essential water-soluble vitamin, the deficiency of which creates anemia (macrocytic anemia), decreased bone marrow cell production (anemia, pancytopenia), neurological problems, as well as metabolic issues (methylmalonyl-CoA acidosis).[4]^:50–51

Vitamin B₁₂ is therefore an important vitamin for the body to absorb. Despite its vital role however, vitamin B₁₂ is structurally very sensitive to the hydrochloric acid found in the stomach secretions, and easily denatures in that environment before it has a chance to be absorbed by the small intestine. Found in fresh animal products (such as liver), vitamin B₁₂ attaches haptocorrin, which has a high affinity for its molecular structure.[5] Coupled together vitamin B₁₂ and haptocorrin create a complex. This haptocorrin–B₁₂ complex is impervious to the insult of the stomach acid, and passes on via the pylorus to the duodenum. In the duodenum pancreatic proteases (a component of pancreatic juice) cleave haptocorrin, releasing vitamin B₁₂ in its free form.

The same cells in the stomach that produce gastric hydrochloric acid, the parietal cells, also produce a molecule called the intrinsic factor (IF), which binds the B₁₂ after its release from haptocorrin by digestion, and without which only 1% of vitamin B₁₂ is absorbed. Intrinsic factor (IF) is a glycoprotein, with a molecular weight of 45 kDa. In the duodenum, the free vitamin B₁₂ attaches to the intrinsic factor (IF) to create a vitamin B₁₂–IF complex. This complex then travels through the small bowel and reaches the terminal tertiary portion of the small intestine, called the ileum. The ileum is the longest of all portions of the small intestine, and has on its surface specialized receptors called cubilin receptors, that identify the B₁₂–IF complexes and take them up into the circulation via endocytosis-mediated absorption.[6]

In short, the essential function of haptocorrin is protection of the acid-sensitive vitamin B₁₂ while it moves through the stomach. Haptocorrin also circulates and binds approximately 80% of circulating B₁₂, rendering it unavailable for cellular delivery by transcobalamin II.[7]

References

1. GRCh38: Ensembl release 89: ENSG00000134827 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Entrez Gene: transcobalamin I (vitamin B₁₂ binding protein".
4. Pettit JD, Moss P (2006). Essential Haematology 5e (Essential). Blackwell Publishing Professional. p. 44. ISBN 1-4051-3649-9.
5. Morkbak AL, Poulsen SS, Nexo E (2007). "Haptocorrin in humans". Clinical Chemistry and Laboratory Medicine. 45 (12): 1751–9. doi:10.1515/CCLM.2007.343. PMID 17990953.
6. Viola-Villegas N, Rabideau AE, Bartholomä M, Zubieta J, Doyle RP (Aug 2009). "Targeting the cubilin receptor through the vitamin B(12) uptake pathway: cytotoxicity and mechanistic insight through fluorescent Re(I) delivery". Journal of Medicinal Chemistry. 52 (16): 5253–61. doi:10.1021/jm900777v. PMID 19627091.
7. Stabler SP (2013). "Vitamin B12 deficiency". The New England Journal of Medicine. 368 (21): 2041–2. doi:10.1056/NEJMc1304350. PMID 23697526.

Further reading

• Guéant-Rodriguez RM, Juilliére Y, Candito M, Adjalla CE, Gibelin P, Herbeth B, Van Obberghen E, Gueánt JL (Sep 2005). "Association of MTRRA66G polymorphism (but not of MTHFR C677T and A1298C, MTRA2756G, TCN C776G) with homocysteine and coronary artery disease in the French population". Thrombosis and Haemostasis. 94 (3): 510–5. doi:10.1160/TH05-04-0262. PMID 16268464.
• Garrod MG, Allen LH, Haan MN, Green R, Miller JW (May 2010). "Transcobalamin C776G genotype modifies the association between vitamin B12 and homocysteine in older Hispanics". European Journal of Clinical Nutrition. 64 (5): 503–9. doi:10.1038/ejcn.2010.20. PMC 2864787. PMID 20216556.
• McGeachie M, Ramoni RL, Mychaleckyj JC, Furie KL, Dreyfuss JM, Liu Y, Herrington D, Guo X, Lima JA, Post W, Rotter JI, Rich S, Sale M, Ramoni MF (Dec 2009). "Integrative predictive model of coronary artery calcification in atherosclerosis". Circulation. 120 (24): 2448–54. doi:10.1161/CIRCULATIONAHA.109.865501. PMC 2810344. PMID 19948975.
• Matteini AM, Walston JD, Bandeen-Roche K, Arking DE, Allen RH, Fried LP, Chakravarti A, Stabler SP, Fallin MD (Jan 2010). "Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty". The Journal of Nutrition, Health & Aging. 14 (1): 73–7. doi:10.1007/s12603-010-0013-1. PMC 3042247. PMID 20082058.
• Lee KM, Lan Q, Kricker A, Purdue MP, Grulich AE, Vajdic CM, Turner J, Whitby D, Kang D, Chanock S, Rothman N, Armstrong BK (Dec 2007). "One-carbon metabolism gene polymorphisms and risk of non-Hodgkin lymphoma in Australia" (PDF). Human Genetics. 122 (5): 525–33. doi:10.1007/s00439-007-0431-2. PMID 17891500.
• Liu T, Qian WJ, Gritsenko MA, Camp DG, Monroe ME, Moore RJ, Smith RD. "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry". Journal of Proteome Research. 4 (6): 2070–80. doi:10.1021/pr0502065. PMC 1850943. PMID 16335952.
• Fintelman-Rodrigues N, Corrêa JC, Santos JM, Pimentel MM, Santos-Rebouças CB (2009). "Investigation of CBS, MTR, RFC-1 and TC polymorphisms as maternal risk factors for Down syndrome". Disease Markers. 26 (4): 155–61. doi:10.1155/2009/504625. PMC 3833707. PMID 19729796.
• Wang SS, Maurer MJ, Morton LM, Habermann TM, Davis S, Cozen W, Lynch CF, Severson RK, Rothman N, Chanock SJ, Hartge P, Cerhan JR (Mar 2009). "Polymorphisms in DNA repair and one-carbon metabolism genes and overall survival in diffuse large B-cell lymphoma and follicular lymphoma". Leukemia. 23 (3): 596–602. doi:10.1038/leu.2008.240. PMC 3066015. PMID 18830263.
• Fedosov SN, Fedosova NU, Kräutler B, Nexø E, Petersen TE (May 2007). "Mechanisms of discrimination between cobalamins and their natural analogues during their binding to the specific B12-transporting proteins". Biochemistry. 46 (21): 6446–58. doi:10.1021/bi062063l. PMID 17487979.
• Carmel R, Parker J, Kelman Z (Nov 2009). "Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels". British Journal of Haematology. 147 (3): 386–91. doi:10.1111/j.1365-2141.2009.07855.x. PMID 19686235.
• Talmud PJ, Drenos F, Shah S, Shah T, Palmen J, Verzilli C, Gaunt TR, Pallas J, Lovering R, Li K, Casas JP, Sofat R, Kumari M, Rodriguez S, Johnson T, Newhouse SJ, Dominiczak A, Samani NJ, Caulfield M, Sever P, Stanton A, Shields DC, Padmanabhan S, Melander O, Hastie C, Delles C, Ebrahim S, Marmot MG, Smith GD, Lawlor DA, Munroe PB, Day IN, Kivimaki M, Whittaker J, Humphries SE, Hingorani AD (Nov 2009). "Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip". American Journal of Human Genetics. 85 (5): 628–42. doi:10.1016/j.ajhg.2009.10.014. PMC 2775832. PMID 19913121.
• Collin SM, Metcalfe C, Refsum H, Lewis SJ, Smith GD, Cox A, Davis M, Marsden G, Johnston C, Lane JA, Donovan JL, Neal DE, Hamdy FC, Smith AD, Martin RM (Nov 2010). "Associations of folate, vitamin B12, homocysteine, and folate-pathway polymorphisms with prostate-specific antigen velocity in men with localized prostate cancer". Cancer Epidemiology, Biomarkers & Prevention. 19 (11): 2833–8. doi:10.1158/1055-9965.EPI-10-0582. PMID 20852008.
• Haggarty P, Campbell DM, Duthie S, Andrews K, Hoad G, Piyathilake C, Fraser I, McNeill G (Jun 2008). "Folic acid use in pregnancy and embryo selection". BJOG. 115 (7): 851–6. doi:10.1111/j.1471-0528.2008.01737.x. PMID 18485163.
• Tanaka T, Scheet P, Giusti B, Bandinelli S, Piras MG, Usala G, Lai S, Mulas A, Corsi AM, Vestrini A, Sofi F, Gori AM, Abbate R, Guralnik J, Singleton A, Abecasis GR, Schlessinger D, Uda M, Ferrucci L (Apr 2009). "Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations". American Journal of Human Genetics. 84 (4): 477–82. doi:10.1016/j.ajhg.2009.02.011. PMC 2667971. PMID 19303062.
• Geisel J, Hübner U, Bodis M, Schorr H, Knapp JP, Obeid R, Herrmann W (Nov 2003). "The role of genetic factors in the development of hyperhomocysteinemia". Clinical Chemistry and Laboratory Medicine. 41 (11): 1427–34. doi:10.1515/CCLM.2003.219. PMID 14656021.
• Martinelli M, Scapoli L, Palmieri A, Pezzetti F, Baciliero U, Padula E, Carinci P, Morselli PG, Carinci F (Mar 2006). "Study of four genes belonging to the folate pathway: transcobalamin 2 is involved in the onset of non-syndromic cleft lip with or without cleft palate". Human Mutation. 27 (3): 294. doi:10.1002/humu.9411. PMID 16470748.
• von Castel-Dunwoody KM, Kauwell GP, Shelnutt KP, Vaughn JD, Griffin ER, Maneval DR, Theriaque DW, Bailey LB (Jun 2005). "Transcobalamin 776C->G polymorphism negatively affects vitamin B-12 metabolism". The American Journal of Clinical Nutrition. 81 (6): 1436–41. PMID 15941899.
• Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, Yoo HS, Kim YS, Kim NS (Dec 2005). "Transcriptome analysis of human gastric cancer". Mammalian Genome. 16 (12): 942–54. doi:10.1007/s00335-005-0075-2. PMID 16341674.
• Ramachandran P, Boontheung P, Xie Y, Sondej M, Wong DT, Loo JA (Jun 2006). "Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry". Journal of Proteome Research. 5 (6): 1493–503. doi:10.1021/pr050492k. PMID 16740002.
• Bailey SD, Xie C, Do R, Montpetit A, Diaz R, Mohan V, Keavney B, Yusuf S, Gerstein HC, Engert JC, Anand S (Oct 2010). "Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study". Diabetes Care. 33 (10): 2250–3. doi:10.2337/dc10-0452. PMC 2945168. PMID 20628086.